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10th International Symposium on Hodgkin Lymphoma

Oct. 22.-25. 2016
Gürzenich, Cologne

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Saturday 22.10.2016

Scientific Session Satellite Symposium Main Program Hematology Educational Workshop
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Session details 08:30–12:00
Hematology Educational

Hematology Educational

Room:Großer Saal
Session details 09:00–10:30
Workshop 1 (Parallel Sessions)

New Concepts of Radiation Field Design, Advanced Technologies and New Normal Organ Constraints

Room:Isabellensaal

  • Radiation eld reduction beyond ISRT? – options and concerns

  • Avoidance of organs at risk / dose-volume constraints – deep inspiration breath hold: techniques and daily monitoring

  • Avoidance of organs at risk / dose-volume constraints – dose / volume constrains for key organs at risk

Session details 09:00–10:30
Workshop 2 (Parallel Sessions)

Epidemiology and Registry Data

Room:Kleiner Saal

  • Welcome and short introduction

  • Experience from the international T cell project

  • Registry studies on Hodgkin Lymphoma – the US experience

  • Registry-based studies on socio-economic impact on outcome in Hodgkin Lymphoma in Brazil

  • Registry-based studies on pregnancy in Hodgkin Lymphoma patients

  • Registry-based research – pros and cons – the statistician’s view

  • General discussion

Session details 10:45–12:15
Workshop 3 (Parallel Sessions)

Pathology and Pathogenesis

Room:Isabellensaal

  • Risk and prognosis in Hodgkin Lymphoma and associations with an active, innate or anergic tumor immune response

  • NF-KB / IRF5 in Hodgkin Lymphoma

  • Noncoding RNAs and microRNA in Hodgkin Lymphoma

Session details 10:45–12:15
Workshop 4 (Parallel Sessions)

PET

Room:Kleiner Saal

  • Pretreatment stage or metabolic volume: which is better to direct treatment strategy?

  • Response assessment in the era of checkpoint inhibitors

Session details 12:45–13:45
Satellite Symposium

Recent Advances in the Treatment of Lymphoma

Room:Großer Saal

  • The FLASH project: establishing a novel surrogate endpoint in first-line FL

  • Update on clinical data of IMiDs® in the treatment of lymphoma

Session details 14:00–15:30
Workshop 5 (Parallel Sessions)

Biomarkers

Room:Großer Saal

  • Methodological issues of circulating cell-free DNA detection in HL

  • Outcome prediction of aSCT using Hodgkin Lymphoma relapse biopsies

  • Nanostring-based outcome prediction in HL patients treated with BEACOPP

  • Integration of IPS factors with gene expression for treatment outcome prediction

  • Biomarkers / companion diagnostics for checkpoint inhibition

Session details 14:00–15:30
Workshop 6 (Parallel Sessions)

Elderly Patients

Room:Kleiner Saal
Session details 14:00–15:30
Workshop 7 (Parallel Sessions)

GHSG Workshop

Room:Isabellensaal
Session details 16:00–17:30
Workshop 8 (Parallel Sessions)

Genetics and Microenvironment

Room:Großer Saal
Session details 16:00–17:30
Workshop 9 (Parallel Sessions)

NLPHL

Room:Isabellensaal

  • Update on classi cation of NLPHL and its distinction from TCRBCL and transformed DLBCL

  • Latest GHSG data on NLPHL

  • Case studies of patients with “apparent” relapse of NLPHL

Session details 16:00–17:30
Workshop 10 (Parallel Sessions)

Late Effects

Room:Kleiner Saal

  • Influence of radiotherapy and chemotherapy in modern Hodgkin Lymphoma treatment on risks of cardiovascular disease and second malignancy

  • Reducing cardiovascular risk in Hodgkin Lymphoma survivors – the SECURE trial

  • Phase 2 trial comparing the feasibility and efficacy of physical activity and multifactorial drug treatment in Hodgkin Lymphoma survivors

Session details 17:45–19:15
Satellite Symposium

Into the Future – New Treatment Options for Hematologic Malignancies

Room:Großer Saal
  • 17:45

    Welcome

  • 17:50

    Midostaurin – a novel therapeutic approach for patients with FLT3-mutated AML

  • 18:05

    The concept of treatment-free remission in CML – results from current studies

  • 18:20

    Panobinostat for relapsed or refractory myeloma: pan-HDAC-inhibition with epigenetic e ects

  • 18:35

    Advances in the treatment of hematologic malignancies: use of CAR T cells

Sunday 23.10.2016

Scientific Session Satellite Symposium Main Program Hematology Educational Workshop
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Session details 07:30–08:30
Satellite Symposium

The Evolution of Chemotherapy: Using the A-DAC Principle to Unlock New Treatment Options in Hodgkin Lymphoma

Room:Großer Saal
  • 07:30

    The evolution of chemotherapy – an introduction from the chair

  • 07:35

    The A-DAC principle – introducing EDO-S101

  • 07:45

    Breaking through resistance – the potential for EDO-S101 (an overview of pre-clinical data in Hodgkin Lymphoma)

  • 08:05

    EDO-S101: pre-clinical data in Multiple Myeloma and initial ndings from phase I in haematological malignancies

  • 08:25

    Unlocking the potential – Q&A session

Session details 08:30–10:00
Scientific Session 1

Interactive Case Discussions

Room:Großer Saal
Session details 10:30–12:00
Scientific Session 2

MRD and Prediction

Room:Großer Saal
Session details 12:15–13:45
Satellite Symposium

New Insights in the Treatment and Management of Lymphoid Malignancies

Room:Großer Saal
  • 12:15

    Welcome

  • 12:20

    Impact of febrile neutropenia in the HD18 trial: nal analysis of the project “daily G-CSF versus Peg lgrastim”

  • 12:35

    BiTE®: a new strategy for hematologic malignancies

  • 13:05

    Multiple Myeloma: new treatment options for patients with Car lzomib

  • Conclusion and closing remarks

Session details 14:00–15:30
Workshop 11 (Parallel Sessions)

Immunomodulation

Room:Kleiner Saal

  • Biological basis for PD-1 based immunotherapy

  • How do we rationally combine immune checkpoint therapy for optimal impact

  • Radiotherapy and immunotherapy combinations

  • Allo transplant vs checkpoint blockade in HL

Session details 14:00–15:30
Workshop 12 (Parallel Sessions)

Current Concepts in Allo TX

Room:Großer Saal

  • Allo-SCT in RR HL. The state of the art

  • The impact of the stem cell source (HLA id Sib vs MUD vs CB vs Haplo) in the outcome after allo-SCT

  • The role of allogeneic stem cell transplantation in the era of new drugs

Session details 14:00–15:30
Workshop 13 (Parallel Sessions)

Grey Zone Lymphoma

Room:Marsilius Saal
Session details 16:00–17:30
Satellite Symposium

Relapsed / Refractory Hodgkin Lymphoma: Nuances in Therapeutic Strategies to Improve Outcomes – a Case-Based Program

Room:Großer Saal
  • 16:00

    Welcome and introduction

  • 16:00

    Avoiding relapse of Hodgkin Lymphoma (HL): have we moved the needle?

  • 16:10

    Case #1: patient with advanced HL who relapses 18 months after initial therapy

  • 16:15

    Relapsed / refractory HL: therapeutic options prior to autologous stem cell transplant (ASCT)

  • 16:30

    Case #2: patient with bulky relapsed HL occurring 10 months following initial therapy

  • 16:35

    Post-ASCT relapse: making the most of what we have

  • 16:50

    Q&A

  • 16:55

    Case #3: patient with HL who has relapsed following ASCT

  • 17:00

    Novel agents in HL: what, how, and when should they be integrated?

  • 17:15

    Challenge the experts

  • 17:25

    prIME PointsTM

Session details 17:45–19:45
Main Program

Opening Ceremony

Room:Großer Saal

  • Movie: A History of Hodgkin Lymphoma

  • Key Note Lectue

  • Awards Ceremony

Session details 20:00
Main Program

Get Together

Room:Kleiner Saal

Monday 24.10.2016

Scientific Session Satellite Symposium Main Program Hematology Educational Workshop
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Session details 07:30–08:30
Satellite Symposium

Future Directions in Lymphoma and Myeloma Therapy

Room:Großer Saal
  • 07:30

    Mode of action of PD1 / PD-L1 monoclonal antibodies in HL

  • 07:50

    Novel therapeutic strategies to improve outcome of patients with aggressive lymphomas

  • 08:10

    Targeting CD38 in Multiple Myeloma

Session details 08:30–10:00
Scientific Session 3

Biology and Microenvironment

Room:Großer Saal
Session details 10:30–12:00
Scientific Session 4

Immunotherapy (Basic Science)

Room:Großer Saal
Session details 12:15–13:45
Satellite Symposium

Evolving Therapy in the HL Treatment Landscape

Room:Großer Saal
  • 12:15

    Welcome and introductions

  • 12:20

    Rationale for I-O therapies in solid and hematological malignancies

  • 12:35

    Balancing the risk-benefit ratio: current treatment regimens and unmet needs in HL

  • 13:00

    I-O in cHL: an eye towards the future

  • 13:25

    Audience Q&A session conclusions

Session details 14:00–15:30
Scientific Session 5

PET – Where Are We?

Room:Großer Saal
Session details 16:00–17:30
Scientific Session 6

Early Stages

Room:Großer Saal
  • 16:00

    Early favorable HL: pros and cons of PET-adapted therapy

  • 16:20

    Early unfavorable: new standard of care?

  • 16:40

    NLPHL

  • 17:10

    Proton radiotherapy for mediastinal Hodgkin Lymphoma: single institution experience

  • 17:30

    abstract talk Abstract Talk: T010 Long-term follow-up of contemporary treatment in early-stage favorable Hodgkin Lymphoma (HL): updated analyses of the German Hodgkin Study Group HD7 and HD10 trial

  • 17:40

    abstract talk Abstract Talk: T012 Results of US intergroup trial of response-adapted chemotherapy or chemotherapy/radiation therapy based on PET for non-bulky stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)

Session details 17:45–19:15
Satellite Symposium

Managing Hodgkin Lymphoma – A World View

Room:Großer Saal

  • Welcome and introduction

  • Diagnostics in practice: the ideal and the pragmatic

  • Prognostic indicators in front-line HL: a practical guide to individualizing therapy

  • Imaging and monitoring strategies: optimizing available resources

  • Optimizing HL management in the relapsed / refractory setting: making the most of available options

  • Concluding remarks

Tuesday 25.10.2016

Scientific Session Satellite Symposium Main Program Hematology Educational Workshop
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Session details 07:30–08:30
Satellite Symposium

Ask the Expert: An Open Forum on Hodgkin Lymphoma

Room:Großer Saal
Session details 08:30–10:00
Scientific Session 7

Pediatric HL

Room:Großer Saal
  • 08:30

    Interim results of EuroNet-PHL-C1

  • 08:50

    Targeted agents in pediatric HL

  • 09:10

    COG / ECOG: AYA HL

  • 10:00

    abstract talk Abstract Talk: T016 Whole body functional and anatomical MRI: accuracy in staging and treatment response monitoring in childhood and adolescent Hodgkin’s Lymphoma compared to conventional multimodality imaging (CRUK C23580/A12707)

  • 10:10

    abstract talk Abstract Talk: T017 Phase III study of response adapted therapy for the treatment of children with newly diagnosed very high risk Hodgkin Lymphoma (Stages IIIB/IVB) (AHOD0831): a report from the Children’s Oncology Group

  • 10:20

    abstract talk Abstract Talk: T018 Outcomes in adolescents and young adults (AYA) with Hodgkin Lymphoma (HL) treated on US cooperative group protocols: an adult intergroup (E2496) and Children’s Oncology Group (COG AHOD0031) comparative analysis

Session details 10:30–12:00
Scientific Session 8

Advanced Stages

Room:Großer Saal
Session details 12:15–13:00
Satellite Symposium

Classification of New Therapeutic Options for CLL and Follicular NHL

Room:Großer Saal
Session details 13:00–13:45
Main Program

Poster Walk

Room:Kleiner Saal
Session details 14:00–15:30
Scientific Session 9

Relapsed HL

Room:Großer Saal
Session details 16:00–17:30
Scientific Session 10

Survivorship

Room:Großer Saal
Session details 17:45
Scientific Session 11

Closing Remarks

Room:Großer Saal

Ground Floor

Allocations

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Kleiner Saal

Saturday, 22.10.2016

Sunday, 23.10.2016

Tuesday, 25.10.2016

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Marsilius Saal

Sunday, 23.10.2016

Basement

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First Floor

Allocations

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Großer Saal

Saturday, 22.10.2016

Sunday, 23.10.2016

Monday, 24.10.2016

Tuesday, 25.10.2016

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Isabellensaal

Saturday, 22.10.2016

Exhibition

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Biology and Microenvironment

Selected for Oral Presentation

  • Show Details

    P026 (P026) Hodgkin cell-derived extracellular vesicles shape fibroblast activity

    • Bösl T
    • Hansen HP
    • Engert A
    • Pogge von Strandmann E
  • Show Details

    P030 (P030) The lymphoid cell specific transcription factor ELF-1 is transcriptionally downregulated and recurrently deleted in classical Hodgkin lymphoma (cHL)

    • Giefing M
    • Zemke N
    • Bodnar M
    • Domanowska E
    • Janiszewska J
    • Paczkowska J
    • Ustaszewski A
    • Martin-Subero JI
    • Ammerpohl O
    • Klapper W
    • Marszalek A
    • Siebert R
  • Show Details

    P036 (P036) Tightly regulated FOXO3 expression is critical for the maintenance of cHL

    • Weitzer CD
    • Xie L
    • Guan H
    • Herrmann F
    • Pick S
    • Wirth T
    • Ushmorov A
  • Show Details

    T004 (T004) Analysis of the mutational landscape and dynamics in Hodgkin Lymphoma using NGS

    • Mata E
    • Díaz-López A
    • Montalban C
    • Fernandez R
    • Bellas C
    • Burgos F
    • Mestre MJ
    • Menárguez J
    • Provencio M
    • Santonja C
    • Piris MA
    • Garcia JF
  • Show Details

    T005 (T005) Award winning High expression of programmed cell death receptor 1 (PD-1) in the tumor microenvironment is associated with inferior event free survival in classical Hodgkin Lymphoma

    • Hollander P
    • Peter P
    • Smedby KE
    • Enblad G
    • Mortensen J
    • Amini RM
    • d´Amore F
    • Molin D
    • Glimelius I
  • Show Details

    T006 (T006) Award winning The AP-1 transcription factor BATF3 regulates MYC expression and is required for tumor cell survival in classical Hodgkin Lymphoma and anaplastic large cell lymphoma

    • Lollies A
    • Hartmann S
    • Schneider M
    • Bracht T
    • Arnolds J
    • Klein-Hitpass L
    • Sitek B
    • Hansmann ML
    • Küppers R
    • Weniger MA

Posters

  • Show Details

    P024 (P024) Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma

    • Wurster KD
    • Hummel F
    • Richter J
    • Giefing M
    • Hartmann S
    • Hansmann ML
    • Kreher S
    • Köchert K
    • Krappmann D
    • Klapper W
    • Hummel M
    • Wenzel S
    • Lenz G
    • Janz M
    • Dörken B
    • Siebert R
    • Mathas S
  • Show Details

    P025 (P025) Determination of the mutational landscape of primary Hodgkin and Reed/Sternberg cells of classical Hodgkin lymphoma

    • Schneider M
    • Döring C
    • Czeschik JC
    • Lollies A
    • Hartmann S
    • Rahmann S
    • Hansmann ML
    • Küppers R
  • Show Details

    P027 (P027) Prognostic implications of an active, innate or anergic immune response in the Hodgkin lymphoma tumor microenvironment

    • Hollander H
    • Rostgaard K
    • Smedby KE
    • Molin D
    • Loskog A
    • de Nully Brown P
    • Enblad G
    • Amini RM
    • Hjalgrim H
    • Glimelius I
  • Show Details

    P028 (P028) Studying the role of oncogenic miR-24-3p in Hodgkin lymphoma

    • Yuan Y
    • Kluive Jr
    • Koerts J
    • de Jong D
    • Rutgers B
    • Diepstra A
    • Visser L
    • van den Berg A
  • Show Details

    P029 (P029) Characterization of Hodgkin lymphoma clonogenic cells using a new L428 in vivo xenograft model in immunodeficient NOD/SCID-gammac-/- mice and peripheral lymphocytes study in Hodgkin Lymphoma patients

    • Cuceu C
    • Al Jawhari M
    • Morat L
    • Frenzel M
    • Lewandowski D
    • Junker S
    • Pflumio F
    • Bourhis J
    • Girinsky T
    • Sabatier L
    • Carde P
    • M’kacher R
  • Show Details

    P031 (P031) Mutations in CD58 and MYB in Hodgkin lymphoma

    • Abdul Razak FR
    • Diepstra A
    • Jong D
    • Koerts J
    • Rutgers B
    • Kluiver J
    • Visser L
    • van den Berg A
  • Show Details

    P032 (P032) Re-fusion of small mononucleated Hodgkin cells leads to giant multinucleated Reed-Sternberg cells in Hodgkin lymphoma

    • Rengstl B
    • Newrzela S
    • Heinrich T
    • Weiser C
    • Thalheimer FB
    • Schmid B
    • Warner K
    • Hartmann S
    • Schroede Tr
    • Küppers R
    • Rieger MA
    • Hansmann ML
  • Show Details

    P033 (P033) Molecular characterization of Bruton’s Tyrosine Kinase Inhibitor in Hodgkin’s Lymphoma: Cellular and Animal Models

    • Muqbil I
    • Aboukameel A
    • Azmi AS
    • Mohammad RM
    • Ramchandren R
  • Show Details

    P034 (P034) Functional analysis to elucidate the susceptibility mechanisms of SNPs at the REL, GATA3 and TCF3 loci in classical Hodgkin Lymphoma

    • Veenstra R
    • Kluiver J
    • de Jong D
    • Koerts J
    • Visser L
    • Diepstra A
    • van den Berg A
  • Show Details

    P035 (P035) IGH-mediated translocations, recurrent in classic Hodgkin lymphoma, frequently correlate with an aggressive behavior

    • Wlodarska I
    • Dierickx D
    • Pluys U
    • Doms K
    • Graux C
    • Van Hoof A
    • Vandenberghe P
    • Michaux L
    • Tousseyn T
  • Show Details

    P037 (P037) In-Vitro and In-Vivo preclinical activity of EDO-S101 in Hodgkin lymphoma

    • Al Jawhari M
    • Cuceu C
    • Frenzel M
    • Stimmer L
    • Junker S
    • Bosq J
    • Carde P
    • Mehrling T
    • Sabatier L
    • Pflumio F
    • M’kacher R
  • Show Details

    P038 (P038) Hodgkin Reed-Sternberg cells in classical Hodgkin lymphoma are surrounded by T regulatory cells while lymphocyte predominant cells of nodular lymphocyte predominant Hodgkin lymphoma are surrounded by T follicular helper cells

    • Visser L
    • Sattarzadeh A
    • Wu R
    • Rutgers B
    • Diepstra A
    • van den Berg A
  • Show Details

    P039 (P039) The incidence of bleomycin induced lung toxicity is increased in Hodgkin lymphoma patients exposed for granulocyte-colony stimulating growth factor

    • Andersen MD
    • Kamper P
    • d’Amore A
    • Clausen M
    • Bentzen H
    • d'Amore F
  • Show Details

    P040 (P040) Correlation between pre-treatment level of soluble PD-L1 and outcome in classical Hodgkin lymphoma included in a prospective study of the Lymphoma Study Association (LYSA)

    • Ghesquieres H
    • Drouet Y
    • Azzaoui I
    • Rossille D
    • Rossi C
    • Roussel M
    • Salles G
    • Traverse-Glehen A
    • Casasnovas O
    • Fest T
  • Show Details

    P041 (P041) Proteasome Inhibitor Therapy (PIT) in Hodgkin Lymphoma (HL): Leveraging Systems Biology Analyses (SBA) for Cell-Specific Transcriptome Alterations and Optimum Combinatorial Therapy

    • Passero Jr. FC
    • Beheshti A
    • Dashnamoorthy R
    • Evens AM
  • Show Details

    P042 (P042) Telomere maintenance mechanisms and Tumor microenvironment are key factors in the outcome of classic Hodgkin lymphoma

    • M’kacher R
    • Cuceu C
    • Morat L
    • Al Jawhari M
    • Frenzel M
    • Shim G
    • Lenain A
    • Ricoul M
    • Hempel W
    • Guilotto E
    • Junker S
    • Girinsky T
    • Badie C
    • Colicchio B
    • Dieterlen A
    • Jeandidier E
    • Moralès O
    • Renaud S
    • Van de Wyngaert Z
    • Carde P
    • Delhem N
    • Sabatier L
  • Show Details

    P043 (P043) Phenotypic characterization of circulating lymphocytes in Hodgkin´s lymphoma (HL) with focus on T cells

    • Palma M
    • Heimersson K
    • Näsman-Glaser B
    • Hansson L
  • Show Details

    P044 (P044) SIP-F1: A new gray zone lymphoma cell line?

    • Rengstl B
    • Hartmann S
    • Eberth S
    • Döring C
    • Pommerenke C
    • Becker PSA
    • Weiser C
    • Warner K
    • Doering C
    • Seidl C
    • Küppers R
    • Abken H
    • MacLeod RA
    • Drexler HG
    • Hansmann ML
    • Newrzela S
  • Show Details

    P045 (P045) CD4 lymphopenia as a prognosis factor in previously untreated Hodgkin lymphoma

  • Show Details

    P046 (P046) Can plasma chemokines and soluble receptor monitoring predict outcome in classical Hodgkin’s Lymphoma (cHL) patients?

    • Stamatoullas A
    • Perdrix A
    • Lemasle E
    • Thill C
    • Camus V
    • Veresezan L
    • Picquenot JM
    • Menard AL
    • Lenain P
    • Contentin N
    • Lanic H
    • Lepretre S
    • Brehar O
    • Cardinael N
    • Fontura ML
    • Fronville C
    • Jardin F
    • Bastard C
    • Tilly H
  • Show Details

    P047 (P047) Expression and prognostic impact of indoleamine 2,3-dioxygenase in Hodgkin’s lymphoma

    • Kryachok I
    • Novosad O
    • Skrypets T
    • Ulianchenko K
    • Tytorenko I
    • Khranovska N
    • Skachkova O
    • Svergun N
    • Gorbach O
  • Show Details

    P048 (P048) Reed-Sternberg Cells on Bone Marrow Cytology: The Very Early Feature on Hemophagocytic Lymphohistiocytosis Associated to Hodgkin Lymphoma

    • Niero-Melo L
    • Lustri LA
    • Polegatto BF
    • Del Castanhel C
    • Cantadori LO
    • Oliveira CC
    • Gaiolla RD
  • Show Details

    P048B (P048B) A novel PTPN1 splice variant regulates JAK/STAT activity in classical Hodgkin’s lymphoma cells

    • Zahn M
    • Marienfeld R
    • Melzner I
    • Heinrich J
    • Rehm A
    • Barth TF
    • Dorsch K
    • Brüderlein S
    • Möller P
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P024 (P024)

Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma

Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of NF-κB, JAK/STAT, AP-1 and IRF transcription factors (TFs), which are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein level in the majority of cHL cell lines and HRS cells of nearly all cHL primary samples. This loss is associated with PDLIM2 promoter methylation, altered splicing and, in rare cases, genomic alterations. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B cell lines, siRNA-mediated PDLIM2 knockdown results in super-activation of TFs NF-κB and AP-1 following PMA stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL), which shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis.
  • Wurster KD
  • Hummel F
  • Richter J
  • Giefing M
  • Hartmann S
  • Hansmann ML
  • Kreher S
  • Köchert K
  • Krappmann D
  • Klapper W
  • Hummel M
  • Wenzel S
  • Lenz G
  • Janz M
  • Dörken B
  • Siebert R
  • Mathas S
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P025 (P025)

Determination of the mutational landscape of primary Hodgkin and Reed/Sternberg cells of classical Hodgkin lymphoma

Despite recent advances in our understanding of classical HL (cHL) the pathogenesis of this disease is still largely unknown. For instance, only a few genetic aberrations in the tumor cells of cHL, the Hodgkin and Reed/Sternberg (HRS) cells, have been identified. In general, the analysis of HRS cells is hampered by the rarity of the HRS cells which usually comprises only about 1% of the tumor tissue. To better understand the pathogenesis of cHL and to identify new genes critically involved in this process, we developed a method to perform whole exome sequencing of microdissected HRS cells. So far 11 primary cHL cases were successfully sequenced. The successful validation of 16 of 21 selected mutations in HRS cells of three cHL cases by direct PCR with microdissected cells and Sanger sequencing showed the reliability of the analysis. In a preliminary analysis of the data, NFKBIE mutations were identified in three cases. Thus, NFKBIE mutations are a recurrent event in cHL.
  • Schneider M
  • Döring C
  • Czeschik JC
  • Lollies A
  • Hartmann S
  • Rahmann S
  • Hansmann ML
  • Küppers R
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P027 (P027)

Prognostic implications of an active, innate or anergic immune response in the Hodgkin lymphoma tumor microenvironment

The classical Hodgkin lymphoma (cHL) tumor microenvironment includes a variable inflammatory response consisting of eosinophils, mast cells, macrophages, regulatory T lymphocytes (Treg) and active lymphocytes. We counted these inflammatory cells in tumor tissue from 459 patients with cHL from Sweden and Denmark, with complete clinical data available for 409 patients. Depending on the predominant cell types and their immunologic function we categorized the immune profile into an active, anergic or innate immune response with the aim to investigate if a specific tumor immune profile can predict survival. Time to progression (TTP) (primary progression, relapse or cHL death) and overall survival (OS) were analyzed using Cox proportional hazards regression. During follow-up (median 12.9 years) 49 patients had disease progression and 78 patients died. A high proportion of Treg (an anergic immune response) conferred shorter TTP when adjusted for age (hazard ratio (HR)=2.25; 95% confidence interval (CI) 1.15-4.41), especially in advanced stages (HR=2.83; 95%CI 1.25-6.40). In addition, a low proportion of Treg combined with a high proportion of macrophages conferred superior TTP when adjusted for age, stage, albumin and bulky tumor (HR=0.23; 95%CI 0.07-0.77). This is the first study to show that a tumor microenvironment characterized by an anergic immune response corresponds to a shorter TTP in cHL, indicating a reduced ability of an anergic immune system to attack the tumor cells. The programmed death receptor 1 (PD-1) is expressed by Treg, and these results warrant further investigation to determine if Treg is a predictor of response to PD-1 blocking drugs.
  • Hollander H
  • Rostgaard K
  • Smedby KE
  • Molin D
  • Loskog A
  • de Nully Brown P
  • Enblad G
  • Amini RM
  • Hjalgrim H
  • Glimelius I
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P028 (P028)

Studying the role of oncogenic miR-24-3p in Hodgkin lymphoma

Introduction: Micro (mi)RNAs negatively regulate gene expression at the transcriptional level by binding to complementary regions in the 3’-UTR. They play important roles in biological processes such as proliferation, metabolism, differentiation and apoptosis. Aberrant expression of miRNAs contributes to several diseases including cancer. Although several miRNAs have been implicated in the pathogenesis of Hodgkin lymphoma (HL), the function of most of the aberrantly expressed miRNAs is unknown. Therefore, the aim of this study is to investigate the role of miRNAs and the underlying mechanism in HL. Results: Small RNA-seq revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to GC-B cells, including 55 up- and 29 downregulated miRNAs. QRT-PCR validation confirmed the differential expression pattern as observed with small RNA sequencing for 15 out of 19 selected miRNAs. Among the upregulated miRNAs, miR-23a, miR-24 and miR-27a were transcribed from one primary miRNA transcript. Loss-of-function analysis for these 3 miRNAs and their family members resulted in decreased growth upon miR-24 inhibition in L428, L1236 and KMH2 and upon inhibition of miR-27a/b in L1236. No effect on cell growth was observed upon inhibition of miR-23a/b. Apoptosis analysis upon miR-24 inhibition revealed increased percentage of apoptosis cells, indicating that the decreased cell growth upon miR-24 inhibition was at least in part caused by an increase in apoptosis. To identify the target genes of these miRNAs we performed argonaute 2 (AGO2)-IP in four HL cell lines. This revealed 1,142 consistently AGO2-enriched genes. Gene set enrichment analysis revealed significant enrichment of the miR-23a/b, miR-24 and miR-27a/b miRNA target gene sets in the IP fraction. Furthermore, 51 out of 1,142 genes were predicated targets of miR-24 based on Targetscan, including 4 out of 5 proven miR-24 targets. Functional annotation analysis revealed a function related to cell growth, cell death and/or apoptosis for 15 out of the 52 genes. Western blotting for 2 of these genes, i.e. CDKN1B and MYC, showed downregulation at the protein level upon miR-24 inhibition. Conclusion: A total of 84 miRNAs were significant differently expressed in HL cell lines compared to GC-B cells. MiR-24 has an oncogenic role in HL by inhibiting apoptosis.
  • Yuan Y
  • Kluive Jr
  • Koerts J
  • de Jong D
  • Rutgers B
  • Diepstra A
  • Visser L
  • van den Berg A
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P029 (P029)

Characterization of Hodgkin lymphoma clonogenic cells using a new L428 in vivo xenograft model in immunodeficient NOD/SCID-gammac-/- mice and peripheral lymphocytes study in Hodgkin Lymphoma patients

The characterization of the cells at the origin of Hodgkin and Reed Sternberg cells in Hodgkin lymphoma (HL) is hampered mostly because of the poor growth of HL cells in vitro and in vivo. Investigation of cell markers and signaling pathways specific to HL clonogenic cells may lead to progress in therapy and improve the prognosis of patients with HL. Using a newly developed murine in vivo L428 xenograft model and circulating lymphocytes of HL patients before treatment, we attempted to determine the immunophenotype and cytogenetic profile of the clonogenic cells. Material and methods: L428 HL cell line was used to establish an in vivo xenograft model in immunodeficient NOD/SCID-gammac-/- mice. In vitro and in vivo clonogenic cells derived from L428 cell line and circulating lymphocytes of 50 HL patients were characterized using immunofluorescence, immunochemistry and cytogenetic. Chromosomal instability was also investigated. Telomere maintenance mechanisms (telomerase activity (TA) and Alternative Lengthening Telomere (ALT)) were explored. Results: We confirmed previous data that L428 cell line contained small (<2%) subpopulations that lacked CD30 and CD15 expression and had greater clonogenic potential in vitro than the corresponding CD30+ and CD15+ cells. These cells were also clonogenic in vivo in NOD/SCID gamma -/- mice. Immunophenotype characterization of the first cells harvested from the mice demonstrated a CD30, CD15 and CD14 negative profile. Over time, the cells acquired CD14 followed by CD15 and finally CD30 surface markers. Cytogenetic analysis confirmed the diploid origin of the cells that grow in the mice. Cell sorting of negative cells in HL cell lines was performed to validate this hypothesis and demonstrate their clonogenic potential to recover the parental cell line. These cells were characterized by a higher telomere instability associated to the presence of higher frequency of dicentric chromosome. A high TA was detected in these cells as well as in the circulating lymphocytes in 10 out of 50 HL patients. Conclusion: We better characterized the origin of the cells which grow in the L428 xenograft model, and their different steps of transformation from “clonogenic cells” to monocytes/macrophages and finally to Hodgkin and HRS cells due to the unique microenvironment of HL. The assessment of TA could be used as a biomarker of the prevalence of clonogenic cells in circulating lymphocytes.
  • Cuceu C
  • Al Jawhari M
  • Morat L
  • Frenzel M
  • Lewandowski D
  • Junker S
  • Pflumio F
  • Bourhis J
  • Girinsky T
  • Sabatier L
  • Carde P
  • M’kacher R
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P031 (P031)

Mutations in CD58 and MYB in Hodgkin lymphoma

Hodgkin lymphoma (HL) is characterized by constitutive activation of several signaling pathways and expression of a distinct set of transcription factors. This characteristic phenotype is partly caused by gene mutations as determined by targeted and whole genome sequencing approaches on cell lines and microdissected HRS cells. Here we studied CD58 and MYB, 2 genes we previously identified by whole exome sequencing (WES) in HL cell lines. CD58 gene mutations observed in 3 HL cell lines were confirmed by Sanger sequencing at the DNA and RNA level. CD58 protein expression as determined by flow, western blot and IHC was absent in all 3 HL cell lines with mutations and present in 4 HL cell lines with wild type CD58. In primary tissue samples, loss of CD58 expression was observed in 11% of the patients. Lack of CD58 was specifically observed in patients who developed a relapse. This suggests that loss of CD58 is a potential immune escape mechanism of HRS tumor cells, especially in clinically aggressive disease. Frame shift mutations resulting in a truncated MYB protein were found in L428 and SUPHD1 cells. The mutation in L428 causes complete loss of most of the C-terminal domain whereas the mutation in SUPHD1 results in a MYB protein with a partial loss of the C-terminal domain. We confirmed the mutations at the DNA and RNA level and confirmed presence of a truncated protein by Western blot with C-terminal and N-terminal domain specific antibodies. RT-PCR with primers specific for each of the alternatively spliced exons, indicated that these were not included in the MYB transcript in any of the HL cell lines. In tissue samples, staining of MYB in HL cases revealed no staining with both antibodies in the vast majority of the cases, indicating complete loss of the MYB protein. Inhibition of MYB by shRNA constructs induced negative effects on cell growth in HL cell lines with wild type MYB (L540 & KMH2) and no or limited effects in HL cell lines with truncated MYB (L428 & SUPHD1). Microarray analyses of L540 & KMH2 cells treated with non-targeting and MYB shRNA constructs revealed 63 consistently MYB induced and repressed genes. In conclusion, we show that loss of CD58 expression is common in HL cell lines and restricted to the HRS cells of tissue samples of relapsed HL. For MYB, strong oncogenic effects were observed especially for the HL cell lines with wild type MYB.
  • Abdul Razak FR
  • Diepstra A
  • Jong D
  • Koerts J
  • Rutgers B
  • Kluiver J
  • Visser L
  • van den Berg A
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P032 (P032)

Re-fusion of small mononucleated Hodgkin cells leads to giant multinucleated Reed-Sternberg cells in Hodgkin lymphoma

The multinucleated Reed-Sternberg (RS) cells are pathognomonic for classical Hodgkin lymphoma (HL) and their presence is essential for diagnosis. However, the development of these giant tumor cells is controversially discussed. It was postulated that RS cells arise from mononucleated Hodgkin cells via endomitosis. Conversely, continuous single cell tracking of HL cell lines by long-term time-lapse microscopy showed that cell fusion is the main route of RS cell formation. In contrast to growth-induced formation of giant Hodgkin cells, fusion of small mononuclear cells followed by size increase gives rise to giant RS cells. Importantly, we nearly exclusively observed fusion of cells originating from the same ancestor, termed re-fusion. In the majority of cases, re-fusion of daughter cells was preceded by an incomplete cytokinesis, visualized by a microtubule bond between the cells. We confirm at the level of individual tracked cells that giant Hodgkin and RS cells have little proliferative capacity, further specifying small mononuclear Hodgkin cells as the proliferative compartment of the HL tumor clone. In addition, sister cells showed a shared propensity for re-fusion, which provides evidence of early RS cell fate commitment. Thus, RS cell generation is neither due to cell fusion of unrelated Hodgkin cells nor to endomitosis, but is mediated by re-fusion of daughter cells that underwent mitosis. This surprising finding indicates the existence of a novel mechanism for the generation of multinuclear RS cells, which might have implications beyond HL, as RS-like cells are frequently observed in several other lymphoproliferative diseases.
  • Rengstl B
  • Newrzela S
  • Heinrich T
  • Weiser C
  • Thalheimer FB
  • Schmid B
  • Warner K
  • Hartmann S
  • Schroede Tr
  • Küppers R
  • Rieger MA
  • Hansmann ML
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P033 (P033)

Molecular characterization of Bruton’s Tyrosine Kinase Inhibitor in Hodgkin’s Lymphoma: Cellular and Animal Models

Abstract: Classical Hodgkin Lymphoma (cHL) is a malignancy of mature (post germinal center) B-lymphocytes that afflicts almost 20,000 individuals annually in North America and Europe alone. While the majority of patients diagnosed with HL are cured with multi-agent chemotherapy, 15 % of patients are refractory to conventional chemotherapy and almost half of patients with high-risk disease relapse. Only 2 agents have been approved in the last 30 years for relapsed HL and novel therapies are needed. Bruton’s Tyrosine Kinase (BTK) is a member of the TEC family and plays a central role in B-cell signaling, activation, proliferation and differentiation. Several studies have shown that BTK is upregulated in a proportion of Reed-Sternberg cells and has been associated with PI3K, mTOR, FAS and NF-κB signaling. Furthermore, pathways upregulated in cHL such as CD40 ligand binding, elevated chemokines such as IL-6 and activation of toll like receptor (TLR) pathways have been associated with BTK upregulation. Thus, BTK inhibition may have therapeutic potential in cHL. Methods: The BTK inhibitor Ibrutinib at 0-15 micro molar doses was incubated for 72 hrs. with a panel of HL cell lines (KM-H2, L1236, L-428). Cell viability was evaluated using trypan blue. Apoptosis was analyzed using annexin V FITC and histone DNA ELISA. Protein expression was analyzed using western blotting with RNA post ibrutinib treatment subjected to RT PCR. Results: Ibrutinib suppressed viability of these HL cell lines in a dose dependent manner (IC50s ~5-7.5 µM in KM-H2, L1236 and L-428). The drug induced statistically significant apoptosis in the responsive cell lines in a dose dependent manner (>50% apoptosis at IC50 doses). Molecular analysis using western blotting and RT-PCR revealed significant induction of apoptotic markers and down-regulation of pro-survival markers. Further characterization of the effect of Ibrutinib on PI3K, mTOR, FAS and NF-kB signaling is ongoing. Ibrutinib is now being evaluated in ICR SCID mice with sub-cutaneous xenografts of KM-H2 and L1236. A pre-clinical efficacy trial using maximum tolerated dose (MTD) given by gavage is ongoing. Conclusion : These are the first studies showing in vitro and ex vivo effects of BTK inhibitors in HL and may provide support for further clinical investigation.
  • Muqbil I
  • Aboukameel A
  • Azmi AS
  • Mohammad RM
  • Ramchandren R
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P034 (P034)

Functional analysis to elucidate the susceptibility mechanisms of SNPs at the REL, GATA3 and TCF3 loci in classical Hodgkin Lymphoma

Introduction Genome Wide Association Studies (GWAS) revealed significant associations for SNPs mapping at the REL, GATA3 and TCF3 loci with cHL susceptibility. In this study, we aim to elucidate the susceptibility mechanism of these associations by establishing possible expression quantitative trait loci (eQTL) effects. Methods EQTL analysis was performed in EBV transformed lymphoblastoid cell lines (LCLs) generated from 96 controls and 70 former cHL patients as well as in three previously published large gene expression studies of HRS cells and total HL tissue samples. Results An eQTL effect for REL was found using cHL total tissue array data with increased REL expression levels for individuals carrying the homozygous risk allele. No significant effects were observed for the HRS cell data and for the LCLs. For GATA3 a significant association was found in the patient derived LCLs with lower GATA3 levels in LCLs of homozygous risk allele carriers, while no effect was observed for the control LCLs, or the HRS cell and the cHL total tissue array data. Only In the control LCLs lower TCF3 expression levels were found for individuals homozygous for the risk allele. To identify the downstream targets of these three transcription factors we performed gene expression arrays of cHL cell lines infected with shRNA constructs. We identified 1805, 1052, 1602 differentially expressed genes for REL, GATA3 and TCF3, respectively. eQTL analysis of the array data focusing only on these downstream targets is ongoing. Conclusion For REL, GATA3 and TCF3 we observed an eQTL effect in at least one of the studied groups. For REL and TCF3 the eQTL pattern is consistent with the proposed susceptibility effects of these genes, i.e. higher REL levels stimulating cell growth and lower TCF3 levels supporting the loss-of-B-cell phenotype for the risk alleles. Surprisingly, for the T-helper 2 specific transcription factor GATA3 the risk allele is associated with decreased levels in B-cells, but apparently not in T-cells. Our data support a functional rol for the risk and protective SNP alleles in cHL susceptibility.
  • Veenstra R
  • Kluiver J
  • de Jong D
  • Koerts J
  • Visser L
  • Diepstra A
  • van den Berg A
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P035 (P035)

IGH-mediated translocations, recurrent in classic Hodgkin lymphoma, frequently correlate with an aggressive behavior

Cytogenetic features of classic Hodgkin lymphoma (cHL) remain largely unknown. Interphase FISH (iFISH) studies, however, suggest that IGH-mediated t(14q32) are recurrent in cHL (PMID: 17079453, 18940474). Recently, we have identified t(14;18)(q32;q21)/IGH-BCL2 and inv(14)(q11q32)/IGH-CEPBE in two patients with nodular sclerosis HL (NSHL) analyzed at time of relapse. To identify additional cHL cases with t(14q32/IGH) and check whether these rearrangements correlate with clinical outcome, we screened by iFISH: (i) 46 relapsed cHL, (ii) 40 cHL with a long-term remission, and (iii) 60 prospective cases. Altogether, IGH rearrangements were detected in 28 patients, including 17 representing the former group (35.4%), 4 cases representing the second group (10%) and 7 prospective cases (11.6%). LSI IGH FISH pattern suggested a reciprocal t(14q32/IGH) in 20 cases, nonreciprocal t(14q32/IGH) in 4 cases, inv(14q32/IGH) or ins(14q32/IGH) in 3 cases and interstitial del(14q32/IGH) in one case. Twenty six cases were further analyzed by iFISH with break-apart (BA) assays for BCL2, BCL3, BCL6 and MYC. In 3 cases with likely inv(14)/ins(14), CEPBE BA was applied. Altogether, we have identified the IGH-BCL2 rearrangement in two cases, including the index case with t(14;18), and the IGH-CEPBE rearrangement in the case with inv(14). All the remaining cases showed a non-rearranged status of the examined loci. The majority of patients (18/28) with t(14q32/IGH) were diagnosed with NSHL. There were 18 male and 10 female patients in age ranging from 18 to 91 years (mean 50). Patients presented with both early (10/26) and advanced (16/26) stage (two not staged). All were treated with chemotherapy with or without radiotherapy, except for two patients who were subjected to a palliative treatment. After induction therapy, complete and partial remission was achieved in 17 and 5 patients, respectively. Thirteen patients are alive (11 without disease and 2 with disease); 13 patients died, including 11 whose death was related with a disease, and two are lost for follow up. In summary, we confirmed that chromosomal aberrations involving 14q32/IGH occur recurrently in cHL. These rearrangements rarely target BCL2 and CEPBE, and do not affect BCL3, BCL6 and MYC. Interestingly, 17 out of 21 (81% ) patients with t(14q32/IGH) showed an aggressive behavior. Our study allows a new insight into the pathogenesis of cHL and might help in further stratification of cHL patients.
  • Wlodarska I
  • Dierickx D
  • Pluys U
  • Doms K
  • Graux C
  • Van Hoof A
  • Vandenberghe P
  • Michaux L
  • Tousseyn T
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P037 (P037)

In-Vitro and In-Vivo preclinical activity of EDO-S101 in Hodgkin lymphoma

Background: EDO-S101 is an alkylating histone-deacetylase inhibitor (HDACi) fusion molecule that combines the strong DNA damaging effect of Bendamustine, with a fully functional pan-HDAC inhibitor, vorinostat. In this work, we investigated the preclinical rationale for the use of EDO-S101 in Hodgkin lymphoma (HL). Material and methods: In-vitro, a panel of 8 HL cell lines was used to study the cytotoxicity of EDO-S101 alone and combined with radiation therapy, and to investigate its cellular and molecular effects. In vivo, we investigated in immunodeficient NOD/SCID-gammac-/- mice xenografted with the L428 the antitumor effect of EDO-S101 alone . This evaluation, based on organ infiltration and survival, was performed following one single (60mg/kg or 80mg/kg) dosing or a repeat- dose (60mg/kg) of EDO-S101. Results: In-Vitro, the IC50 of EDO-S101 ranged between 1.6 to 6.3mM in 8 Hl cell lines after a 48 h-exposure. All HL cell lines showed a high sensitivity to EDO-S101; a clonogenic survival assay confirmed these observations. Multiple mechanisms of action of EDO-S101 were identified. In one group of HL cell lines (L428-L428-s, L540, SUP-HD, L591 and KMH2), activation of apoptosis was independent of the P53 status. The combination of EDO-S101 with irradiation demonstrated a dramatical enhancement of apoptotic cell death via G2 arrest. In a second group (L1236 and HDLM2), with the higher sensitivity to EDO-S101, resistance to apoptosis was associated with a higher frequency of chromatid aberrations involved in mitotic cell death. The effect of radiation was marginal in this group. In-Vivo, in mice engrafted with the L428 cells, treatment with EDO-S101 reduced drastically L428 cells infiltration, and prolonged survival of EDO-S101 treated mice in comparison with those untreated. Histological evaluation of the infiltration of tumoral cells after EDO-S101 treatment showed a significant reduction of tumor cell infiltration, more pronounced after a single dose of 80 mg/kg EDO-S101 than after two administrations of 60mg/kg. We observed a high liver weight heterogeneity in untreated mice, contrasting with homogeneous weight in treated mice. The absence of necrotic cells and cell degeneration in treated mice could be correlated to the anti-tumoral effect of EDO-S101 confirming the efficacy of EDO-S101. Conclusion: Our results show the antitumoral activity of EDO-S101 in pre-clinical models of HL, both in-vitro and in-vivo.
  • Al Jawhari M
  • Cuceu C
  • Frenzel M
  • Stimmer L
  • Junker S
  • Bosq J
  • Carde P
  • Mehrling T
  • Sabatier L
  • Pflumio F
  • M’kacher R
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P038 (P038)

Hodgkin Reed-Sternberg cells in classical Hodgkin lymphoma are surrounded by T regulatory cells while lymphocyte predominant cells of nodular lymphocyte predominant Hodgkin lymphoma are surrounded by T follicular helper cells

While it is clear that there is an important role for the microenvironment in Hodgkin lymphoma (HL), the composition and functionality is still a matter of discussion. Both a Th2 and a Th1 phenotype has been described in classical HL (cHL), irrespective of the Epstein Barr virus (EBV) status of the tumor cells. A systematic comparison between cHL and nodular lymphocyte predominant HL (NLPHL) has not been performed before and studies on the composition of the cells in- versus outside of the tumor area are missing. We compared the composition of the microenvironment of 14 cHL (7 EBV+ and 7 EBV-) and 10 NLPHL suspensions by flowcytometry. CD26 expression was used to identify cells in- (CD26-) and outside (CD26+) the tumor cell area. Results: In EBV+ cHL there were more CD56+CD16+ NK cells, and more CD69+, Granzyme B+ and TIA-1+ CD8+ cells than in EBV- cHL. We saw no differences between EBV+ and EBV- cHL when looking at the location of the cells. Compared to cHL, NLPHL contained more PD-1+ CD4+ cells and PD-1+CD57+CD4+ cells, while cHL showed more CCR7+CD45RA+CD4+, FoxP3+CD4+, CD25+CD4+, CXCR5+ICOS+CD4+, CXCR3+CD8+ and CD56+ cells. In cHL, we found more CD69+CD4+ and FoxP3+CD4+ cells inside, and more CD25+CD8+ cells outside the tumor cell area. In NLPHL, the distribution of CD69+CD4+ cells and CD25+CD8+ cells was similar to cHL. In addition, we found more CD69+CD8+, and more PD1+CD4+ cells inside, and more FoxP3+CD25+CD4+ cells outside the tumor cell area. Both HL subtypes are characterized by high numbers of CD69+CD4+ cells inside the tumor cell area, and a shift of CD25+CD8+ cells from in- to outside the tumor cell area. Conclusions: PD-1+CD4+ T follicular helper cells normally provide help to germinal center B cells and the increase in the tumor cell area of NLPHL indicates a similar function for LP cells. In cHL, the increase of FoxP3+ T regulatory cells might provide an immune suppressive environment for the HRS cells. Both types of HL depend on different cells in the direct tumor cell environment, fitting the different nature of the tumor cells.
  • Visser L
  • Sattarzadeh A
  • Wu R
  • Rutgers B
  • Diepstra A
  • van den Berg A
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P039 (P039)

The incidence of bleomycin induced lung toxicity is increased in Hodgkin lymphoma patients exposed for granulocyte-colony stimulating growth factor

Background In Hodgkin lymphoma (HL) the risk of developing bleomycin pulmonary toxicity (BPT) is well described. A number of factors that could potentially increase the risk of this condition have been suggested e.g. increasing age, bleomycin dose, smoking history. The use of granulocyte-colony stimulating factor (G-CSF) has also been proposed as a potential risk factor for BPT. In the present study, we have investigated the incidence of BPT in the face of possible risk factors in a cohort of HL patients treated at our institution between 1990 and 2014. Methods Information on clinico-pathological parameters including the occurrence of BPT, the use of filgrastim/pegfilgrastim and smoke habits was obtained from clinical records. BPT was defined as pulmonary symptoms occurring during the course of chemotherapy, presence of infiltrates on chest X-ray or CT-scan and absence of infection. Patient characteristics were correlated to the presence of BPT and use of G-CSF using the chi2-test. Overall- and progression-free survival (OS and PFS), were analyzed by the Kaplan-Meier method. Results 413 patients with a median age of 38.5 yrs (range: 16-86 yrs) were analyzed. The M:F ratio was 1,3. A total of 155 patients (38%) had disseminated disease. B-symptoms and bulky lesions were present in 48% and 31% of the patients, respectively. A history of smoking was reported in 47% of all patients. A total of 36 patients (9%) were diagnosed with BPT. The incidence of BPT was found to be higher among patents with high stage (p<0,001) and among those presenting with B-symptoms (p=0.008), i.e. the subsets that were likely to have received the largest amounts of bleomycin. A trend was found towards a higher incidence with increasing age (p=0.06). No correlation was found between BPT and a smoking history (p=0,37). Patients presenting with BPT were more likely to have been exposed to the use of G-CSF (p=0,03). Interestingly, the highest number of BPT events was observed among the patients exposed to the PEGylated forms of G-CSF (p=0,02). When stratifying the analysis according to age, the above correlations remained significant in the age group above 45 years, but did not seem to impact the younger patients. Conclusion In the present study, the occurrence of BPT was correlated to the presence of disseminated disease and B-symptoms at the time of diagnosis. We also found a higher incidence of BPT among the patients that were exposed to G-CSF during the course of chemotherapy.
  • Andersen MD
  • Kamper P
  • d’Amore A
  • Clausen M
  • Bentzen H
  • d'Amore F
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P040 (P040)

Correlation between pre-treatment level of soluble PD-L1 and outcome in classical Hodgkin lymphoma included in a prospective study of the Lymphoma Study Association (LYSA)

Introduction: Classical Hodgkin Lymphoma (CHL) is characterized by PD-L1/L2 deregulation with the effectiveness of PD-1 blockage treatment. Pre-treatment level of soluble PD-L1 (sPD-L1) was more elevated in diffuse large B-cell lymphoma (DLBCL) patients than in controls and was associated with overall survival. We evaluated pre-treatment sPD-L1 level of 126 CHL patients included in a prospective study of the Lymphoma Study Association (LYSA) and 37 controls. Methods: The cohort consisted in 126 CHL patients enrolled between 1998 and 2002 in a prospective study of the LYSA assessing the prognostic values of plasma cytokines and soluble receptors. A peripheral blood sample for plasma was collected from all patients at diagnosis before any treatment. The protein expression of sPD-L1 was evaluated in duplicate using an ELISA kit. A Zero-Inflated Binomial-Negative regression model was used to compare sPD-L1 levels in CHL patients and controls. Correlation between log-transformed sPD-L1 level and clinical characteristics, EBV status and cytokine levels measured before any treatment (IL-10, TNFα, TNF-R1, TNF-R2, IL-6, IL-1Rα, sCD30), response to initial treatment and progression-free survival (PFS) were investigated. Results: the median age of the 126 CHL patients was 33 years (range, 15-93), 68% had an Ann Arbor stage I-II and 71% had an IPS score of 0-2. Nodular sclerosis was the main histologic subtype (83%). The EBV status was positive in 18 (27%) patients. 67% patients were treated with ABVD, 14% of patients progressed or relapsed and 11% died. sPD-L1 mean level in CHL patients was 3.56 times more elevated in cases than in controls (95% CI: 2.66-4.76, p= 8.2e-13; estimated means for cases and controls: 869 vs 3093 pg/ml; medians: 549 vs 1954 pg/ml). No statistically significant correlation/association was found between sPD-L1 level and age, Ann Arbor stage, ECOG-PS, IPS, lymphocyte count, EBV status, the different evaluated cytokines, response to treatment and PFS. Conclusions: CHL patients have a PD-L1 level in plasma which is higher than controls and DLBCL patients. Further studies are needed to decipher the prognostic role of sPD-L1 level in larger cohort including patients with more advanced stages and treated with immune checkpoint inhibitors.
  • Ghesquieres H
  • Drouet Y
  • Azzaoui I
  • Rossille D
  • Rossi C
  • Roussel M
  • Salles G
  • Traverse-Glehen A
  • Casasnovas O
  • Fest T
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P041 (P041)

Proteasome Inhibitor Therapy (PIT) in Hodgkin Lymphoma (HL): Leveraging Systems Biology Analyses (SBA) for Cell-Specific Transcriptome Alterations and Optimum Combinatorial Therapy

Introduction: NF-κB has been shown to be critical for HL cell survival. Ixazomib is a new oral PI with favorable pharmacodynamic and pharmacokinetics; we recently reported activity of ixazomib in HL cells and in vivo SCID xenografts (Ravi et al. Cancer Research. 2016). SBA favored tumor inhibition via downregulation of MYC and CHK1 with CHK1 involved in Myc alteration through chromatin modification & histone H3 acetylation. Continued dissection of cell-specific transcriptome changes with PIT is needed and potential combination therapy with ixazomib should be explored. Methods: We examined ixazomib-induced transcriptome changes in L540 & L428 cells that were ixazomib sensitive and also with generated resistance. Key genes were derived from overlapping Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). SBA were used to identify genes related to treatment response; and based upon the aforementioned results, we studied the HDAC inhibitor (HDACi), belinostat, combined with ixazomib. Results: On GSEA (Figure A), ixazomib induced downregulation of mitotic cell cycle in L540 cells, while L428 cells had noted upregulation. Chromatin architecture was downregulated in L540, while L428 had no change. Catabolic activity and vesicular function linked to protein localization and transport were upregulated in L540 & L428 cells. Furthermore, analysis of “key genes” predicted greater ‘tumor promotion’ in ixazomib-resistant L428 vs ixazomib-sensitive L428 and L540 cells (Figure B & C). Among 66 common key genes in L540 & L428, the most connectivity was seen between CDKN1A (p21), JUN, GADD45A, ATF4, HSPA8, SQSTM1 (p62), CSF2, CEBPB and its inhibitory binding partners DDIT3 and TRIB3 (associated with cell cycle, apoptosis, response to oxidative stress & autophagy). For combination studies, ixazomib + belinostat was highly synergistic with combination index <0.5. On Western blot, ixazomib + belinostat resulted in increased p21, cleaved caspases, decreased autophagy (ie, proteins p62 and cathepsin) and also decreased Myc, which had previously been implicated with ixazomib. Conclusions: Ixazomib alone has prominent in vitro and in vivo activity in HL, and via SBA, we identified rational synergistic therapy with HDACi. In addition, we identified HL cell-specific transcriptome changes affecting varied and distinct pathways involving cell cycle, autophagy and apoptosis. Continued understanding of cell and drug-specific omic alterations are warranted.
  • Passero Jr. FC
  • Beheshti A
  • Dashnamoorthy R
  • Evens AM
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P042 (P042)

Telomere maintenance mechanisms and Tumor microenvironment are key factors in the outcome of classic Hodgkin lymphoma

Background: About 15-20% of patients with advanced stage Hodgkin lymphoma (HL) still die following relapse or progressive disease and a similar proportion of patients are over-treated, leading to treatment-related late sequelae, including solid tumors and organ dysfunction. We analyzed telomere maintenance mechanisms (TMMs) of HL cell lines as well as the samples from HL patients treated with standard therapy and compared the TMMs with favorable and unfavorable clinical outcome. Materials and Methods: Frozen lymph node samples obtained from 38 HL patients during diagnostic lymph node biopsy and from 24 patients with lymphadenitis were entered in this study. All HL patients were stage I (84.2%) and II (15.8%) with mean age of 36.7 years and 94.7% were nodular sclerosis. Seven HL cell lines were used as a positive control. Telomerase activity (TA) and alternative lengthening telomere (ALT) profile were assessed as well as Epstein Barr Virus (EBV) status and protein expression levels. The TMMs were correlated to clinical outcomes of patients (10.3 years) as well as to radiation sensitivity of HL cell lines. Results: The major finding of this study is the presence of both TA and ALT mechanisms in selected lymph nodes of HL patients. This TMMs heterogeneity was confirmed in HL cell lines. Hodgkin and Reed Sternberg (HRS) cells demonstrated an ALT profile, while the small cells exhibited a higher telomerase activity. We identified in the same tumor lymph node HRS cells containing ALT-associated PML bodies, a hallmark of ALT, and separate small cells expressing telomerase. Similarly, in HL cell lines, a high level of TA was detected in L428 and SUP-HD1. L1236 cell line demonstrated a lower TA and presented an ALT profile. The latent membrane protein (LMP1) staining revealed the presence of EBV genome in HRS cells in 13 lymph nodes (34.2%). A higher expression of TRF2/PML (ALT profile) and CD68 in EBV positive patients was correlated with Overall Survival (p=0.02), Freedom From Progression (p=0.02) and Event Free Survival (p=0.003). ALT HL cell lines demonstrated a lower radiation sensitivity as compared to TA HL cell lines. Conclusion: The presence of both TMMs (TA and ALT) in HL lymph nodes and HL cell lines is a singular oncology phenomenon. TMMs, related to tumor microenvironment in HL lymph nodes, are associated with treatment response and survival of HL patients.
  • M’kacher R
  • Cuceu C
  • Morat L
  • Al Jawhari M
  • Frenzel M
  • Shim G
  • Lenain A
  • Ricoul M
  • Hempel W
  • Guilotto E
  • Junker S
  • Girinsky T
  • Badie C
  • Colicchio B
  • Dieterlen A
  • Jeandidier E
  • Moralès O
  • Renaud S
  • Van de Wyngaert Z
  • Carde P
  • Delhem N
  • Sabatier L
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P043 (P043)

Phenotypic characterization of circulating lymphocytes in Hodgkin´s lymphoma (HL) with focus on T cells

Background. The malignant cells in HL comprise only a small fraction of the total tumor population but orchestrate an inflammatory microenvironment of reactive cells that sustains tumor cell survival and growth. HL patients (pts) have high systemic levels of inflammatory cytokines and chemokines and low lymphocyte count (<0.6 x 10^9/L) is a well-established prognostic factor in advanced disease. The aim of this pilot study was to characterize the phenotype of circulating lymphocytes in HL pts. Material and methods. Peripheral blood samples were obtained from 10 HL pts and 12 sex- and age-matched healthy controls. Nine pts had classical HL and 1 had nodular lymphocyte predominance (NLP) HL. Five pts had limited (stage I-IIA) and 5 had advanced (IIB-IV) disease. Pts with ongoing acute EBV infection were excluded. All pts had negative serology for HIV. Absolute numbers of CD19+, CD3+, CD4+, CD8+, NK and NKT cells, functional T helper subpopulations (Th1/Th2/Th17), CD4+ and CD8+ memory cell subsets and expression of CTLA-4, PD-1, CD69 and Ki-67 on CD4+ and CD8+ T cells were assessed by flow-cytometry. Results. HL pts with advanced disease had lower lymphocyte counts compared to controls (median 0.9 vs 1.7 x 10^9/L, p=0.01) while no difference was observed for pts with limited disease. Compared to controls, HL pts had lower CD19+ cell numbers irrespective of disease stage (0.075 vs 0.05 x 10^9/L in pts with limited and advanced disease vs 0.19 x 10^9/L in controls, p=0.009 and p= 0.0003, respectively). Pts with advanced disease had also significantly lower numbers, compared to controls, of CD3+ (median 0.78 vs 1.36 x 10^9/L, p=0.04), CD4+ (median 0.3 vs 0.5 x 10^9/L, p=0.04), Tregs (median 0.008 vs 0.017 x 10^9/L, p=0.004), Th2 (median 0.18 vs 0.28 x 10^9/L, p<0.05) and Th17 cells (median 0.03 vs 0.08 x 10^9/L, p=0.006), while no difference was observed for Th1. HL pts had lower numbers of naive CD8+ cells irrespective of disease stage, while central memory CD4+ cells were lower in advanced disease. No difference was observed with regard either to the numbers of proliferating (Ki67+) or PD-1- and CTLA-4-expressing CD4+ and CD8+ cells. On the other hand, CD69+CD4+ cells were significantly higher in pts with limited disease compared to controls (median 0.04 vs 0.01 x 10^9/L, p=0.04). Conclusions. These observations suggest that the immune microenvironment in HL plays a role that is far from being only local. Further studies are ongoing in larger cohorts of pts.
  • Palma M
  • Heimersson K
  • Näsman-Glaser B
  • Hansson L
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P044 (P044)

SIP-F1: A new gray zone lymphoma cell line?

Lymphoid cancers are mainly classified according to their clinical presentation, morphology, immunology and molecular genetic features. Diagnosis of Hodgkin lymphoma (HL) is mainly based on pathognomonic Hodgkin and Reed-Sternberg cells (HRS). However, in the group of non-Hodgkin lymphomas (NHL), diffuse large B-cell lymphoma (DLBCL) can resemble typical features of HL. In some cases, a diagnostic pitfall exists at the interface of HL and DLBCL, so that, morphological overlaps and missing clear-cut diagnostic criteria complicate classification of these so-called gray zone lymphomas (GZL). In a recent study, we analyzed a newly established GZL cell line (SIP-F1) derived from a lymph node biopsy of a male 20-year-old lymphoma patient. Histological sections of the primary GZL were characterized by striking pleomorphism of in part multinuclear blast infiltrates and areas of necrosis. Immunohistochemistry revealed tumor cell positivity for the markers CD15, CD20 and CD30. SIP-F1 presented clonal Ig gene rearrangement and flow cytometry analysis showed expression of B-cell markers as well as 50-60% positivity for HL marker CD30. In addition, we observed tumor growth of SIP-F1 in a xenograft mouse model, morphologically resembling the primary tumor with lacunar HRS-like cells growing in sheets. For closer characterization, we performed gene expression profiling (GEP) and compared SIP-F1 to several B-cell lymphoma cell lines. The GEP of SIP-F1 did not cluster with any of the compared entities. Interestingly, but yet quite surprisingly, cytogenetic analysis revealed a normal karyotype. As SIP-F1 is positive for EBV, the cell line probably displays more a transformed B-cell clone than a GZL cell line. The patient, SIP-F1 is derived from, showed fast tumor rejection after initialization of chemotherapy. We were able to receive T cells for a co-culture study and could show that his immune system regained anti-tumor strength. In conclusion, considering the paucity in prospective differentiation of GZL cases, their distinct clinical behavior and treatment, we think that SIP-F1 could be a helpful tool to study morphological and molecular features of GZL and to better understand the biology of these unusual cases, although we are still tackling the question, what is the real tumor cell clone.
  • Rengstl B
  • Hartmann S
  • Eberth S
  • Döring C
  • Pommerenke C
  • Becker PSA
  • Weiser C
  • Warner K
  • Doering C
  • Seidl C
  • Küppers R
  • Abken H
  • MacLeod RA
  • Drexler HG
  • Hansmann ML
  • Newrzela S
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P045 (P045)

CD4 lymphopenia as a prognosis factor in previously untreated Hodgkin lymphoma

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P046 (P046)

Can plasma chemokines and soluble receptor monitoring predict outcome in classical Hodgkin’s Lymphoma (cHL) patients?

The usual prognostic scores used in cHL fail to identify some patients with worst outcome either in early or advanced stage HL. Pre-treatment cytokines, soluble receptor, cytokine signature (Casasnovas JCO 2007) and TARC profile have been described as biological markers correlated to tumour burden, to response and outcome. To evaluate the impact of TARC, IL6, IL1-RA, sCD30 and TNF-R1 levels on response and outcome, we collected plasma from 50 newly diagnosed cHL patients at baseline, during therapy and at the end of chemotherapy. We also analysed the correlation of usual prognostic factors with cytokines and soluble receptor level. Between April 2010 and November 2013, 50 cHL patients were enrolled (26 M/ 24F), median age was 31 years (18,5-63). Main clinical characteristics were as follow: stage I-II in 24 patients (according to EORTC classification: favourable: 7 and unfavourable: 17) and stage III-IV in 26 patients (IPS 1-2: in 15 patients). Thirty five patient were treated with ABVD and 15 patients with eBEACCOP. Radiotherapy was added in 24 patients. Mean TARC level was 281 pg/ml (27-83098), mean IL6 level was 2.9 pg/ml (0,6-175), mean IL1-RA was 252 pg/ml (0,9-6609), mean sCD30 level was 33 U/ml (8,8-1007), and mean TNR-F1 level was 2129,5 ng/ml (314-8463). Baseline cytokines level or cytokines signature did not correlate significantly with any clinical or biological factors nor with FDG-PET response. Ten patients disclosed relapse or progressive disease (R/R), only two patients died. With a median follow-up of 48 months, the event free survival (EFS) and overall survival (OS) at 3 years are 82% (95% CI 68-90) and 96% ( 95% CI 85-99) respectively. None of the classical prognostic factors as early response evaluated with FDG-PET were correlated with PFS. Neither baseline cytokines levels nor cytokine signature or early reduction of IL1-RA, sCD30, TNR-F1 level impacted significantly the outcome, but a trend was noted with early reduction of TARC and IL6. The decrease of TARC and IL6 seems to predict response to therapy and EFS. Unfortunately we failed to demonstrate any correlation between baseline cytokines or cytokine signature with biological or clinical characteristics, and outcome in this population. Surprisingly none of the usual prognostic factors predict outcome. These results could be perhaps explained by the small number of patients and should be confirmed in a larger prospective study.
  • Stamatoullas A
  • Perdrix A
  • Lemasle E
  • Thill C
  • Camus V
  • Veresezan L
  • Picquenot JM
  • Menard AL
  • Lenain P
  • Contentin N
  • Lanic H
  • Lepretre S
  • Brehar O
  • Cardinael N
  • Fontura ML
  • Fronville C
  • Jardin F
  • Bastard C
  • Tilly H
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P047 (P047)

Expression and prognostic impact of indoleamine 2,3-dioxygenase in Hodgkin’s lymphoma

Background: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. IDO is a key factor maintaining immune tolerance and expression correlates with poor clinical outcome in different types of cancer and hematological malignancies. Nowadays, not enough attempts have been made to evaluate IDO expression and its prognostic score value. We assessed the impact of the IDO expression on clinical outcome in patients with Hodgkin lymphoma (HL). Methods: The case group included 23 patients (5 male and 18 female) with HL (median age: 19-60 years, range: 39.5). With early stage were diagnosed 52.2% and 47.8% with advanced. Only 26% cases had B-symptoms. ABVD or BEACOPP (14/esc) were administered as a first-line therapy. In 65.2% and 34.8% cases, achievement remission and progression disease after treatment, respectively. The relative mRNA expression levels of IDO were measured in pre-treatment tumor tissue specimens from HL patients using real-time qPCR analysis. Results: The mRNA expression of IDO was found in 15 cases (65.2%) and further this group was considered as IDO-positive. The presence of IDO expression was significantly associated with advanced stage of disease and B-symptoms (p<0.05). The relapse was more frequently found in cases with IDO+ compared IDO- HL (30.47% versus 4.3%, p< 0.05). 13% patients with IDO+ expression died and had an early relapse or refractory disease. ROC analysis revealed that IDO+ expression in the tumor is an important marker which is associated with reduced progression-free (PFS) and overall survival (OS) in HL patients (Se=87.5 %; Sp=78 %; AUC=0.85). 5-year PFS for patients with IDO+ expression was 44% versus 89% of IDO- expression (p=0.0003). Two-sample comparison between the IDO+ versus IDO- expression was done by the Cox F-test. The difference was significant for PFS and OS (p=0.03). Conclusions: The obtained results suggest that the IDO-positive expression can predict clinical outcome in patients with HL and seems to be promising for the future studies.
  • Kryachok I
  • Novosad O
  • Skrypets T
  • Ulianchenko K
  • Tytorenko I
  • Khranovska N
  • Skachkova O
  • Svergun N
  • Gorbach O
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P048 (P048)

Reed-Sternberg Cells on Bone Marrow Cytology: The Very Early Feature on Hemophagocytic Lymphohistiocytosis Associated to Hodgkin Lymphoma

I] Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from primary or acquired immune dysfunction. In adults, HLH is most frequently associated to infections, autoimmune diseases, and lymphomas, although Hodgkin lymphoma (HL) has been less frequently described. This immune activation leads to a variety of clinical and laboratory features, including pancytopenia, which makes bone marrow examination an important tool in order to identify possible trigger factors for HLH. II] Case presentation: A 53 year-old white female, was referred to the Hospital das Clínicas de Botucatu –UNESP (São Paulo, Brazil) with a 4-day history of mental confusion. She had no palpable lymphadenomegaly, hepatosplenomegaly or abdominal mass. Complete blood count showed markedly pancytopenia. Lactate dehydrogenase was normal and serum ferritin was 9.621 mg/dl. Bone marrow (BM) cytology evaluation showed markedly hemophagocytosis and some large cells were identified as “Owl Eye Cell” and “Mononuclear Hodgkin’s Cells”. The bone marrow clot evaluation showed frequent epithelioid granulomas, without necrosis, and bi-nucleated and mononuclear cells with large nuclei and evident nucleoli, featuring classic Reed-Sternberg cells and Hodgkin’s cells. Immunohistochemistry confirmed the diagnosis of bone marrow infiltration by HL with granulomatous reaction. The Ziehl-Neelsen and Grocott-Gomori stains were negative. III] Discussion: BM cytological evaluation is immediately required in cases of pancytopenia for diagnostic purpose, regardless the level of blood counts. Especially in HLH, it is part of a systematic front-line clinical investigation for possible immune triggers. Epithelioid granulomas in BM or lymph nodes of patients with a nonspecific clinical presentation is a diagnostic challenge as it can be associated with a variety of autoimmune, inflammatory and neoplastic conditions. HL can present with granulomas in about 14% of cases, although it is unusually seen in BM biopsy. In this context, a careful morphological analysis with immunohistochemistry study is highly recommended considering that the absence of a typical HL presentation can sometimes postpone diagnosis and compromise disease outcome. IV] Conclusion: This case highlights the importance of prompt investigation of pancytopenia in the context of HLH, with an early diagnosis of HL being made by BM cytology in a patient with no other symptoms that could suggest lymphoma.
  • Niero-Melo L
  • Lustri LA
  • Polegatto BF
  • Del Castanhel C
  • Cantadori LO
  • Oliveira CC
  • Gaiolla RD
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P048B (P048B)

A novel PTPN1 splice variant regulates JAK/STAT activity in classical Hodgkin’s lymphoma cells

Background Chronic activation of the Janus kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) signaling pathways is a hallmark of a variety of B cell lymphomas including the classical Hodgkin’s lymphoma (cHL). Constitutive JAK/STAT signaling is crucial for survival and proliferation of Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of cHL. Although the exact molecular basis of this constitutive JAK/STAT signaling in cHL has not been understood completely, accumulating reports highlight the role of an inactivation or reduced expression of negative JAK/STAT regulators like Silencer of Cell signaling 1 (SOCS1) or Protein-Tyrosine Phosphatase 1B (PTP1B) in this process. Given the essential role of PTP1B and SOCS1 for the constitutive JAK-STAT signaling in cHL, the identification and characterization of the regulatory mechanisms controlling the activity of these negative JAK/STAT regulators is crucial for the understanding of their role for the pathogenesis of cHL. Here, we report the expression of different truncated PTP1B mRNA variants identified in cHL cell lines and primary cHL tumor samples lacking either one or several exon sequences. We describe the expression of a shorter PTP1B isoform in cHL as a novel negative control mechanism for PTP1B involved in the dis-regulation of the JAK-STAT pathway. Methods PTP1B mRNA of cHL cases and cell lines was isolated and sequenced by Sanger sequencing. PTP1B protein expression was determined by western blot and immunohistochemistry analyses. Expression analysis of PTP1B mRNA variants was done by qPCR. To determine the role of PTP1BΔ6 for JAK/STAT signaling, stably transfected L428 cell clones either expressing PTP1BWT, PTP1BC215S, or PTP1BΔ6 were generated. Functional analysis of the novel PTP1BΔ6 variant was achieved by western blot analysis using phospho-STAT antibodies, luciferase reporter analysis and EMSA. The impact of the PTP1B variants on cell proliferation was examined by MTS assays. Results In order to determine the molecular basis of the reduced or absent PTP1B expression in selected cHL cases, we isolated and sequenced the PTP1B mRNA. In contrast to the previously published study highlighting inactivating point mutations in the PTP1B gene of PMBL and cHL cases, we obtained a set of PTP1B variants which lack different exon sequences. One of these novel PTP1B variants, lacking exon 6 (PTP1BΔ6), was found to be expressed at low levels in cHL cell lines. However, serum stimulation of cHL augmented the expression of PTP1BΔ6 significantly. Functional characterization of PTP1BΔ6 revealed a positive impact on IFNγ and IL-4 induced JAK/STAT activity in HEK293 or HEK293-STAT6 cells, and on the basal STAT activity in stably transfected L-428 and U-HO1 cHL cell lines. Furthermore, PTP1BΔ6 expression increased the proliferation of L-428 and U-HO1 cells and the reduced cytotoxic effect of the chemotherapeutical agents gemcitabine and etoposide distinctively. Conclusions Collectively, these data suggest that the activity of PTP1B in cHL is regulated by different molecular mechanisms including the expression of shorter PTP1B variants like the novel PTP1BΔ6 variant which acts as a positive regulator of JAK/STAT signaling in cHL.
  • Zahn M
  • Marienfeld R
  • Melzner I
  • Heinrich J
  • Rehm A
  • Barth TF
  • Dorsch K
  • Brüderlein S
  • Möller P
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P026 (P026)

Hodgkin cell-derived extracellular vesicles shape fibroblast activity

abstract talk Abstract Talk in Genetics and Microenvironment (Saturday, 22.10. 16:00)

In Hodgkin lymphoma (HL) the malignant cells are greatly outnumbered by non-malignant immune cells supporting tumor growth and progression. Hodgkin Reed Sternberg (HRS) cells grow highly dependent on the microenvironment, which is actively shaped by a very complex cross-talk between the tumor cells and the reactive infiltrate. HRS cells secrete cytokines and angiogenic factors capable of recruiting and inducing the proliferation of surrounding cells to finally orchestrate their cellular microenvironment and to inhibit the development of an efficient antitumor immune response. Within this scenario, the role of extracellular vesicles (EVs) released by HRS cells which can communicate with other cells in trans has not been addressed yet. Recently, we demonstrated that EVs released by HRS cells impact on the formation of a tumor supportive niche by stimulating IL-8 release. Here, we investigate the role of tumor cell-derived vesicles on fibroblast activity and thus their impact on creating a tumor favorable surrounding. With single and co-cultures of the malignant cells and healthy stromal cells, the reciprocal effects on their cellular functions were analyzed. Using Fibroblast mediated eotaxin as a marker we could show that the bi-directional cross-talk is not entirely cell-cell contact dependent. Not only soluble factors, but also EVs had a positive effect on migration and chemotaxis, showing concentration depending effects. EVs released by malignant cells are internalized by fibroblasts and induce an inflammatory phenotype, which resembles the phenotype of cancer associated fibroblasts (CAFs). As a result of EV exposure, fibroblasts show selective changes in the secretome with enhanced expression of pro-inflammatory cytokines and hits related to NFκB-Signaling. Further experiments indicate that in this context, NFκB-Signaling is induced by TNF-α transported via EVs. Results are further supported by in vivo experiments using a HL Xenograft model.
  • Bösl T
  • Hansen HP
  • Engert A
  • Pogge von Strandmann E
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P030 (P030)

The lymphoid cell specific transcription factor ELF-1 is transcriptionally downregulated and recurrently deleted in classical Hodgkin lymphoma (cHL)

abstract talk Abstract Talk in Genetics and Microenvironment (Saturday, 22.10. 16:00)

ELF-1 and ELF-2 belong to the ETS-family of transcription activators or repressors implicated in processes recurrently deregulated in human neoplasms. Recently, we have shown that genes hypermethylated in cHL are enriched for binding sites of ETS-family members ETS-1 (1.28 fold), ELF-1 (1.07 fold) and ELF-2 (1.91 fold). We hypothesized that hypermethylation of genes in cHL might be secondary towards genomic alterations of these B-cell related transcription factors. In line, we have recently reported recurrent alterations and significant downregulation of ETS-1 expression in cHL. Encouraged by this finding, here we analyzed the two other ETS family members in cHL. We show significant downregulation of ELF-1 (8.82 fold, p<0.0001, tag 40067_at) and 1.36 fold of ELF-2 (tag 507_s_at) in cHL cell lines (n=4) compared to GCB pools (n=20) (U95 microarray). This was further validated for ELF-1 in primary biopsies where using immunohistochemistry (AB99401) we observed loss or downregulation of the protein in HRS cells in 26/35 (74%) cases but not in no-tumor bystander cells. In case of ELF-2 no reduction of protein abundance was observed. To identify the underlying mechanism we sequenced the ELF-1 coding region in 7 cHL cell lines but no mutations were identified. In contrast, we analyzed copy number (CN) alterations of the ELF-1 locus in primary biopsies using combined immunophenotyping and in situ hybridization (FICTION) and identified deletions in 5/11 (45%) analyzed cases. Similarly, deletions or LOH were found in 4/7 (57%) cHL cell lines (Affymetrix SNP 6.0 array). Also epigenetic mechanism may contribute to ELF-1 downregulation as using next-generation miRnome sequencing we observed 3.26 fold overexpression (p=0.0018) of the hsa-miR-330-3p in cHL cell lines (n=7) compared to non-Hodgkin lymphomas (n=10). Hsa-miR-330-3p shows significant affinity (p=0.0013) towards the 3’UTR region of ELF-1 basing on in silico analysis (miRWalk). In conclusion, we show recurrent loss of ELF-1 expression in HRS cells that at least in part is attributable to the genomic deletions and overexpressed hsa-miR-330-3p. Moreover, our data support the concept, that downregulation of the ELF-1 transcription factor may lead to consequent hypermethylation and silencing of its target genes contributing to the loss of B-cell phenotype of HRS cells.
  • Giefing M
  • Zemke N
  • Bodnar M
  • Domanowska E
  • Janiszewska J
  • Paczkowska J
  • Ustaszewski A
  • Martin-Subero JI
  • Ammerpohl O
  • Klapper W
  • Marszalek A
  • Siebert R
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P036 (P036)

Tightly regulated FOXO3 expression is critical for the maintenance of cHL

abstract talk Abstract Talk in Genetics and Microenvironment (Saturday, 22.10. 16:00)

FOXO (forkhead box O) transcription factors regulate genes involved in cell cycle arrest, apoptosis, or oxidative stress response. Recently, we have shown that FOXO1 is specifically repressed in classical Hodgkin lymphoma (cHL) and thus acts as a tumor suppressor in this tumor entity. In contrast, FOXO3 was reported to be markedly expressed in the malignant Hodgkin and Reed-Sternberg (HRS) cells of cHL, but not in other B-cell lymphoma subtypes. We confirmed a high FOXO3/FOXO1 ratio in cHL by analysing publically available gene expression profiling (GEP) data and found that this ratio is similiar to those of plasma cells (PC) and multiple myeloma (MM). Of note, cHL FOXO3 expression was higher than in non-HL, but still less than in terminally differentiated MM cell lines. These intermediate FOXO3 levels might reflect the „abortive PC differentiation“ phenotype of cHL. Moreover, analysis of GEP data of microdissected HRS cells revealed a positive correlation between FOXO3 and PRDM1 expression, the master regulator of PC differentiation and a tumor suppressor in cHL. This is similar to our previously published findings showing that FOXO1 regulates PRDM1α, the active isoform of PRDM1. Using ChIP, we next proved that FOXO3, too, directly binds to the PRDM1α promoter in cHL. To further investigate this interaction, we overexpressed a constitutively active variant of FOXO3 (FOXO3(A3)ER) in cHL cell lines. FOXO3 activation increased PRDM1α expression levels and inhibited proliferation of cHL cell lines. So far, frequent genomic deletions are known to restrict FOXO3 levels in cHL. Aiming to identify additional factors involved in the tight regulation of FOXO3 in cHL, we found that miR-155 negatively influences FOXO3 expression. Paradoxically, knockdown of FOXO3 with the help of a specific shRNA also showed an antitumor effect in two of three cHL cell lines, whereas FOXO1 downregulation was not toxic. Our data suggest that intermediate levels of FOXO3 contribute to abortive PC differentiation of cHL and that tightly regulated FOXO3 expression might be critical for the oncogenic program of cHL.
  • Weitzer CD
  • Xie L
  • Guan H
  • Herrmann F
  • Pick S
  • Wirth T
  • Ushmorov A
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T004 (T004)

Analysis of the mutational landscape and dynamics in Hodgkin Lymphoma using NGS

abstract talk Abstract Talk in Biology and Microenvironment (Monday, 24.10. 08:30)

Few studies have been aimed to the identification of driver mutations in classical Hodgkin Lymphoma (cHL), and only occasional gene mutations in members of the NF-kappaB and JAK/STAT pathways, and, more recently B2M, have been previously described. We analyzed 57 cHL tumor samples (FFPE) using massive parallel sequencing (Ion Torrent™ semiconductor technology). To increase coverage a previous tumor cell enrichment process by punch tissue cores from selected tumor-rich areas was implemented. In addition, we have also analyzed an independent group of 12 patients with primary refractory cHL (patients that did not achieve complete response after first line ABVD, or who presented with primary progressive disease), using the same methodology for NGS, but with an enrichment procedure based on laser microdissection of HRS cells (CD30+). Overall, the results show very high genomic heterogeneity with a range of 10-400 SNVs per sample, most of them (~60%) missense type. We found a relatively large number of genes recurrently mutated at low frequency and only a few genes mutated in up to 15-20% of the patients, reflecting a high level of genomic instability in the neoplasm. Specific mutations in genes previously described in cHL (NFKBIA, TNFRSF14) and in diffuse large B-cell lymphomas (CARD11, STAT6, CREBBP, CMYB) were consistently found, as well as new SNVs in genes not previously described (STAT6, BTK, NFKB2). Of note, we found high prevalence of mutations affecting BTK and the BCR pathway, suggesting some dependencies of active BCR signaling albeit the absence of BCR expression by HRS cells. Consistent with this interpretation, incubation of a panel of cHL cellular models with either Ibrutinib or AVL-292, selective-BTK inhibitors, in vitro constrains cell proliferation and causes cell death. Indeed, gene expression and GSEA analysis of the cHL HDML-2 cell line showed a similar basal BCR pathway activation levels than the HBL1 DLBCL cell followed by an intense inhibition after ibrutinib incubation. In conclusion, cHL is characterized by high genomic instability, including numerous mutations in genes related with B-cell function and specific signaling pathways. Pathogenic predictions of the different SNVs identify potential driver mutations that can be associated with the pathogenesis of the disease and might represent new therapeutic targets.
  • Mata E
  • Díaz-López A
  • Montalban C
  • Fernandez R
  • Bellas C
  • Burgos F
  • Mestre MJ
  • Menárguez J
  • Provencio M
  • Santonja C
  • Piris MA
  • Garcia JF
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T005 (T005)

High expression of programmed cell death receptor 1 (PD-1) in the tumor microenvironment is associated with inferior event free survival in classical Hodgkin Lymphoma

abstract talk Abstract Talk in Biology and Microenvironment (Monday, 24.10. 08:30)

Award winning Young Investigator Award

Immune checkpoint inhibition targeting the programmed cell death receptor 1 (PD-1) pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Use of PD1-inhibitors may be justified early on in selected patients if patients with high risk of treatment failure could be identified at the time of diagnosis. Our aim was to investigate the prognostic impact of PD-1 expression in tumor infiltrating lymphocytes in diagnostic cHL biopsies. Patients from Aarhus, Denmark (n=283) diagnosed 1990-2006 aged 15-86, and Sweden (n=132) diagnosed 1999-2002 aged 18-74 were included. The patients were mostly treated with chemotherapy (mainly ABVD) ± radiotherapy. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1 and the percentage of positive cells was estimated using a digital image analysis program. Fifty-seven patients (15%) presented with a high expression of PD-1, defined as ≥10% positive lymphocytes in the tumor microenvironment. Overall survival (OS) and event free survival (EFS) (treatment failure or death from any cause) were analyzed using log rank test and Cox proportional hazards regression. The median follow-up time was 10.8 years. Among patients with a high expression of PD-1 there were 29 (51%) events, and among those with a low expression 104 (32%)(Figure 1). A high PD-1 expression was associated with an inferior EFS (age-adjusted hazard ratio (HR)=1.69; 95% confidence interval (95%CI) 1.12-2.54), an observation which persisted also in a fully adjusted analysis (adjusted for age, albumin <40g/L, B-symptoms, bulky tumor, country, extranodal tumor involvement, sex, stage IIB-IV, and white blood cell count >15x109/L) (HR=1.80; 95%CI 1.19-2.90). High PD-1 was not significantly associated with worse OS. There was a weak correlation between high expression of PD-1 and intratumoral Epstein-Barr virus negativity (Spearman correlation coefficient 0.12, p=0.015), and nodular sclerosis histologic subtype (correlation coefficient 0.10, p=0.04). This is the first study to show that high expression of PD-1 in the tumor microenvironment of cHL is associated with inferior EFS (fully adjusted multivariate analyses). Patients with high expression of PD-1 have a tumor permissive exhausted immune system and may therefore be more likely to experience treatment failure after conventional treatment regimens.
  • Hollander P
  • Peter P
  • Smedby KE
  • Enblad G
  • Mortensen J
  • Amini RM
  • d´Amore F
  • Molin D
  • Glimelius I
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T006 (T006)

The AP-1 transcription factor BATF3 regulates MYC expression and is required for tumor cell survival in classical Hodgkin Lymphoma and anaplastic large cell lymphoma

abstract talk Abstract Talk in Biology and Microenvironment (Monday, 24.10. 08:30)

Award winning Young Investigator Award

The malignant cells in classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) are characterized by deregulated transcription factor activity of several signaling pathways including constitutive active JAK/STAT and AP-1. Our group and others have performed gene expression profiling (GEP) of cHL and ALCL and identified BATF3, a member of the AP-1 transcription factor family, as one of the most up-regulated genes in cHL and ALCL cells. In the present study, up-regulated expression of BATF3 was confirmed at mRNA and protein level in cHL and ALCL cells. To assess BATF3 function, small hairpin (sh)RNA vectors against BATF3 were generated to downregulate BATF3 in lymphoma cell lines. Transduction experiments demonstrate that downregulation of BATF3 leads to reduced cell proliferation and induced apoptosis in cHL and ALCL cell lines. To identify BATF3-regulated targets in BATF3-knockdown cells, GEP was performed. GEP after BATF3 knockdown demonstrated a significant downregulation of known MYC target genes and immunoblot analysis confirmed downregulation of MYC in shBATF3-transduced cells. Chromatin-immunoprecipitation (ChIP) experiments demonstrated that BATF3 regulates MYC expression by binding to an AP-1 element present in the MYC promoter. To examine whether BATF3 activity was connected to the constitutive JAK/STAT activation in cHL and ALCL, we treated cHL and ALCL cell lines with the JAK2 inhibitor TG101348 and found decreased levels of BATF3 protein, suggesting that BATF3 is regulated by STAT factors. Additionally, activation of JAK/STAT signaling by interleukin stimulation induced BATF3 expression in cHL and ALCL cell lines. ChIP experiments validated STAT binding to the BATF3 promoter, indicating that STATs directly regulate BATF3 expression. In conclusion, we recognized a new oncogenic axis in cHL and ALCL and revealed a complex transcription factor network in which BATF3 links STAT signaling to MYC expression.
  • Lollies A
  • Hartmann S
  • Schneider M
  • Bracht T
  • Arnolds J
  • Klein-Hitpass L
  • Sitek B
  • Hansmann ML
  • Küppers R
  • Weniger MA

Early Stages

Selected for Oral Presentation

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    T010 (T010) Long-term follow-up of contemporary treatment in early-stage favorable Hodgkin Lymphoma (HL): updated analyses of the German Hodgkin Study Group HD7 and HD10 trial

    • Sasse S
    • Bröckelmann PJ
    • Görgen H
    • Plütschow A
    • Mueller H
    • Kreissl S
    • Bürkle C
    • Borchmann S
    • Fuchs M
    • Borchmann P
    • Engert A
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    T012 (T012) Results of US intergroup trial of response-adapted chemotherapy or chemotherapy/radiation therapy based on PET for non-bulky stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)

    • Straus DJ
    • Pitcher B
    • Kostakoglu L
    • Grecula JC
    • Hsi ED
    • Schoder H
    • Jung SH
    • Popplewell LL
    • Chang JE
    • Moskowitz CH
    • Wagner-Johnson N
    • Leonard JP
    • Friedberg JW
    • Kahl BS
    • Cheson BD
    • Bartlett NL

Posters

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    P049 (P049) Long-Term Follow-Up of Contemporary Treatment in Early-Stage Unfavorable Hodgkin Lymphoma (HL): Updated Analyses of the German Hodgkin Study Group HD8 and HD11 Trial

    • Sasse S
    • Bröckelmann PJ
    • Görgen H
    • Plütschow A
    • Mueller H
    • Kreissl S
    • Bürkle C
    • Borchmann B
    • Fuchs M
    • Borchmann P
    • Engert A
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    P050 (P050) Final Results of a Quality Assurance Program within the German Hodgkin Study Group HD13/14 trial – A report from the radiotherapy reference panel integrating modern guidelines

    • Eich HT
    • Kriz J
    • Plütschow A
    • Engenhart-Cabillic R
    • Haverkamp U
    • Herfarth K
    • Lukas P
    • Schmidberger H
    • Staar S
    • Baues C
    • Fuchs M
    • Engert A
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    P051 (P051) Clinical outcome of patients with early stage favorable Hodgkin lymphoma treated with ABVD x 2 cycles followed by PET/CT restaging and 20 Gy of involved-site radiotherapy

    • Kamran SC
    • Jacene HA
    • Chen YH
    • Mauch PM
    • Ng AK
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    P052 (P052) Optimized “butterfly” VMAT reduces mean dose to coronary arteries for early stage HL patients undergoing mediastinal radiotherapy

    • Filippi AR
    • Levis M
    • Girardi A
    • Fiandra C
    • Piva C
    • Donegani I
    • Ragona R
    • Ricardi U
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    P053 (P053) Biological evaluation in the treatment planning. Is there a use for patients with Hodgkin’s Lymphoma?

    • Kriz J
    • Haverkamp U
    • Pepper N
    • Elsayad K
    • Kröger K
    • Reinartz G
    • Glashörster M
    • Kittel C
    • Eich HT
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    P054 (P054) The effect of deep inspiration breath hold (DIBH) Intensity-Modulated Radiation Therapy (IMRT) on sparing healthy tissues in the treatment of lymphoma involving the mediastinum

    • Eastman B
    • Uhl J
    • Mosienko V
    • Murphy J
    • Sanghvi P
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    P055 (P055) Multicentric Italian Experience in Treatment of Nodular Lymphocyte Predominant Hodgkin lymphoma (NLPHL) in the Rituximab Era

    • Gotti M
    • Merli F
    • Re A
    • Rusconi C
    • Pulsoni A
    • Rigacci L
    • Merli M
    • Liberati M
    • Ferretti V
    • Zoboli V
    • Fama A
    • Dalceggio D
    • Meli E
    • Annechini G
    • Puccini B
    • Ferrario A
    • Appolloni V
    • Sciarra R
    • Frigeni M
    • Arcaini L
    • Bonfichi M
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    P056 (P056) Construction of a Decision Model to Aid Treatment Choices for Early Stage Hodgkin Lymphoma (ES HL): Bringing Survivorship Forward

    • Kelly MJ
    • Parsons SK
    • Cohen JT
    • Castellino SM
    • Kelly KM
    • Keller F
    • Henzer TJ
    • Kumar A
    • Johnson P
    • Meyer RM
    • Morton LM
    • Radford J
    • Raemaekers J
    • Hodgson DC
    • Evens AM
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    P057 (P057) Doses to organs at risk at different modes of 3D-conformal radiotherapy for mediastinal stage II Hodgkin Lymphoma (HL)

    • Ilyin NV
    • Vinogradova JN
    • Ivanova EI
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    P058 (P058) Residual site radiation therapy (RS RT): An opportunity to increase safety of combined modality therapy (CMT) for early stage Hodgkin lymphoma (HL)

    • Straus DJ
    • Cahlon O
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    T011 (T011) Proton radiotherapy for mediastinal Hodgkin Lymphoma: single institution experience

    • Dedeckova K
    • Mocikova H
    • Markova J
    • Gaherova L
    • Kantorova I
    • Ondrova B
    • Vondracek V
    • Vitek P
    • Kubes J
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P049 (P049)

Long-Term Follow-Up of Contemporary Treatment in Early-Stage Unfavorable Hodgkin Lymphoma (HL): Updated Analyses of the German Hodgkin Study Group HD8 and HD11 Trial

Background: Combined modality treatment (CMT) is currently considered standard of care in patients with early-stage unfavorable HL. By gradually increasing chemotherapy intensity an improvement of treatment efficacy and by reducing radiotherapy intensity a reduction of toxicity were attained. Long-term follow-up (FU) is needed to ensure the safety and efficacy of the applied therapies. Methods: We analyzed updated FU data of 2459 patients with early-stage unfavorable HL treated in the HD8 and HD 11 trial. In HD8 patients were randomized to either 30Gy IF- or extended-field (EF)-RT after 2xCOPP/ABVD and in HD11 patients received 20 or 30Gy IF-RT after 4xABVD or 4xBEACOPPbaseline. Progression-free (PFS) and overall survival (OS) were analyzed according to the Kaplan-Meier method. Cumulative incidences of secondary neoplasias (SN) were calculated and compared between groups using Pepe & Mori’s test. Results: The median FU was 153 and 106 months for patients in HD8 (n=1064) and HD11 (n=1395), respectively. New FU data were available for less than 50% of patients and last information was obtained from population registries in 23-27%. In HD8, non-inferiority of IF- compared to EF-RT was confirmed with HRs of 0.98 (95% confidence interval CI: 0.76-1.25) and 0.88 (CI:0.66-1.16) for PFS and OS, respectively. We observed a non-significant trend towards more SN (15-year cumulative incidence 17.1% versus 14.2%, respectively, p=0.3) and deaths from SN after EF-RT versus IF-RT. In HD11, no difference in PFS was found with BEACOPPbaseline compared to ABVD when followed by 30Gy IF-RT (HR: 1.1 (CI: 0.7-1.5)). In contrast, there was a significant difference in 10-year PFS rates estimated at 77.6% versus 83.3% in ABVD-treated patients who had received 20Gy instead of 30Gy IF-RT with a HR of 1.5 (CI: 1.0-2.1). After BEACOPPbas, 20Gy were non-inferior to 30Gy IF-RT with a HR of 1.0 (CI: 0.7-1.5) for PFS. No differences in terms of OS or SN were observed. Summary: Moderate intensification of chemotherapy does not improve the outcome but might facilitate the reduction of IF-RT-dose. Continued FU is necessary to assess long-term toxicity of the applied treatment strategies. 10-year PFS and OS estimates in early-stage unfavorable HL treated with 4xABVD + 30Gy IF-RT leave room for improvement.
  • Sasse S
  • Bröckelmann PJ
  • Görgen H
  • Plütschow A
  • Mueller H
  • Kreissl S
  • Bürkle C
  • Borchmann B
  • Fuchs M
  • Borchmann P
  • Engert A
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P050 (P050)

Final Results of a Quality Assurance Program within the German Hodgkin Study Group HD13/14 trial – A report from the radiotherapy reference panel integrating modern guidelines

Introduction: Since the foundation of the German Hodgkin Study Group (GHSG) in 1978 a central radiotherapy (RT) reference centre was established to evaluate and to improve the quality of treatment. During the study generations the quality assurance programs (QA) were continuously adapted and refined. The purpose of this analysis is to show the results of the work within the fifth study generation (HD13/14) and to demonstrate the establishment of a QA including modern RT-techniques e.g. intensity modulated RT (IMRT), image guided RT (IGRT) and involved node RT (IN-RT). Methods: With the fourth study generation (HD10-12) a central prospective review of all diagnostic imaging to create an individual treatment plan for every study patient was established in early stages and the quality of involved field RT was evaluated by an expert panel of radiation oncologists retrospectively. In the era of modern conformal RT this QA-program had to be adapted fundamentally and within several meetings a new process of evaluation has been developed. The findings were compared to the results of the QA within the fifth study generation (HD13-15). Results: The expert panel analyzed the RT-parameters of 1037 (28%) patients (HD13 n=465, HD14 n=572). In 85% simulation films and in 87% verification films were available. RT was assessed as unacceptable in 46% (HD13= 38%, HD14=52%), acceptable in 9% (HD13= 9%, HD14= 9%) and according to the protocol in 45% (HD13= 52%, HD14= 38%). These findings were compared to a data set of eleven patients treated within the sixth study generation (HD16-18) which was reviewed using the “new” revised QA-program including criteria for conformal techniques. Conclusion: The value for QA of RT within the GHSG trials is well known. To develop a QA-program of modern RT the expert panel defined criteria for analyzing current RT-procedures. With this schedule the QA of the GHSG serves as a model for other study groups.
  • Eich HT
  • Kriz J
  • Plütschow A
  • Engenhart-Cabillic R
  • Haverkamp U
  • Herfarth K
  • Lukas P
  • Schmidberger H
  • Staar S
  • Baues C
  • Fuchs M
  • Engert A
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P051 (P051)

Clinical outcome of patients with early stage favorable Hodgkin lymphoma treated with ABVD x 2 cycles followed by PET/CT restaging and 20 Gy of involved-site radiotherapy

The publication of the GHSG HD10 trial changed the treatment paradigm for early-stage, favorable Hodgkin lymphoma (HL). Two cycles of ABVD followed by 20 Gy of involved-field radiotherapy (IFRT) has become a widely accepted treatment strategy for these patients. However, PET/CT is now increasingly used for response assessment after chemotherapy, and IFRT has largely been replaced by involved-site radiotherapy (ISRT). In this study, we describe our experience of 2 cycles of ABVD followed by PET/CT assessment, and ISRT to 20 Gy for patients with early-stage, favorable HL. With IRB approval, records of 20 patients (11 females, 9 males) with early-stage, favorable HL per the GHSG criteria, treated between 2008-2015, were reviewed. All patients underwent PET/CT for initial staging and for restaging after 2 cycles of ABVD. This was followed by ISRT to 20 Gy in 10 fractions, using 3-dimensional conformal technique. PET-response after 2 cycles of ABVD was independently assessed by a nuclear medicine physician with Deauville score assignment. Actuarial rates of relapse-free survival (RFS) and overall survival (OS) were calculated. RFS was defined as the time from start of chemotherapy to relapse or death, whichever occurred first. The median age at diagnosis was 33 years (range 20-82). All but 2 patients were without B symptoms, and 50% had 1 site of disease. Median ESR was 10 (range 1-16). Median maximal tumor dimension was 38 mm (range 12-80 mm). After 2 cycles of ABVD, 95% of patients had a Deauville score of 1-2, and 1 patient had a score of 3. Median follow-up is 46.9 months. As of this analysis, all patients are alive without disease. One patient had an out-of-field relapse, but was salvaged with chemotherapy followed by autologous stem cell transplant. This patient had 80 mm disease at time of diagnosis and a Deauville 2 score after chemotherapy. The 4-year RFS rate is 90.9% (95% CI: [50.8, 98.7]). Figure 1 shows RFS in this 20-patient cohort. Our results showed that with careful patient selection based on initial disease characteristics and PET-response to chemotherapy, the use of a more restricted radiotherapy treatment volume of ISRT to 20 Gy following ABVD x 2 is associated with an excellent outcome with no local recurrences or marginal misses.
  • Kamran SC
  • Jacene HA
  • Chen YH
  • Mauch PM
  • Ng AK
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P052 (P052)

Optimized “butterfly” VMAT reduces mean dose to coronary arteries for early stage HL patients undergoing mediastinal radiotherapy

Background and Objective: A linear correlation was shown between the occurrence of coronary artery disease (CAD) and radiation dose received by coronary arteries for Hodgkin’s lymphoma (HL) patients, derived by mean heart dose/long-term follow-up datasets. The purpose of this study was to delineate coronary arteries and optimize radiation planning on these substructures by using an optimized multi-arcs volumetric arc therapy (VMAT) solution, then to compare it to standard 3D-CRT with the aim of showing a potential dosimetric benefit for VMAT. Materials and methods: We compared the plans of 14 HL patients (3 males and 11 females) with stage I-IIA mediastinal disease without axillary involvement, treated with involved site radiotherapy (ISRT); 11 had a bulky presentation at diagnosis. In every patient, a deformable fusion was performed with a dedicated software between the planning CT and the pre-ISRT contrast enhanced CT scan. The following structures were delineated: whole heart; left main, left descending, circumflex and right coronary arteries; aortic, pulmonary, mitral and tricuspid valves; right and left atria; right ventricle, left ventricle and interventricular septum; left ventricular apex, mid cavity, base and lateral wall. Two experienced radiation oncologists contoured target volumes (CTV), and heart substructures, after a validation session with a cardiologist and a heart radiologist. The VMAT approach consisted of multi non-coplanar arcs (the so-called “butterfly” VMAT or B-VMAT) and was compared with 3D-CRT. Mean and max dose received by the coronary arteries were compared by Student’s T test. Results: Maximum doses to coronary arteries resulted similar; conversely, lower mean doses were delivered by using B-VMAT, reaching a significant difference for the left main trunk (p = 0.002), the circumflex coronary artery (p = 0.014) and the right coronary artery (p = 0.002). Most significant findings are illustrated by the table and box-plots. Discussion: This study suggests that an optimized intensity modulated RT solution (B-VMAT) is able to reduce the dose to coronary arteries for HL patients with mediastinal disease. As the dose-response relationship is linear, this reduction should translate in lower incidence of CAD.
  • Filippi AR
  • Levis M
  • Girardi A
  • Fiandra C
  • Piva C
  • Donegani I
  • Ragona R
  • Ricardi U
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P053 (P053)

Biological evaluation in the treatment planning. Is there a use for patients with Hodgkin’s Lymphoma?

Introduction: The aim of the present analysis is to evaluate the value of a biological treatment planning for patients with Hodgkin’s Lymphoma (HL). Because patients with HL have become longtime survivors the main goal of ongoing studies is to minimize treatment related late toxicity. Especially for patients with mediastinal involvement the use of IMRT should be considered carefully with regard to pulmonary toxicity. Methods: We included 27 patients with mediastinal involvement of HL. All patients received chemotherapy followed by 30.6 Gy Involved-Field RT. 20 patients were treated with APPA, 5 patients with a 5-field IMRT (5F-IMRT) and 3 patients with a 7-field IMRT (7F-IMRT). To compare the different techniques we calculated 3 treatment plans for every patient. We evaluated Dmean, V5, V10, V15, V20 and V30 of the lung, Dmax of the spinal cord and V50 of the body. To determine the probability of pneumonitis we used a biological evaluation of Eclipse© by Varian and compared them to values we calculated using the parameters of Quantec. We analyzed the follow-up CTs of all patients to test whether they had a radiogenic pneumonitis. Results: A total of 81 plans were calculated. The 7F-IMRT achieves the highest values with respect to Dmean, V5, V10, V15 and V20 of the lung. Regarding V30 APPA is inferior (14.9 Gy APPA vs 2.9 Gy 7F-IMRT median). With respect to Dmax of the spinal cord the 7F-IMRT is superior to 5F-IMRT and APPA (32.1 Gy APPA, 24.9 Gy 5F-IMRT and 19.9 Gy 7F-IMRT median). The 7F-IMRT achieves the highest NTCP-values: Left lung: (range 0.0-2.1%); 5F-IMRT (range 0.0-4.0%) and 7F-IMRT (range 0.0 – 5.1%). Right lung: APPA (range 0.0-2.1%); 5F-IMRT (range 0.0-2.9%) and 7F-IMRT (range 0.0-8.0%). The values calculated by using the Quantec-parameters were as follows: Left lung: APPA (range 1.4-12.2%); 5F-IMRT (range 1.6-15%) and 7F-IMRT (range 1.7 – 16.4%). Right lung: APPA (range 2.3-12.6%); 5F-IMRT (range 2.4-13.9%) and 7F-IMRT (range 2.3-18.2%). No patient had radiologic signs of pneumonitis by reviewing the follow up CTs. Conclusion: APPA is superior to IMRT with respect to the mean lung doses. This finding is underlined by the NTCP-values. If the local doses (e.g. V30) in the field of the PTV are observed, IMRT is superior. The calculated values show an increased risk by using the 7F-IMRT. The biological evaluation achieves remarkable results in both cases, that are usefull in the judgement of treatment plans.
  • Kriz J
  • Haverkamp U
  • Pepper N
  • Elsayad K
  • Kröger K
  • Reinartz G
  • Glashörster M
  • Kittel C
  • Eich HT
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P054 (P054)

The effect of deep inspiration breath hold (DIBH) Intensity-Modulated Radiation Therapy (IMRT) on sparing healthy tissues in the treatment of lymphoma involving the mediastinum

Survivors of Hodgkin’s lymphoma (HL) have an increased risk of developing secondary malignancies and cardiovascular disease. This risk is directly correlated to the amount of radiation exposure and is significant even with the use of modern radiation therapy modalities. Deep inspiration breath hold (DIBH) techniques have been shown to lead to the delivery of lower amounts of radiation to organs at risk (OARs) during the treatment of breast cancer and Hodgkin’s lymphoma. In this study, we evaluated the ability to DIBH techniques to decrease the amount of radiation exposure of OAR in 16 consecutive HL lymphoma patients with mediastinal involvement. Majority of patients had Stage II bulky disease. For each patient four different plans were calculated – two utilizing deep inspiration breath hold technique and two with free breathing with IMRT and APPA plans created for both breathing modalities. DIBH plans delivered significantly decreased mean doses to the heart with Dmean of 474.5cGy (DIBH-IMRT) and 779.0cGy (DIBH-APPA), compared to the free breathing plans with 1125.6cGy (FB-IMRT) and 1709.3cGy (FB-APPA). In addition, specific cardiac substructures such as the coronary arteries and the aortic valve also received reduced mean doses of radiation. The coronary arteries in DIBH-IMRT plans received on average Dmean of 888cGy, DIBH-APPA plans -1528Gy, FB-IMRT 1921cGy and DIBH-APPA – 2529cGy. Similar trend is present within the average dose delivered to the aortic valve with average Dmean for DIBH-IMRT plans of only 894cGy, compared to average Dmean of 1694cGy for DIBH-APPA plans, 2718cGy for FB-IMRT plans, and 2874cGy for FB-APPA plans. Mean dose of lung exposure for DIBH-IMRT plans is also significantly lower than FB-IMRT plans (p=0.003). The volume of lung tissue receiving low dose radiation is significantly decreased in the DIBH-IMRT plan compered to the FB-IMRT plan, however the volume receiving 2000cGy is comparable between the DIBH and FB plans. These findings are consistent with previous reports and suggest that utilizing DIBH could greatly decrease the radiation exposure of OAR and decrease the long-term complications young cancer survivors face.
  • Eastman B
  • Uhl J
  • Mosienko V
  • Murphy J
  • Sanghvi P
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P055 (P055)

Multicentric Italian Experience in Treatment of Nodular Lymphocyte Predominant Hodgkin lymphoma (NLPHL) in the Rituximab Era

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by the expression of B-cell associated antigen CD20. Due to this characteristic it has been proposed the use of the anti-CD20 antibody but at now, there is no consensus on which chemotherapy regimen should be used. In patients with stage IA two prospective studies evaluated the role of the anti-CD20 antibody in monotherapy (GHSG and Stanford); both of them concluded that rituximab cannot be recommended as a first-line therapy and ESMO guidelines recommend radiotherapy for this subset of patients. In other stages chemotherapy is generally recommended, but there is no consensus on whether classical HL-directed regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), or B-cell lymphoma-directed regimens, such as R-CHOP (rituximab, cychlophosphamide, doxorubicin, vincristine, prednisone) should be used. In order to plan clinical trials and to test our potential accrual we performed a retrospective analysis of patients treated between 2000 and 2016 in 8 Italian hematologic centers. We identified 113 pts affected by NLPHL (41 stage I without symptoms, 40 stage II, 21 stage III, 11 stage IV). 11 patients had extranodal disease (pancreas, intestine, skin, lung, liver, bone marrow, muscle), 14 had spleen involvement and 9 had B symptoms. Median age at diagnosis was 43, male:female ratio was 2.9. Median follow-up is 62 months (range 1-199 months). 5yr-OS and 3yr-EFS were respectively 95.5% and 85.9%.13 patients had relapse of NLPHL, 5 patients had transformation to DLBCL at a median of 14 months, 4 patients died (1 from acute myelogenous leukemia, 1 from progression of disease, 1 from stomach cancer and 1 for interstitial pneumonia during ABVD). Treatments for non-stage I pts were as follows: 29 ABVD ± IFRT (II 19, III 6, IV 4), 13 R-ABVD (II 5, III 5, IV 3), 24 R-CHOP ± IFRT (II 10, III 10, IV 4) and 6 other (2 observation, 2 IFRT, 1 Rituximab, 1 CHOP like).3-years event-free survival are as follows: 78.5% (58-90) for ABVD±RT, 100% for R-ABVD and 74% for R-CHOP (48-88). No statistically significant difference was observed in terms of EFS neither for therapy regimen (p 0.512) , nor for stage and spleen involvement (p 0.33). Our data do not show any difference among classical HL-directed regimens, B-cell lymphoma-directed regimens or composite approach. A prospective randomized large cohort evaluation should be taken into account
  • Gotti M
  • Merli F
  • Re A
  • Rusconi C
  • Pulsoni A
  • Rigacci L
  • Merli M
  • Liberati M
  • Ferretti V
  • Zoboli V
  • Fama A
  • Dalceggio D
  • Meli E
  • Annechini G
  • Puccini B
  • Ferrario A
  • Appolloni V
  • Sciarra R
  • Frigeni M
  • Arcaini L
  • Bonfichi M
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P056 (P056)

Construction of a Decision Model to Aid Treatment Choices for Early Stage Hodgkin Lymphoma (ES HL): Bringing Survivorship Forward

Introduction: Decision-making for the treatment of ES HL patients continues to involve consideration of the tradeoff between shorter-term progression-free survival (PFS) and the impact of late effects (LE) on overall survival (OS). To evaluate the complex decision process arising from these factors, there is a desire to obtain integrated data that assimilates short-term outcomes, LE, and quality adjusted life expectancy (QALE) to help aid treatment choices. Methods: We analyzed PFS and OS from 4 large, modern randomized trials comparing chemotherapy alone with combined modality therapy (CMT) for ES HL (Meyer NEJM 2012; Wolden JCO 2012; Raemaekers JCO 2014; Radford NEJM 2015). We constructed a detailed Markov model comparing QALE after initial therapy for ES HL using chemotherapy alone vs CMT. The model incorporated: 3-year PFS from PET- patients; quality of life associated with relapse and cure; cure rates after relapse; 15-year latency period before onset of increased mortality from LE; and “discounting” of future life years. We also performed sensitivity analyses to determine the amount that CMT (with contemporary radiotherapy) must increase LE-associated mortality for that impact to outweigh its early PFS advantage. Results: All 4 trials demonstrated that short-term PFS was superior with CMT, including PET response-adapted paradigms, however OS was at least equivalent in each study. Collectively, the analyses showed that if CMT-associated LE increased deaths >15-20% (relative) compared with chemotherapy alone, then treatment with the latter was associated with overall improved QALE. This finding was consistent across a range of patient ages and among varied estimates for SMR after cure for those treated with chemotherapy alone (see Figure). Furthermore, sensitivity analyses demonstrated that these findings were most sensitive to assumptions regarding the impact of CMT on mortality after cure, and insensitive to moderate changes in the assumed short-term impact of CMT on PFS. Conclusions: We identified the “break-even point” whereby chemotherapy alone was associated with superior QALE vs CMT (ie, 15-20% relative increased death from LE). This model provides the base analytic framework to aid the complex decision of treating ES HL. Future model iterations may incorporate patient & tumor characteristics, patient preferences, and cost-effectiveness of varied therapeutics in order to help guide individualized decisions for providers and patients with HL.
  • Kelly MJ
  • Parsons SK
  • Cohen JT
  • Castellino SM
  • Kelly KM
  • Keller F
  • Henzer TJ
  • Kumar A
  • Johnson P
  • Meyer RM
  • Morton LM
  • Radford J
  • Raemaekers J
  • Hodgson DC
  • Evens AM
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P057 (P057)

Doses to organs at risk at different modes of 3D-conformal radiotherapy for mediastinal stage II Hodgkin Lymphoma (HL)

Purpose. In this study we evaluated the doses for organs at risk (lungs, heart, spinal cord) and CTV-PTV volume at 3D-conformal radiotherapy (3DCRT, ISRT) and intensity-modulated radiotherapy (IMRT) for mediastinal stage II HL (30-36Gy). Patients and methods. From March 2014 to March 2015 63 patients with mediastinal stage II HL had chemotherapy 3-4 cycles ABVD than there was 3DCRT: 52 patients – involved site radiation therapy (ISRT) and 11 patients – IMRT. We compared CTV-PTV volumes and the doses to organs at risk in these groups. Results. CTV volume was not distinguished (401 ± 15,0 cm3 and 385 ± 61,5 cm3). PTV was significantly more at ISRT than IMRT-groupe (1270 ± 84,0 cm3 and 604 ± 89,0 cm3, p< 0,01). Besides, at IMRT-groupe were less compared with ISRT-groupe V20 left lung (24,0 ± 3,8 % and 33,5 ± 1,4%, p< 0,05), right lung (28,0 ± 1,3 % and 16,6 ± 2,4 %, p< 0,05), V30 heart (50,0 ± 4,4% and 8,1 ± 2,2 %, p< 0,01), mean heart dose (29,4 ± 3,8 Gy and 7,0 ± 1,5 Gy, p< 0,001). Mean dose for spinal cord was similar in these groups. Conclusion. IMRT compared to 3DCRT (ISRT) substantially reduces V20 lungs, V30 heart and mean dose for heart without compromising the dose to the target in patients with mediastinal stage II HL.
  • Ilyin NV
  • Vinogradova JN
  • Ivanova EI
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P058 (P058)

Residual site radiation therapy (RS RT): An opportunity to increase safety of combined modality therapy (CMT) for early stage Hodgkin lymphoma (HL)

In randomized controlled trials, the addition of RT to chemotherapy increases the progression-free survival but not overall survival in early stage HL. Extended field (EF) and involved field (IF) RT are both associated with late morbidity and mortality, particularly due to second malignancies and cardiovascular events. There do not appear to be safe doses of RT that will remain therapeutic, Doses as low as 20 Gy in CMT do not seem to reduce the risk of second cancers below that seen with traditionally therapeutic doses of 35-45 Gy. The risk of coronary heart disease is increased by 7.4% per Gy in median heart dose. Likewise the reduction of radiation therapy portals from EF to IF RT has not reduced the risk of second cancers. The latest iteration of IF RT is involved site RT (IS RT). However, despite the early observation that initially bulky nodal sites are at higher risk for recurrence than non-bulky sites following adequate chemotherapy, all initial nodal sites are still treated regardless of whether or not they resolve with chemotherapy despite their initial size. Involved site RT still results in large fields encompassing the pre-chemotherapy extent of disease, and as a result, in substantial off-target radiation exposure to adjacent organs. There is no data indicating that lowering the RT dose further in CMT will remain therapeutic. Given the paradigm of treating all initial nodal sites of involvement, it will also be difficult to further substantially reduce off-target radiation exposure, even with new techniques such as three-dimensional conformal RT, intensity modulated RT, deep inspiratory breath hold, or even proton beam RT. Because of these considerations, we propose a change in the paradigm of treating all initial nodal sites of involvement when administering adjuvant RT following adequate chemotherapy. It is unclear whether initial nodal sites that have completely resolved with chemotherapy are at increased risk for recurrence. Rather, we propose clinical trials to test the concept of only treating the PET-negative residual remaining masses on CT imaging following chemotherapy (residual site RT – RS RT). A step in this direction was taken with the HD15 trial.
  • Straus DJ
  • Cahlon O
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T011 (T011)

Proton radiotherapy for mediastinal Hodgkin Lymphoma: single institution experience

Introduction: Conventional radiotherapy (RT) based on photons has achieved its physical limits. Proton beam offers promising dosimetric benefits compared to photons, due to its potential to decrease unintended healthy tissue irradiation. Mediastinal proton RT can be safely provided with the awareness of targeting to a moving structure. The technological progress in proton RT allows solving this issue. It can be reasonably managed via pencil beam scanning technique with repainting and/or the use of deep inspiration breath hold method. We present our preliminary clinical experience with this technique. Methods: Between May 2013 and June 2016, 39 patients (pts) with Hodgkin lymphoma (HL) underwent mediastinal proton RT. Pencil beam scanning technique was used in all pts. Overall 33 of 39 pts were evaluable for acute toxicity and early response. Proton RT was indicated in the first-line treatment in 30 pts, 3 pts were re-irradiated after previous photon RT. Median age at the time of RT was 32 years (range, 13-59 years). RT volume definition: involved field 9 pts, residual disease 10 pts, involved site 14 pts. RT to PET negative disease was indicated in 23 pts as a part of combined modality of treatment after chemotherapy. RT to PET positive disease after chemotherapy was performed in 10 pts. Median total dose was 30 GyE (range, 19.8-40 GyE). Overall 17 pts underwent RT in deep inspiration breath hold, the rest of pts received RT in free breathing after 4D control of mediastinal structures movement. Results: Of evaluable pts, 31 are in complete remission. Two pts with multiple sites of progression achieved a local control of disease. Acute and subacute RT toxicity was mild (pharyngeal mucositis gr. 2 in 3 pts, leukopenia gr.3 in 1 pt, leukopenia gr 2 in 1 pt, radiodermatitis gr.2 in 1 pt). No case of radiation pneumonitis or Lhermitte sign was observed. No pt required growth factor application or hemosubstitution during RT. Conclusion: Proton RT offers promising and safe option for most pts indicated for mediastinal RT. Proton irradiation has low acute toxicity profile and a potential to decrease the risk of significant late toxicity. Proton RT should be considered in all HL patients indicated for mediastinal RT or re-irradiation. This work was supported by grant awarded by AZV 16-29857A, Ministry of Health in Czech Republic and Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague, Czech Republic
  • Dedeckova K
  • Mocikova H
  • Markova J
  • Gaherova L
  • Kantorova I
  • Ondrova B
  • Vondracek V
  • Vitek P
  • Kubes J
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T010 (T010)

Long-term follow-up of contemporary treatment in early-stage favorable Hodgkin Lymphoma (HL): updated analyses of the German Hodgkin Study Group HD7 and HD10 trial

abstract talk Abstract Talk in Early Stages (Monday, 24.10. 16:00)

Background: Combined modality treatment (CMT) is considered as standard of care in patients with early-stage favorable HL. During the years, a gradual toxicity reduction through balancing extent and intensity of radiotherapy (RT) and chemotherapy was achieved. Long-term follow-up (FU) of the pivotal trials is needed, to ensure the applied therapies are safe and beneficial for our patients. Methods: We analyzed updated FU data of 1817 patients who were treated for early-stage favorable HL in previously published GHSG trials between 1993 and 2003. In the HD7 trial patients were randomized to either 40Gy extended-field (EF)-RT only or CMT with 2xABVD, and in HD10 to either 4x or 2xABVD and 30 or 20Gy involved-field (IF)-RT respectively. Progression-free (PFS) and overall survival (OS) were analyzed according to the Kaplan-Meier method. Cumulative incidences of secondary neoplasias (SN) were compared using Pepe & Mori’s test. The level of significance was set to 0.05. Results: The median FU was 120 and 98 months for patients in HD7 (n=627) and HD10 (n=1190), respectively. New FU data beyond the last evaluation were available for <50% of patients and last information was obtained from population registries in 18-30%. In HD7, CMT was superior to EF-RT with 15-year PFS estimates of 72.8% vs. 52.2% and a hazard ratio (HR) of 0.45 (95% confidence interval CI: 0.33-0.61). No significant differences were observed regarding OS or SN. In HD10, non-inferiority of 2xABVD + 20Gy IF-RT to more intensive treatment was confirmed with HRs of 1.0 (CI:0.6-1.5) and 0.9 (CI:0.5-1.6) and 10-year estimates of 87.2% and 94.1% for PFS and OS, respectively. No significant differences in SN were observed. Summary: Long-term FU data of HD7 and HD10 confirm the current treatment-standard in early-stage favorable HL consisting of 2xABVD + 20Gy IF-RT. In order to assess the risk of secondary neoplasia and long-term organ toxicity a prolonged follow-up period is required.
  • Sasse S
  • Bröckelmann PJ
  • Görgen H
  • Plütschow A
  • Mueller H
  • Kreissl S
  • Bürkle C
  • Borchmann S
  • Fuchs M
  • Borchmann P
  • Engert A
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T012 (T012)

Results of US intergroup trial of response-adapted chemotherapy or chemotherapy/radiation therapy based on PET for non-bulky stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)

abstract talk Abstract Talk in Early Stages (Monday, 24.10. 16:00)

Interim positron-emission tomography (PET) following 1-3 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in newly-diagnosed, non-bulky stage I and II HL patients (pts) is a useful biomarker that predicts relapse rates of ≤10% for PET- pts. Relapse rates are higher in pts who are PET+. Interim PET thus provides an opportunity to minimize treatment for the majority of pts who are interim PET - and only intensify treatment for those who are PET+. This strategy could reduce short and long term treatment toxicity for the majority of pts. To test this hypothesis, the US Intergroup conducted a phase II clinical trial, CALGB/Alliance 50604, for newly-diagnosed non-bulky stage I and II HL pts. Between 5/15/10 and 5/4/12, 164 previously untreated pts with non-bulky stages I/II HL were enrolled. Pts received 2 cycles of ABVD followed by PET. Deauville scores 1-3 were negative (≤ liver uptake), while scores of 4-5 were positive, based on central review. PET- pts received 2 more cycles of ABVD, and PET+ pts received 2 cycles of escalated BEACOPP + 3060 cGy involved-field radiation therapy (IF RT). Median age was 31 years (18-58). There were 88 males and 76 females. Pt. stages were IA (16), IB (4), IIA (90), IIB (35), IIAE (4), and IIBE (3). All pts were PET+ prior to treatment. 144/164 patients had cycle 2 PET and adequate follow-up for assessment: 131 (91%) were PET- and 13 (9%) PET+. Of 20 not analyzed, 13 were excluded (6 never treated and 2 treated with < 2 cycles) and 7 had insufficient follow up. At a median follow-up time of 2 years, 8/131 (6%) PET- pts relapsed or progressed with an estimated 3-year progression-free-survival (PFS) of 92%. 4/13 (31%) PET+ pts. failed (3 relapsed, 1 suicide) with an estimated 3-year PFS of 66%. By Cox model, observed hazard ratio comparing PET- and PET+ PFS for pts is 6.04 (1.82, 20.08). There was 1 death (suicide). These early results demonstrate that the 91% of pts PET- after 2 cycles of ABVD had an excellent PFS with total of 4 ABVD cycles. Updated results will be presented.
  • Straus DJ
  • Pitcher B
  • Kostakoglu L
  • Grecula JC
  • Hsi ED
  • Schoder H
  • Jung SH
  • Popplewell LL
  • Chang JE
  • Moskowitz CH
  • Wagner-Johnson N
  • Leonard JP
  • Friedberg JW
  • Kahl BS
  • Cheson BD
  • Bartlett NL

Advanced Stages

Selected for Oral Presentation

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    T001 (T001) BEACOPP escalated followed by radiotherapy of initial bulk or residual disease in advanced-stage Hodgkin Lymphoma: long-term follow-up of the GHSG HD9 and HD12 trials

    • von Tresckow B
    • Kreissl S
    • Haverkamp H
    • Sasse S
    • Diehl V
    • Engert A
    • Borchmann P
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    T002 (T002) Overall survival (OS) impact of BEACOPP versus ABVD in advanced Hodgkin Lymphoma: a pooled analysis of 4 randomized trials

    • André M
    • Fortpied C
    • Viviani S
    • Bellei M
    • Carde P
    • Hutchings M
    • Gianni A
    • Brice P
    • Casasnovas O
    • Gobbi P
    • Zinzani PL
    • Dupuis J
    • Iannitto E
    • Rambaldi A
    • Brière J
    • Perrot A
    • Heczko M
    • Valagussa P
    • Douxfils J
    • Joubert C
    • Federico M
    • Mounier N
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    T003 (T003) Long-term follow-up of SWOG S0816: response-adapted therapy of advanced stage Hodgkin Lymphoma using early interim FDG-PET imaging

    • Friedberg JW
    • Li H
    • Schöder H
    • Straus DJ
    • Moskowitz CH
    • LeBlanc M
    • Rimsza LM
    • Bartlett NL
    • Evens AM
    • Mittra ES
    • LaCasce AS
    • Sweetenham JW
    • Barr PM
    • Fanale MA
    • Knopp MV
    • Noy A
    • Hsi ED
    • Cook JR
    • Lechowicz MJ
    • Gascoyne RD
    • Leonard JP
    • Kahl BS
    • Cheson BD
    • Fisher RI
    • Press OW

Posters

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    P001 (P001) Sequential Brentuximab Vedotin (BV) and Adriamycin, Vinblastine, and Dacarbazine (AVD) for Older Patients with Untreated Hodgkin Lymphoma (HL): Findings from a Phase II Window Study

    • Evens AM
    • Hamlin PA
    • Nabhan C
    • Advani RH
    • Fanale M
    • Petrich A
    • Smith SM
    • Bociek G
    • Winter J
    • Gordon LI
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    P002 (P002) Preliminary results of a phase II study of brentuximab vedotin using a response adapted design in the first line treatment of patients with Hodgkin lymphoma unsuitable for chemotherapy due to age, frailty or co-morbidity (BREVITY)

    • Gibb A
    • Pirrie S
    • Linton K
    • Paterson K
    • Davies A
    • Collins G
    • Menne T
    • McKay P
    • Fields P
    • Miall F
    • Nagy E
    • Wheatley K
    • Warbey V
    • Barrington S
    • Radford J
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    P004 (P004) Gray Zone Lymphoma (GZL) with Features Intermediate Between Diffuse Large B-cell Lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL): Diagnostic Experiences and Challenges from a Multicenter Study

    • Pilichowska M
    • Pittaluga S
    • Ferry JA
    • Hemminger J
    • Gupta G
    • Kritharis A
    • Gascoyne RD
    • Evens AM
    • Jaffe ES
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    P005 (P005) Hodgkin lymphoma in Sweden since 2000: better survival only in elderly women – a Swedish Lymphoma Registry study

    • Engelbrekt Wahlin B
    • Övergaard N
    • Peterson S
    • Digkas E
    • Glimelius I
    • Lagerlöf I
    • Johansson AS
    • Palma M
    • Hansson L
    • Linderoth J
    • Goldkuhl C
    • Molin D
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    P006 (P006) Advanced Hodgkin Lymphoma in the East of England Cancer Network: A 10 year comparative analysis of outcomes for ABVD and escalated BEACOPP treated patients aged 16–59

    • Collins A
    • Fowler A
    • Karanth M
    • Saha C
    • Russel J
    • Shyamsundar V
    • Docherty S
    • Maw K
    • Padayatty J
    • Hodson A
    • Wimperis J
    • Sadullah  S
    • Grigoropoulos N
    • Uttenthal B
    • Follows G
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    P007 (P007) Superiority of Modified Progression Free Survival (mPFS) to Evaluate Chemotherapy Effectiveness for Advanced Stage Hodgkin Lymphoma

    • Connors JM
    • Gerrie AS
    • Scott DW
    • Sehn LH
    • Villa D
    • Savage KJ
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    P008 (P008) Treatment results for Hodgkin Lymphoma in Brazil: first report from the Brazilian Prospective Hodgkin’s Lymphoma Registry

    • Biasoli I
    • Castro N
    • Delamain M
    • Silveira T
    • Farley J
    • Pinto Simões B
    • Solza C
    • Praxedes M
    • Baiocchi O
    • Gaiolla R
    • Franceschi F
    • Bonamin C
    • Boquimpani C
    • Clementino N
    • Perini G
    • Pagnano K
    • Steffenello G
    • Tabacof J
    • de Freitas Colli G
    • Soares A
    • de Souza C
    • Chiattone CS
    • Milito C
    • Morais JC
    • Spector N
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    P009 (P009) Dose-Dense/Dose-Intense ABVD (dd-di ABVD) in advanced stage Hodgkin's Lymphoma (HL): A Long-Term Follow Up Study

    • Filippo R
    • Luigi A
    • Gino S
    • Pietro F
    • Secondo L
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    P010 (P010) THE SWITCH FROM ABVD TO eBEACOPP AS FRONT-LINE THERAPY FOR HIGH-RISK STAGE III-IV CLASSICAL HODGKIN LYMPHOMA (cHL) PATIENTS RESULTS IN AN INVERSION OF EVENT-FREE SURVIVAL (EFS) OF PROGNOSTIC GROUPS

    • Aurer I
    • Basic-Kinda S
    • Dujmovic D
    • Radman I
    • Dreta B
    • Dotlic S
    • Galunic-Bilic L
    • Dobrenic M
    • Kralik M
    • Roncevic P
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    P011 (P011) HALO Study: a phase 1/2 clinical trial of Brentuximab-Vedotin and Bendamustin in elderly patients with previously untreated advanced hodgkin lymphoma. Preliminary data

    • Viviani S
    • Fontanet B
    • Rambaldi A
    • Perrot A
    • Patti C
    • Gastaud L
    • Sorasio R
    • Debaigt C
    • Chamorey E
    • Gallamini A
    • Thyss A
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    P012 (P012) Transformation of nodular Hodgkin's lymphoma with lymphocyte predominance to T-cell-rich large B-cell lymphoma

    • Moiseeva TN
    • Al-Radi LS
    • Dorokhina EI
    • Goryacheva SR
    • Margolin OV
    • Magomedova AU
    • Julhakyan HL
    • Kravchenko SK
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    P013 (P013) ABVD AS THE TREATMENT OPTION IN HODGKIN LYMPHOMA WITH LARGE MEDIASTINAL TUMOR

    • Andjelic B
    • Jakovic L
    • Antic D
    • Todorovic M
    • Bila J
    • Djurasinovic V
    • Sretenovic A
    • Vukovic V
    • Jelicic J
    • Smiljanic M
    • Mihaljevic B
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    P014 (P014) PERIPHERAL BLOOD EOSINOPHILIA IS A GOOD RISK FACTOR IN POOR PROGNOSIS GROUP: ADVANCED HODGKIN LYMPHOMA WITH LOW ALC/AMC

    • Jakovic LR
    • Mihaljevic BS
    • Andjelic BM
    • Bogdanovic AD
    • Perunicic Jovanovic MD
    • Bumbasirevic VZ
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    P015 (P015) Lower socioeconomic status is associated with shorter survival in HL patients – an analysis from the Brazilian Hodgkin Lymphoma Registry

    • Biasoli I
    • Castro N
    • Delamain M
    • Silveira T
    • Farley J
    • Pinto Simões B
    • Solza C
    • Praxedes M
    • Baiocchi O
    • Gaiolla R
    • Franceschi F
    • Bonamin C
    • Boquimpani C
    • Clementino N
    • Perini G
    • Pagnano K
    • Steffenello G
    • Tabacof J
    • de Freitas Colli G
    • Soares A
    • de Souza C
    • Chiattone CS
    • Raggio R
    • Milito C
    • Morais JC
    • Spector N
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    P016 (P016) THE IMPACT OF OUTCOME OF INTERIM PET/CT ON ADVANCED HODGKIN LYMPHOMA TREATED WITH BEACOPP-14

    • Medvedovskaya E
    • Leontjeva A
    • Demina E
    • Ryabukhina J
    • Tumyan G
    • Kokosadze N
    • Trofimova O
    • Larionova V
    • Dolgushin M
    • Odzharova A
    • Mukhortova O
    • Aslanidis I
    • Osmanov D
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    P017 (P017) ADVANCED HODGKIN LYMPHOMA – A RISK STRATIFICATION OF ABVD TREATED FEMALES IN GENERATIVE AGE

    • Andjelic B
    • Jakovic L
    • Antic D
    • Todorovic M
    • Bila J
    • Djurasinovic V
    • Sretenovic A
    • Vukovic V
    • Jelicic J
    • Smiljanic M
    • Mihaljevic B
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    P018 (P018) ADVANCED STAGE HODGKIN LYMPHOMA IN MOROCCAN ADULTS: CLINICO-PATHOLOGICAL FEATURES AND THERAPEITIC OUTCOMES

    • Kaddouri W
    • Anoun S
    • Khoubila N
    • Cherkaoui S
    • Lamchahab M
    • Quachouh M
    • Rachid M
    • Madani A
    • Quessar A
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    P019 (P019) General population-derived specific survival applied to Hodgkin Lymphoma

    • Gobbi PG
    • Bellei M
    • Marcheselli L
    • Chisesi T
    • Merli F
    • Galimberti S
    • Iannitto E
    • Luminari S
    • Manni M
    • Stelitano C
    • Musto P
    • Pavone V
    • Vitolo U
    • Federico M
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    P020 (P020) The diagnostics and therapy of Hodgkin lymphoma in pregnancy, the experiences of one center

    • Gahérová L
    • Móciková H
    • Marková J
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    P021 (P021) Difficulties in distinguishing syncytial variant of nodular sclerosis classical Hodgkin’s lymphoma from diffuse large B-cell lymphoma and complete remission after intensive chemotherapy

    • Okatani T
    • Asaoku H
    • Fujiwara M
    • Sato Y
    • Seto M
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    P022 (P022) Systemic Hodgkin's Disease with osseal involvement

    • Banti A
    • Papadakis E
    • Kioumi A
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    P023 (P023) Brentuximab Vedotin Alone and in Combination With Dacarbazine or Bendamustine in Patients Aged ≥60 Years With Newly Diagnosed Hodgkin Lymphoma: Interim Results of a Phase 2 Study

    • Friedberg JW
    • Forero-Torres A
    • Cline-Burkhardt VJM
    • Bordoni RE
    • Patel-Donnelly D
    • Flynn PJ
    • Chen R
    • Fong A
    • Yasenchak CA
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P001 (P001)

Sequential Brentuximab Vedotin (BV) and Adriamycin, Vinblastine, and Dacarbazine (AVD) for Older Patients with Untreated Hodgkin Lymphoma (HL): Findings from a Phase II Window Study

Introduction: Outcomes for older patients (pts) with HL remain sub-optimal. We initiated a multicenter study examining sequential brentuximab vedotin (BV) given before and after AVD chemotherapy (NCT01476410). Methods: Pts ages ≥60 years with stage II-IV, untreated HL were eligible. All pts received 2 “lead-in” cycles of single-agent BV 1.8 mg/kg (q 3 weeks), followed by 6 cycles of standard AVD chemotherapy. Responding pts then receieved consolidation therapy (Tx) with BV x 4 cycles. Study design is Simon two-stage with plan of 48 total pts. The primary endpoint is complete remission (CR) rate after AVD (ie, prior to BV consolidation) using FDG-PET. If ≥12 CRs were observed among 20 evaluable pts, accrual continued to the 2nd stage. Results: 26 pts enrolled to the first study stage, of which 20 were evaluable for response. Characteristics for all pts included: median age 69 years (60-88); median ECOG PS of 1 (0-2); 92% stage III/IV disease; IPS 3-7 in 54%; and median CIRS co-morbidity score 5 (0-19). 6 pts were non-evaluable for response (n=3 withdrew consent/refused further therapy; n=2 toxicity; and n=1 death due to pancreatitis). Among 20 evaluable pts, overall response rate (ORR) to BV lead-in was 85% with 30% CR. After 3 AVD cycles, ORR and CR rates were 95% and 70%, respectively. The best ORR (including after BV consolidation therapy) was 95% with a CR rate of 90%. By intent-to-treat, best ORR and CR rates were 81% and 77%, respectively. Grade 3/4 AEs occurring in >1 pt were infection (15%), pancreatitis (4%), and peripheral neuropathy (PN) (4%); 31% of pts experienced grade 2 PN. Reasons for discontinuation of Tx included: 7/26 (27%) completed Tx; 7/26 (27%) on active Tx; 4/26 (15%) due to toxicity (grade 2: infusion reaction, hepatic, pneumonitis; and grade 3 wound infection); 3/26 (12%) refused additional Tx; 3/26 (12%) discontinued for PN (all grade 2 status-post cycles 6, 8,10); 1/26 (4%) due to lack of response; and 1 (4%) death (due to pancreatitis). At median follow-up of 22 months, 92% of all pts are alive, the progression-free survival is 85%, and notably, 95% of all evaluable pts are disease-free. Conclusions: Sequential integration of BV before and after standard AVD chemotherapy for newly diagnosed older HL pts is feasible and highly promising. The planned interim analysis confirmed the requisite CR rate needed for continuation to the 2nd stage of this multicenter phase II study. Updated results will be reported at the meeting.
  • Evens AM
  • Hamlin PA
  • Nabhan C
  • Advani RH
  • Fanale M
  • Petrich A
  • Smith SM
  • Bociek G
  • Winter J
  • Gordon LI
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P002 (P002)

Preliminary results of a phase II study of brentuximab vedotin using a response adapted design in the first line treatment of patients with Hodgkin lymphoma unsuitable for chemotherapy due to age, frailty or co-morbidity (BREVITY)

Introduction: Results of standard treatment for older patients (pts) with classical Hodgkin lymphoma (cHL) are sub-optimal and alternative approaches are required. Brentuximab vedotin (BV) is a CD30 targeted antibody-drug conjugate which in the pivotal* phase 2 trial in relapsed/refractory cHL produced an objective response rate of 75%, complete remission rate of 34% and manageable toxicity. BREVITY is a study of efficacy/tolerability of BV in older, frail or comorbid pts with previously untreated cHL. Methods: This was a phase II, Simon 2-stage, single arm study requiring 30 evaluable pts. Primary outcome was complete metabolic response rate (CMR, Deauville Score 1-3) by centrally reviewed PET-CT after 4 cycles of BV. Secondary outcomes included PFS, OS, toxicity and comorbidity assessment (CIRS-G). Inclusion criteria were previously untreated cHL stage 2 (with B symptoms and/or mediastinal bulk) or stages 3/4 with cardiac/respiratory compromise (at any age) or an ECOG score 1-3 and considered unfit for standard chemotherapy (in pts ≥60 yrs). BV dose was 1.8 mg/kg every 3 weeks, reduced to 1.2 mg/kg for toxicity. Pts in CMR/PMR after 4 doses BV continued to a total of 16 cycles if CT and/or PET-CT every 4 cycles confirmed ongoing response. PFS/OS data is not mature. Results: 38 pts were recruited Feb 2014-Oct 2015 at 12 UK centres; demographics are shown in Table 1. 35 pts were treated and evaluable for toxicity, 31 are evaluable for response. Median follow-up for alive pts is 11.6(range 0.9, 21.4) months. A median of 4 cycles were given per pt (range 1, 16). 28(12%) cycles in 14 pts were modified due to toxicity and 11 pts stopped treatment due to adverse events (AEs). 695 AEs were reported of which 601(86%) were grade 1/2. 26(74%) pts had at least 1 AE ≥grade 3, most commonly infection, myelosuppression or neuropathy. CMR rate at PET4 was 25.8%(95% CI 13.7, 43.2) and combined CMR/PMR rate was 83.7(95%CI: 67.4, 92.9). To date 21(67.7%) pts have progressed. Discussion: In this study BV monotherapy produced a high objective response rate although the CMR rate after 4 cycles did not meet the pre-specified 40% level. Toxicity was greater than in the pivotal* study where pts were younger/fitter and led to treatment termination in some pts. Nevertheless BV is effective in this older comorbid population. A follow-on study incorporating BV at lower dose in combination with other agents and growth factor support aimed at improving the CMR rate is in development.
  • Gibb A
  • Pirrie S
  • Linton K
  • Paterson K
  • Davies A
  • Collins G
  • Menne T
  • McKay P
  • Fields P
  • Miall F
  • Nagy E
  • Wheatley K
  • Warbey V
  • Barrington S
  • Radford J
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P004 (P004)

Gray Zone Lymphoma (GZL) with Features Intermediate Between Diffuse Large B-cell Lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL): Diagnostic Experiences and Challenges from a Multicenter Study

BACKGROUND: GZL (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and cHL) was described in 2005 and included in the 2008 WHO classification. Most cases present with mediastinal disease and share features with cHL and primary mediastinal large B-cell lymphoma (PMBCL). Non-mediastinal lymphomas with similar pathologic features have also been reported. Because of rarity and diagnostic complexity, data on GZL are limited and further study of this entity is desired. METHODS: Clinical data from cases originally diagnosed as GZL were collected from 19 academic centers across the US and Canada (Evens AM et al. Am J Hematol 90:778-83, 2015). To further characterize the diagnostic features and correlations, 73 cases (majority from the above series and n=4 subsequent cases) were submitted for central pathology review using criteria of the 2016 revised WHO classification. Initial diagnostic samples were evaluated with a panel comprising CD20, CD79a, PAX5, OCT2, BCL6, MUM1, CD30, CD15, CD3 and EBV by in situ hybridization (EBER). Beyond the tumor cell immunoprofile, diagnostic criteria included tumor cell density and morphology, necrosis, and the microenvironment. cHL nodular sclerosis grade 2 (cHL-NS2) were classified according to prior criteria (MacLennan K. et al Cancer 64: 1686-93, 1989). 5 cases were rejected for insufficient material/technical issues; 68 cases were evaluated by 5 hematopathologists and consensus diagnosis was reached at multiheaded scope review. RESULTS: Of 68 cases submitted with an original diagnosis of GZL, only 26 cases were confirmed as GZL on consensus review (14M/12F, median age 38 years, range 19-69). 11/26 biopsies were mediastinal in origin, and in an additional 4 cases, a mediastinal mass was present clinically; 11 had only peripheral lymphadenopathy (ie, non-mediastinal). 42 cases were re-classified as follows: NS cHL, n=27 (n=10 of which were cHL-NS2); DLBCL NOS, n=4; nodular lymphocyte predominant HL (NLPHL), n=3; EBV positive LBCL, n=3; PMBCL, n=2; lymphocyte-rich cHL, n=1; and B-cell lymphoproliferative disorder, n=1. Most cases of cHL diagnosed as GZL had strong CD20 expression. Furthermore, cHL-NS2 was frequently misdiagnosed as GZL typically due to confluent growth of lacunar cells. CONCLUSIONS: Diagnosis of GZL remains a challenge. Rarity of the cases, and overlap with cHL-NS2, contribute to the difficulty. Further biologic and clinical analyses may contribute to improved understanding.
  • Pilichowska M
  • Pittaluga S
  • Ferry JA
  • Hemminger J
  • Gupta G
  • Kritharis A
  • Gascoyne RD
  • Evens AM
  • Jaffe ES
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P005 (P005)

Hodgkin lymphoma in Sweden since 2000: better survival only in elderly women – a Swedish Lymphoma Registry study

Two major areas of dispute in Hodgkin lymphoma are treatment of advanced stages and of elderly patients. For advanced stages the debate is whether BEACOPPesc/14 or ABVD is to be considered standard. ABVD is standard in many countries, especially for those with IPS 0-2. There is no golden standard for therapy in elderly patients. In Sweden CHOP has been the standard treatment in patients >70 years during the study period. Outcome is also inferior in elderly compared with younger patients. We have analysed data from all 2345 Hodgkin lymphoma patients (1257 men and 1088 women, median age 42, range 16-99) diagnosed from 2000 through 2014 in the Swedish Lymphoma Registry. Median follow-up was 6.7 years. Overall survival (OS) at 3 and 5 years were 83% and 79%, without any differences between calendar periods (2000-2004, 2005-2009, and 2010-2014). In the most recent calendar period (2010-2014), longer survival was observed among patients ≥61 years (P = 0.027), but not among those <61 (P = 0.49). This improvement was restricted to women with advanced stage disease (P = 0.005). Stage IV disease was more common in the most recent calendar period (2010-2014) compared to the first (2000-2004), both in women (22% vs 15%, P = 0.003) and in men (28% vs 21%; P = 0.006), likely explained by the increasing use of PET-CT. In multivariate analysis, adjusted for all factors significant in univariate analysis, of patients ≥61 years, CHOP (compared with ABVD) was an independent adverse factor for OS (HR 1.7; 95% CI, 1.1-2.7; P = 0.027). Patients <61 with advanced stages treated with BEACOPPesc/14 and ABVD showed identical OS in univariate and multivariate analysis (P = 0.51). In conclusion, outcome was not improved over time except in elderly women. The implementation of FDG-PET/CT has resulted in a stage migration with an increased proportion of patients with stage IV disease. ABVD seems superior to CHOP for elderly who tolerate this regimen. BEACOPP and ABVD show equal OS in younger patients with advanced stage disease, supporting the use of PET/CT-adapted ABVD as initial therapy.
  • Engelbrekt Wahlin B
  • Övergaard N
  • Peterson S
  • Digkas E
  • Glimelius I
  • Lagerlöf I
  • Johansson AS
  • Palma M
  • Hansson L
  • Linderoth J
  • Goldkuhl C
  • Molin D
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P006 (P006)

Advanced Hodgkin Lymphoma in the East of England Cancer Network: A 10 year comparative analysis of outcomes for ABVD and escalated BEACOPP treated patients aged 16–59

The majority of young patients presenting with advanced stage Hodgkin lymphoma (HL) in the UK are managed with ABVD. However, following the 2009 HD9 trial publication, escalated BEACOPP (escB) was introduced as a treatment option in certain UK cancer centres. Here we present the data from advanced stage HL patients aged 16 to 59, who presented between 2004 and 2014 in the East of England Anglia Cancer Network with a referral population of 2.64 million. 250 cases were diagnosed, giving an incidence of 0.95 cases per 100,000 which is in-line with expected incidence of advanced HL in this age group. Six of the eight Anglia cancer centres introduced escalated BEACOPP for patents as determined by physician and patient choice. Over this 10 year period, 44 patients were managed with escB, 202 with ABVD, 3 with an alternative regimen and 1 patient died pre-treatment. The 5 year progression free survival (PFS) for all patients was 82% and 5 year overall survival (OS) was 92%. There was a clinician / patient preference for escB for worse prognosis patients as escB patients had a higher international prognostic score (IPS) than patients treated with ABVD (IPS3+: escB 75% vs ABVD 38%, p<0.0001). For the whole cohort, PFS was better for patients treated with escB compared with ABVD (5 year PFS 95% vs 80%; HR 4.3 (95%CI:1.97-9.7), p=0.0261)), but there was no OS difference (5 year OS 97% vs 92%; HR 2.6 (95%CI:0.69-10.4), p=0.312). However, patients with IPS 3+ had both a PFS and OS advantage when treated with escB compared with ABVD (5 year PFS 96% vs 74%; HR 9.24 (95%CI:3.43-24.89), p=0.012: 5 year OS 100% vs 84%; p=0.0325). The use of consolidation radiotherapy(RT) was equal between regimens with 11% of patients receiving RT with both escB and ABVD. 29 ABVD-treated and 3 escB-treated patients had at least one subsequent transplant procedure (including 6 allografts post ABVD and 3 allografts post escB, including one allograft for tAML/MDS). Of the 20 pre-menopausal women treated with escB, 11 of 14 aged <30 regained menstrual periods (5 pregnancies) but only 1 of 6 aged > 30 regained menstrual periods which were not sustained beyond 3 years. Our data reflect clinical trials results which indicate a first remission PFS but not OS advantage for unselected young advanced stage HL patients treated with escB compared with ABVD. However, our data strongly suggest that patients with a poor IPS score derive a PFS and OS benefit from treatment with escB compared with ABVD.
  • Collins A
  • Fowler A
  • Karanth M
  • Saha C
  • Russel J
  • Shyamsundar V
  • Docherty S
  • Maw K
  • Padayatty J
  • Hodson A
  • Wimperis J
  • Sadullah  S
  • Grigoropoulos N
  • Uttenthal B
  • Follows G
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P007 (P007)

Superiority of Modified Progression Free Survival (mPFS) to Evaluate Chemotherapy Effectiveness for Advanced Stage Hodgkin Lymphoma

Background Assessment of the effectiveness of chemotherapy for advanced stage Hodgkin lymphoma may be obscured by the incorporation of radiotherapy in primary treatment when standard endpoints such as progression free survival (PFS) are used. Ineffective chemotherapy may be “rescued” by the addition of radiotherapy residual PET-positive masses. Use of a modified PFS endpoint (mPFS), in which addition of radiotherapy after the conclusion of chemotherapy is scored as an event, more accurately assesses chemotherapy effectiveness. Methods We examined the records of 207 consecutive adult patients (age 16-82 y, median 36; males 55%) with advanced stage HL (IIIA, 23%; IIIB, 24%; IVA, 17%; IVB, 36%) treated between 2004 and 2015 with ABVD with or without involved field radiotherapy (IFRT). Standard PFS events were the first of relapse or progression (REL/PROG) despite primary treatment (ABVD +/- IFRT) or death from any cause; mPFS events were the first of radiotherapy given after ABVD if the post-ABVD PET was positive (PET-RT), relapse or progression after primary treatment (REL/PROG) or death from any cause. Results We observed 56 PFS events (REL/PROG, 54; death 2) and 64 mPFS events (PET-RT, 17; REL/PROG 45; death 2). Thus, 8/64 (13%) of the relevant events (failure of the primary chemotherapy to cure the lymphoma) were unappreciated using the standard PFS endpoint. This resulted in an overestimate of the effectiveness of primary chemotherapy (2-y PFS 78%; 2-y mPFS 72%) and of the duration of survival free of death, relapse or progression (time to 25% treatment failures using standard PFS = 2.8 y; using mPFS = 1.1 y) (Figure 1). These overestimates occur because the addition of radiotherapy to the primary chemotherapy “rescues” patients whose primary chemotherapy has failed (PET positive residual disease still present after completion of the primary chemotherapy) and creates the appearance of successful treatment. Conclusion Use of the mPFS endpoint provides a superior assessment compared to standard PFS if the goal of a clinical trial testing treatment for advanced stage Hodgkin lymphoma is to identify the most effective chemotherapy regimen. This is particularly important in an era when post-chemotherapy evaluation with PET has become standard and major efforts are being made to determine the potential benefit of adding novel agents such as antibody-drug conjugates and checkpoint inhibitors to standard chemotherapy.
  • Connors JM
  • Gerrie AS
  • Scott DW
  • Sehn LH
  • Villa D
  • Savage KJ
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P008 (P008)

Treatment results for Hodgkin Lymphoma in Brazil: first report from the Brazilian Prospective Hodgkin’s Lymphoma Registry

Introduction: Data about Hodgkin Lymphoma (HL) in developing countries are scarce. In 2009, a prospective registry of HL was implemented in Brazil. Methods: Twenty institutions take part in the registry. Clinical, treatment and outcome data were prospectively collected in a web-based platform, and are reported here for the first time. Results: 756 HL patients (pts) with diagnosis until December 31, 2014 were identified. Twenty-one pts with nodular-predominant HL, 11 pts younger than 13 years-old and 38 pts with HIV were excluded, with 686 pts available for this analysis. Median age was 30 years-old (13-90); 67 (10%) pts were older than 60. Females comprised 346 pts (50%). Median time from onset of symptoms to diagnosis was 6 (0-60) months. Forty-four (7%) pts had limited disease, 180 (26%) had intermediate disease and 445 (65%) had advanced disease by GHSG criteria. Stage IVB was present in 26%, B symptoms in 69%, low albumin in 63% and a high-risk IPS score in 38%. Median time from diagnosis to beginning of treatment was 0.72 months (0-10.87 months). Median follow-up was 37 months (0.53-94) for all patients, and 40 months (4-94) for patients alive. ABVD was the first-line treatment in 93% of pts. Twenty-one patients died during treatment. After completed treatment, the complete remission (CR) rate was 73%, unconfirmed CR was 12%, partial remission was 4%, stable disease was 2% and progressive disease was 9%. Among those who received ABVD, the median number of cycles was 4 for limited and intermediate and 6 for advanced disease. Radiotherapy (RT) was used in 33% of advanced disease pts, 65% of intermediate disease pts, and 77% of limited disease pts. The median dose of RT was 36 Gy for localized disease, and 32 Gy for advanced disease. The median time from the end of chemotherapy to the beginning of RT was 1.7 months. The 3-year OS and 3-year PFS were 90% and 74%, respectively. The 3-y PFS in limited disease, intermediate disease and advanced disease were 95%, 88% and 66% (p<0.0001), respectively. The 3-year OS for limited disease, intermediate disease and advanced disease were 100%, 96% and 86% (p=0.0001), respectively. Conclusions: Advanced stage and poor risk patients predominated. Radiation doses used for localized disease appear higher than current recommendations. Outcomes for advanced disease appear to be 5-10% lower than in developed countries, in part due to very advanced disease at diagnosis, and to an excess of deaths during treatment.
  • Biasoli I
  • Castro N
  • Delamain M
  • Silveira T
  • Farley J
  • Pinto Simões B
  • Solza C
  • Praxedes M
  • Baiocchi O
  • Gaiolla R
  • Franceschi F
  • Bonamin C
  • Boquimpani C
  • Clementino N
  • Perini G
  • Pagnano K
  • Steffenello G
  • Tabacof J
  • de Freitas Colli G
  • Soares A
  • de Souza C
  • Chiattone CS
  • Milito C
  • Morais JC
  • Spector N
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P009 (P009)

Dose-Dense/Dose-Intense ABVD (dd-di ABVD) in advanced stage Hodgkin's Lymphoma (HL): A Long-Term Follow Up Study

One-hundred forty-three patients with advanced-stage HL were treated with a dose-dense three-weekly version of the ABVD regimen, which was also dose intensified, in the first 4 cycles, by escalating doxorubicin. Specifications are contained in the published article (Russo F BHJ 166,1,118, 2014). Twelve patients (8.4%) received radiotherapy (RT) on residual mediastinal or extramediastinal bulk disease. Results were compared with a historical series of 111 patients treated with standard ABVD+/-RT. The demographics and clinical characteristics are in Tab1. Ninety-six percent of patients completed the planned 6 cycles (median time=16.8 weeks). Median actual dose intensities were 20.87 (23.11 cycles1-4), 6.72, 3.89 and 248 mg/m2/week for doxorubicin, bleomycin, vinblastine and dacarbazine, respectively. This corresponded to a 66.9% (85.0%, cycles 1-4) increase in dose intensity for doxorubicin, (total dose 380 mg/m2) and of 32% for the other agents, over standard ABVD. Intensified ABVD confirmed to be highly tolerated with low rates of hospitalization during treatment, a low incidence of G3/ G4 events, low post-treatment cardiac and pulmonary toxicities and a very low rate of gonadic toxicity. Only two cases of second cancer were recorded. One-hundred-eleven out of 143 (79%) showed a PET normalization at the end of 2nd cycle. Comparison between intensified and standard ABVD showed complete remission (CR) rates 93.7% in intensified ABVD and 80.2% in standard ABVD, respectively (p=0.002). EFS and OS rates at 7 years were 85.7% vs 68.1% and 93.9% vs 76.3%. At univariate analysis the predictive factors of low CR rate were IPS≥3 ( p=0.032), and PET2pos (p <0.001). At multivariate analysis PET2pos (p<0.001) was the only independent risk factor predictive of low CR rate. Seven-yr EFS was significantly better in patients with PET2neg (log rank 13.2, p<0.001) and in patients with IPS 0-2 (log rank 4.3, p=0.032). At Cox regression analysis PET2 was the only independent factor predictive of EFS. As on 09/2015, one-hundred-thirty-five out of 143 are alive with 131 free of disease (123 in 1stCR,8 in 2ndCR). Intensified ABVD seems to be adequately powered to exploit early disease chemo-sensitivity yielding high percentage of PET2neg , high rate of response and survival, without new severe or critical short and long-term toxicities. Selective use of low dose RT in residual PET+ tissue seems to rescue a subset of patients with bulky disease and suboptimal response.
  • Filippo R
  • Luigi A
  • Gino S
  • Pietro F
  • Secondo L
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P010 (P010)

THE SWITCH FROM ABVD TO eBEACOPP AS FRONT-LINE THERAPY FOR HIGH-RISK STAGE III-IV CLASSICAL HODGKIN LYMPHOMA (cHL) PATIENTS RESULTS IN AN INVERSION OF EVENT-FREE SURVIVAL (EFS) OF PROGNOSTIC GROUPS

When ABVD is used as the chemotherapy backbone for newly diagnosed cHL, patients with favorable stage I-II (EF), unfavorable stage I-II (EU), favorable stage III-IV (Hasenclever index 0-2) (AF) and unfavorable stage III-IV (Hasenclever index ≥3) (AU) differ in EFS with the latter having the worst prognosis. GHLSG has reported that the introduction of eBEACOPP-based chemotherapy for EU and advanced stage groups annuls this difference. To our knowledge, no other group has reproduced these findings. Since 2010, after the end of accrual into the EORTC 20012 trial, we recommend eBEACOPP as front-line therapy for AU. During 2014/5 this recommendation was extended to AF and EU patients. Here we analyze the outcome of different prognostic groups of newly diagnosed cHL patients below 60 years of age treated at our institution during the period of almost 5 years when eBEACOPP was used as initial treatment only for AU patients. There were 13 patients in the EF group, one was treated with ABVD only, one with radiotherapy (RT) only, and 11 with the combination of ABVD and RT. None relapsed or died. 38 patients were in the EU group. All started ABVD, two switched to eBEACOPP because of interim PET positivity; 33 received RT and five chemotherapy only. Two progressed immediately after RT, additional 8 relapsed, 2 died. EFS at three years was 72% and OS 97%. 20 patients were in the AF group. All received ABVD, three switched to eBEACOPP because of interim PET positivity; four received additional RT. Two patients died, one due to sepsis after switching to eBEACOPP and one, treated with ABVD, due to bleomycin-related pneumonitis; additional two relapsed. EFS at three years was 79% and OS 90%. 34 patients were in the AU group. 30 started treatment with eBEACOPP and 4 with ABVD, one switched to eBEACOPP because of interim PET positivity; 10 received additional RT. One patient died during treatment, presumably due to pulmonary embolism; one relapsed. EFS at three years was 94% and OS 97%. The difference in EFS between EU and AF is statistically significant (p=0.023) (Fig.1). If eBEACOPP is used for front-line treatment only in patients with high-risk advanced stage disease, this results in paradoxical inversion of EFS between prognostic groups. eBEACOPP should be considered for all newly diagnosed HL patients younger than 60, except those in the lowest risk group.
  • Aurer I
  • Basic-Kinda S
  • Dujmovic D
  • Radman I
  • Dreta B
  • Dotlic S
  • Galunic-Bilic L
  • Dobrenic M
  • Kralik M
  • Roncevic P
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P011 (P011)

HALO Study: a phase 1/2 clinical trial of Brentuximab-Vedotin and Bendamustin in elderly patients with previously untreated advanced hodgkin lymphoma. Preliminary data

Treatment of elderly patients with HL remains a difficult challenge as results and tolerance of the standard treatment with ABVD remains very inferior to adults. Bendamustine (Be), andwith Brentuximab Vedotin (BV), are active drugs, which have demonstrated a good tolerance and an high level of response in relapsing/refractory HL. To assess the safety and the efficacy of the combination of this two drugs in elderly HL , we conduct a prospective multicentric open-label stydy of Brentuximab-Vedotin (BV): 1.2 mg/kg D1 and Bendamustin (Be) 90 mg/m2/day , D1 and D2, every 3 weeks up to 6 cycles, for patients from 60 to 80 years of age, with advanced HL, stage 2B to 4,. Ten centers, 5 from Italy and 5 from France, participate to the study. A total of 60 patients are planned to be included. An evaluation by TEP-Scan will be performed after the 2nd cycle and treatment will be pursued until the 6th cycles for patients in CR according to Lugarno’s criteria. A supplementary control by TEP-scan is planned after the 4th cycle for patients in PR after 2 cycles. . Patients with progressive disease at any time or not in CR after 4 cycles will receive salvage therapy according the choice of the local investigator. A final evaluation by PET-Scan is planned for all patients after the 6th cycle. A centralized review of all TEP-Scan is planned. . The patients will be followed up for 3 years. The study is divided in 2 phases: the phase 1 with 12 patients with the main objective to evaluate the tolerability and toxicity of Be-BV and the phase 2 with 48 patients, with the primary objective to evaluate the efficacy in terms of response rate after treatment completion. The secondary objectives of the phase 2 are to evaluate the efficacy in terms of PFS, EFS and OS at 3 years, to evaluate the efficacy in terms of complete response rate after two cycles of Be-BV and to evaluate the feasibility of the treatment Currently, we have enrolled 14 patients: 9 patients have performed the first TEP-Scan evaluation after 2 cycles: 7 were in complete response and 2 in partial responses according to local evaluation. The 2 patients in PR after 2 cycles were in CR at the evaluation by PET-Scan after 4 cycles. None unexpected toxicity has been observed and the trial remains open to inclusions. The precise design of the study and updated results will be presented for the symposium. Study is supported by a grant of Millenium US/Takeda France
  • Viviani S
  • Fontanet B
  • Rambaldi A
  • Perrot A
  • Patti C
  • Gastaud L
  • Sorasio R
  • Debaigt C
  • Chamorey E
  • Gallamini A
  • Thyss A
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P012 (P012)

Transformation of nodular Hodgkin's lymphoma with lymphocyte predominance to T-cell-rich large B-cell lymphoma

Aim. To describe clinical features of transformation of nodular Hodgkin's lymphoma (HL) with lymphoid predominance (NLHLP) to T-cell-rich large B-cell lymphoma (TCRLBCL), to evaluate the effectiveness of therapy program BEACOPP-14 in this group of patients. Materials and methods. During the period from 2010 to 2016 the transformation NLHLP to TCRLBCL was diagnosed in 15 patients. Male to female ratio 4: 1, median age 40 (23-68) years. NLHLP diagnosis was based on histological and immunohistochemical study of the biopsy of the tumor, the stage of disease - by standard for LH methods. Results. Of the 46 patients with NLPLH observed in National Reserch Center for Hematology, transformation NLHLP to TCRLBCL was diagnosed in 15 (33%) patients (13 untreated patients with a long history of lymphadenopathy, and 2 patients with relapsed Hodgkin's lymphoma after 3 years and 21 years ). All patients had advanced stages of disease. All untreated patients had previous long-term asymptomatic lymphadenopathy. B - symptoms were noted in 11 (73%) cases. Extranodal involvement had 12 (80%) patients: liver damage - in 7 (47%), lung involves - in 5 (33%), spleen involves - in 10 (67%), bone marrow lesions was found in 9 (60%) patients and was proved by histological and immunohistochemical study. Follow-up of the 15 patients: 1 patient with transformation to TCRLBCL in relapse (in 21year after the end of LH treatment) was not treated (refusal of treatment, death), 1 patient received ABVD and achieved complete remission, the remaining 13 patients received BEACOPP-14, complete remission was achieved in 11 (85%), partial remission - in 2 (15%) patients. In one young patient with transformation NLHLP to TCRLBCL with aggressive clinical presentation of disease complete remission was consolidated by high-dose chemotherapy followed by autologous peripheral blood stem cells transplantation. Conclusions. The clinical features of transformation NLHLP to TCRLBCL are advanced stages of disease with presence of B-symptoms, frequent involvement of extranodal sites and bone marrow. Therapy by BEACOPP-14 program can lead to complete remission in 85% of patients.
  • Moiseeva TN
  • Al-Radi LS
  • Dorokhina EI
  • Goryacheva SR
  • Margolin OV
  • Magomedova AU
  • Julhakyan HL
  • Kravchenko SK
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P013 (P013)

ABVD AS THE TREATMENT OPTION IN HODGKIN LYMPHOMA WITH LARGE MEDIASTINAL TUMOR

Background: Large mediastinal tumor is considered as an unfavorable prognostic factor for Hodgkin’s lymphoma (HL). Patients with advanced Ann Arbor clinical stages (CS III and IV) are considered as advanced disease. Nevertheless, some study groups are also stratifying patients with large mediastinal tumor as advanced disease. Aim: The aim of this study was to assess the outcome of ABVD treated HL patients with large mediastinal tumor, as well to identify risk factors for poor outcome. Patients and methods: A study was performed on 173 HL patients with large mediastinal tumor (more than one-third of the maximum horizontal chest diameter on CXR) diagnosed between 1997 and 2011. The standard initial treatment was 6-8 cycles of ABVD +/- radiotherapy. Beside the patients with advanced CS, this study also included patients wirh CS II who were according to institutional guidelines treated the same as patients with advanced CS. Results: The median age was 29 (range 16-68). The median follow up was 94 months. Five-year event free survival (EFS) was 62% and 5-year overall survival (OS) was 76%. In univariate analysis, there was no difference in survival based on CS, both in OS (log rank; p=0.180) and EFS (log rank; p=0.126). Worse OS was found only in patients with IPS≥3 (5-year OS 62.5% vs. 82.1%; log rank, p=0.011), while presence of age>45, male gender, ESR≥50 mm/h, B symptoms or EN disease didn’t influence OS (log rank; p=0.499, p=0.145, p=0.631, p=0.111, p=0.900, respectively). Worse EFS was found in patients with IPS≥3 (5-year EFS 51.8% vs. 67.6%) and males (5-year EFS 54.8% vs.66.7%) (log rank; p=0.037, p=0.016, respectively), while presence of age>45, ESR≥50 mm/h, B symptoms or EN disease didn’t influence EFS (log rank; p=0.960, p=0.885, p=0.295, p=0.887, respectively). The multivariate Cox regression analysis identified IPS≥3 as the independent prognostic factor for OS (p=0.023; RR=1.982; 95% CI 1.100-3.570) and male gender for EFS (p=0.011; RR=1.852; 95% CI 1.153-2.974). Conclusion: The initial approach in patients with CS II and large mediastinal tumor shouldn’t be different from advanced clinical stages. More effective approach seems to be required, especially in males and patients with high IPS.
  • Andjelic B
  • Jakovic L
  • Antic D
  • Todorovic M
  • Bila J
  • Djurasinovic V
  • Sretenovic A
  • Vukovic V
  • Jelicic J
  • Smiljanic M
  • Mihaljevic B
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P014 (P014)

PERIPHERAL BLOOD EOSINOPHILIA IS A GOOD RISK FACTOR IN POOR PROGNOSIS GROUP: ADVANCED HODGKIN LYMPHOMA WITH LOW ALC/AMC

We studied the prognostic significance of the absolute neutrophil/lymphocyte ratio (ANC/ALC), the absolute lymphocyte/monocyte ratio (ALC/AMC), absolute eosinophil count (AEoC) and their contribution to prognostic value of the International Prognostic Score (IPS) in 361 advanced Hodgkin lymphoma (HL) patients. The receiver operating characteristic curve identified the best cut-off values as 4.3 for ANC/ALC and 2.0 for ALC/AMC. Univariate analysis showed that all analyzed factors were associated with lower OS: ANC/ALC>4.3 (OS5yrs with/without risk factor 72% vs. 85%, respectively, p<0.01); ALC/AMC<2 (OS5yrs with/without risk factor 64% vs. 86%, respectively, p<0.01); AEoC<0.5x10e6/L (OS5yrs with/without risk factor 76% vs. 88%, respectively, p<0.01); IPS >2 (OS5yrs with/without risk factor 66% vs. 86%, respectively, p<0.01). Apart from AEoC, these factors also had a significant impact on EFS - ANC/ALC>4.3 (EFS5yrs with/without risk factor 55% vs. 72%, respectively, p<0.01); ALC/AMC <2 (EFS5yrs with/without risk factor 46% vs. 73%, respectively, p<0.01); IPS >2 (EFS5yrs with/without risk factor 51% vs. 71%, respectively, p<0.01). Overall survival multivariate analysis identified ALC/AMC<2, IPS>2 and AEoC<0.5x10e6/L as prognostic factors for poor OS (p<0.01; p<0.01; p<0.01 respectively). In a respective model for EFS, ALC/AMC<2 and IPS>2 were also significant (p<0.01; p<0.05, respectively). After evaluating ALC/AMC and IPS, we stratified patients into 3 progressively-worse-outcome groups (low-risk: 0; intermediate: 1 risk factor; high: 2 risk factors) both for OS (91%; 74%; 56%, p<0.01) and EFS (77%; 58%; 41%, p<0.01). Furthermore, we observed that patients with eosinophilia, AEoC>0.5x10e6/L had significantly better OS in group with ALC/AMC<2 (82% vs. 58%, p<0.01), as well as in low IPS group (97% vs. 84%, p<0.05), but not in group with high IPS (75% vs. 64%, p>0.05). Our study encourages the combination of ALC/AMC with IPS, thus providing an improved risk prediction in advanced HL patients. Moreover, present peripheral blood eosinophilia separates patients with better prognosis in poor prognostic group.
  • Jakovic LR
  • Mihaljevic BS
  • Andjelic BM
  • Bogdanovic AD
  • Perunicic Jovanovic MD
  • Bumbasirevic VZ
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P015 (P015)

Lower socioeconomic status is associated with shorter survival in HL patients – an analysis from the Brazilian Hodgkin Lymphoma Registry

Introduction: Socioeconomic status (SES) is a well-known determinant of outcomes in cancer. We have previously reported that Hodgkin’s lymphoma (HL) patients (pts) with a lower SES had inferior survival in a different cohort from Rio de Janeiro. Methods: SES stratification was done using an asset/education-based household index widely used in publicity and political polls in Brazil. Results: 624 classical HL pts with diagnosis until December 31 2014, ≥ 13 y-old and HIV-, treated with ABVD, were analysed. The median follow-up was 35.6 months for all pts, 67% (390/578) were classified as higher SES and 33% (188/578) as lower SES. The 3-y PFS in higher and lower SES were 78% and 64% (p<0.0001), respectively. The 3-year OS in higher and lower SES were 94% and 82% (p<0.0001), respectively. Lower SES pts were more likely to be ≥ 60 years (16% vs 8%, p=0.003), to have a poor performance status (20% vs 10%, p=0.001) and high risk IPS (44% vs 31%, p=0.004), to present with advanced disease (71% vs 58%, p=0.003) and to have histopathology other than nodular sclerosis (31% vs 19%, p=0.002). Also, time to diagnosis > 4 months was more frequent in lower SES pts (69% vs 53%, p=0.0001). After adjustments for potential confounders (age, PS, advanced disease, IPS, histopathology and time to diagnosis), lower SES remained associated with poorer survival (HR = 3.15 [1.8-5.2] for OS and HR = 1.67 [1.2-2.31] for PFS). Twenty-one patients died during treatment, accounting for a death rate of 7.5% and 1.3% for lower and higher SES (p=0.0001). Infections and treatment toxicity accounted for 81% of deaths during treatment. No differences were found according to the distance and travel time from residence to hospital, or to availability of someone to transport pts to hospital in an emergency. Independent factors associated with death during treatment were: age ≥60 year, poor PS, advanced disease, lower SES and low educational level. Deaths after the conclusion of treatment occurred in 48 patients, mostly due to progressive disease. However, follow-up is still short for analysis of long-term outcomes. Conclusions: SES is an independent factor associated with shorter survival in Brazil. Along with age, advanced disease, and poor PS, SES and educational level allow the identification of vulnerable patients who might benefit from a program of intensive medical and social supervision, or from management modifications to reduce serious infections and drug toxicity during treatment.
  • Biasoli I
  • Castro N
  • Delamain M
  • Silveira T
  • Farley J
  • Pinto Simões B
  • Solza C
  • Praxedes M
  • Baiocchi O
  • Gaiolla R
  • Franceschi F
  • Bonamin C
  • Boquimpani C
  • Clementino N
  • Perini G
  • Pagnano K
  • Steffenello G
  • Tabacof J
  • de Freitas Colli G
  • Soares A
  • de Souza C
  • Chiattone CS
  • Raggio R
  • Milito C
  • Morais JC
  • Spector N
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P016 (P016)

THE IMPACT OF OUTCOME OF INTERIM PET/CT ON ADVANCED HODGKIN LYMPHOMA TREATED WITH BEACOPP-14

Introduction: To assess the role of interim positron emission tomography/computed tomography (PET/CT) and compare its with PET\CT results after the end of treatment the patients (pts) with advanced stages classical Hodgkin lymphoma (cHL). Methods: 114 newly diagnosed cHL pts received 6 cycles EACOPP every 14 days (doxorubicin 50 mg\m2, cyclophosphamide, etoposide, procarbazine, vincristine, prednisone). Consolidation radiotherapy was given to 78 (68%) pts. Interim PET/CT (iPET) imaging after 2 cycles was done in 54 (48%) pts. Results: With a median follow-up 35 months, 3-year progression-free survival (3-PFS) were 85%, overall survival - 92%. In 33 pts (61%) the iPET was negative - Deauville score 1-2 (DS 1-2). The residual uptake was higher than the mediastinal blood pool (MBP) uptake but below the liver uptake (DS 3) in 17 pts (31%) and 4 pts (8%) were PET-positive (DS 4-5). Сomplete metabolic response (CMR) after 2 cycles predicted higher 3-PFS compared PETpos (100% v 75%; p=0,0035 - figure 1). Patients with residual metabolic activity had equally good outcomes (100% v 92%; p=0,1). Of the 60 pts who not done iPET, 24 (40%) were performed PET\CT after the end of 6 EACOPP-14. There is not difference of outcome between 19 pts with CMR after the end of chemotherapy and 36 pts with CR\uCR according chest\abdominal\pelvic CT with contrast of diagnostic quality (3-PFS 78% v 91%; p<0,1). Conclusion: The intensive EACOPP-14 program showed good and early response for pts with advanced stage cHL. Predictive value of metabolic response after 2 cycles was higher than PET-negativity after the end of chemotherapy.
  • Medvedovskaya E
  • Leontjeva A
  • Demina E
  • Ryabukhina J
  • Tumyan G
  • Kokosadze N
  • Trofimova O
  • Larionova V
  • Dolgushin M
  • Odzharova A
  • Mukhortova O
  • Aslanidis I
  • Osmanov D
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P017 (P017)

ADVANCED HODGKIN LYMPHOMA – A RISK STRATIFICATION OF ABVD TREATED FEMALES IN GENERATIVE AGE

Background: Recent trials demonstrated that treatment results of BEACOPPesc are likely better than ABVD for advanced Hodgkin Lymphoma (HL). However, BEACOPPesc is associated with more toxic effects, with post treatment infertility as one of the major concerns. Aim: The aim of this study was to identify females in generative age with advanced HL who do not require more aggressive approach than ABVD. Patients and methods: This study was performed on 147 females younger than 40 years with advanced HL, diagnosed between 1997 and 2011. The initial treatment was 6-8 cycles of ABVD +/- radiotherapy. Prognostic relevance of IPS, ESR≥50 mm/h, as well presence of B symptoms, bulky disease and extranodal disease (EN) were examined. Results: For the whole group 5-year overall survival (OS) was 81% and 5-year event free survival (EFS) was 66%. Based on examined parameters, in univariate analysis worse OS had patients with IPS≥3 (5-year OS 61.1% vs. 87.3%; log rank, p=0.000) and EN (5-year OS 71.9% vs. 83.5%; log rank, p=0.036). Worse EFS had patients with IPS≥3 (5-year EFS 41.7% vs. 73.9%) and EN (5-year EFS 40.6% vs.73.0%) (log rank; p=0.000, p=0.000, respectively). The multivariate analysis identified IPS≥3 as the independent prognostic factor both for OS (p=0.002) and EFS (p=0.023), as well as EN for EFS (p=0.027). Subsequently, we analyzed the subgroup of 111 patients with low IPS. Thirty patients without bulky disease (27.0% of low IPS patients, 20.4% of the entire group) had better OS (5-year OS 100% vs. 82.7%, log rank, p=0.028) and trend toward better EFS (5-year EFS 90% vs. 67.9%, log rank; p=0.06), with only 2 deaths until the end of follow up. Based on IPS score (0, 1, 2), presence of ESR≥50 mm/h, B symptoms and EN there was no difference both in OS (log rank; p=0.166, p=0.359, p=0.459, p=0.865, respectively) and EFS (log rank; p=0.098, p=0.933, p=0.383, p=0.187, respectively). Moreover, bulky disease in this subgroup retained its prognostic significance in multivariate analysis for OS (p=0.044; RR=4.577; 95% CI 1.042-20.106). Conclusion: ABVD is very effective for females with advanced HL younger than 40 years with low IPS and without bulky disease.
  • Andjelic B
  • Jakovic L
  • Antic D
  • Todorovic M
  • Bila J
  • Djurasinovic V
  • Sretenovic A
  • Vukovic V
  • Jelicic J
  • Smiljanic M
  • Mihaljevic B
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P018 (P018)

ADVANCED STAGE HODGKIN LYMPHOMA IN MOROCCAN ADULTS: CLINICO-PATHOLOGICAL FEATURES AND THERAPEITIC OUTCOMES

Introduction: Advanced stage Hodgkin lymphoma (ASHL) is still a major concern to face in both developed and developing countries. Five-year survival rate ranges between 51% and 94.6% in Western literature. However, few is known about the features of ASHL in developing countries. The purpose of this study is to describe the clinic-pathological features of ASHL in Morocco. Methods: Retrospective descriptive study of diagnosed ASHL carried over a period of 6.5 years from January 2007 to August 2013 in a single Moroccan University Hospital, including all patients with ASHL (stage III and IV of Ann Arbor) aged over 18. Patients with retroviral infections and secondary HL were excluded. The diagnosis was based on histological examination of biopsy and immunohistochemistry. Patients were classified according to the classification of Ann Arbor, and stratified according to the score of IPS. Results: Four hundred and seventy-eight patients were diagnosed with HL (all stages) during the period study, among them 200 patients ASHL account for 46.3. The age was ranged between 18 and 91 years old (yo) with a median age of 32 yo. Sex ratio H/F was 1.66. Seventy three percent of ASHL patients didn’t have medical insurance and 47% were jobless. the median time to diagnosis was 6 months [1-52]. Lymphadenopathy was the most common presentation (61.5%). Eighty three patients (41,5%) were stage III, 117 patients (58,5%) were stage IV. Eighty two percent of the patients reported B symptoms. Nodular sclerosis was the predominant histological presentation of ASHL in adult (60.5%) followed by mixed cellularity (17.5%). Ninety nine percent of lymphoma’s biopsies were CD30+, 82.5% were CD15+ and LMP-1 was positive in 33.6%. Bulky disease was present in 37% of the ASHL. IPS score was ranged between 0 and 6 with a median of 3, 42,5% patients had a score less than 2. Survival was rated in patients treated with 8 cycles of ABVD +/- Radiotherapy (150 patients fulfilled the inclusion criteria). Twenty-one percent of patients were treatment failure, 12% relapsed. The death rate was 20.6% of which 45% was by progression disease. The 5-years overall survival and event free survival of ASHL patients were 70,9% and 41,7% respectively. Conclusion: This current pattern for epidemiological features and outcomes of ASHL enables delineate key populations in order to explore risk factors for ASHL and strategies to improve treatment outcomes, especially intensification strategies.
  • Kaddouri W
  • Anoun S
  • Khoubila N
  • Cherkaoui S
  • Lamchahab M
  • Quachouh M
  • Rachid M
  • Madani A
  • Quessar A
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P019 (P019)

General population-derived specific survival applied to Hodgkin Lymphoma

Mortality of patients (pts) affected with cancer can be partially unrelated to tumor, while accurate clinical investigation must be focused mainly on that tumor related. Specific survival (SS) is obtained by subtracting expected mortality (EM) – inferred from national or regional mortality tables – to the observed one. The expected survival (ES) is that enjoyed in the absence of tumor. ES corresponds to the time still at patients’ disposal in case of hypothetical full recovery and represents an absolute ceiling of maximal mean attainable SS for a given tumor in a given time. SS limits of variability clinically correspond to full recovery and death, and SS can be evaluated by the measure of how much, in a given time/site, a group of pts has approached the potentially attainable ES. On this full range of prognostic variability relies the comparability of SS, whatever time/site are involved. The number of years lost with respect to those expected represents a useful additional measure. ES and SS are subjected to the same conditioning factors, being contextualized into the evolving conditions of the health services, and depending on customs and behaviours. SS allowed comparison of the effectiveness of some chemotherapy regimens administered to pts with advanced-stage (IIB-IV) Hodgkin lymphoma (HL), whatever histologic subtype, age 16-65 years, of two randomized trials of the past decades. The IIL-HD9601 (1996-2000) enrolled 355 pts in three different arms: ABVD, Stanford-V and MOPPEBVCAD (MEC). The GISL-HD2000 (2000-2007) randomized 307 pts into three arms: ABVD (identical to IIL-HD9601), BEACOPP and COPPEBVCAD (CEC), a variant of MEC adopting cyclophosphamide instead of mechlorethamine at the dose considered with identical anti-lymphoma activity. CEC, ABVD and MEC showed the smallest ratio of expected/observed deaths. BEACOPP, ABVD and MEC allowed the relatively minimal loss of years of life per patient. The evaluation of the curves of ES confirmed the starting prognostic homogeneity of each arm of randomization (12-year ES from 0.965 [MEC] to 0.987 [BEACOPP]). The 12-year SS was 0.88, 0.81, 0.79, 0.79 for CEC, ABVD, BEACOPP, Stanford-V and MEC, respectively. The estimation of SS inferred from national or regional mortality tables allows a potentially unbiased comparison between treatments adopted in different time-spans, since it takes into account the social and health status along time. This method could be extended to other neoplasia.
  • Gobbi PG
  • Bellei M
  • Marcheselli L
  • Chisesi T
  • Merli F
  • Galimberti S
  • Iannitto E
  • Luminari S
  • Manni M
  • Stelitano C
  • Musto P
  • Pavone V
  • Vitolo U
  • Federico M
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P020 (P020)

The diagnostics and therapy of Hodgkin lymphoma in pregnancy, the experiences of one center

Hodgkin lymphoma is one of the most frequently diagnosed malignancies in pregnancy. In the group of nine patients of one center with manifestation of Hodgkin lymphoma in pregnancy we demonstrate the management of diagnostic and therapeutic procedures. Seven patients were diagnosed in 20-30th week of pregnancy; one with progressive lymphadenopathy already before confirmation of pregnancy and one patient with the diagnosis in 7th week. Only in one case there was induced abortion, and in one case the corticotherapy was started in the third trimester, in the rest of patients (7) the therapy was started after the delivery. Although there are some publications about therapy with single vinblastin, respectively combination chemotherapy ABVD in the second half of pregnancy, our experiences are based on preferation of thorough observation in pregnancy and indication of specific chemotherapy after delivery. This work was supported by grant awarded by AZV 16-29857A, Ministry of Health in Czech Republic and Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague, Czech Republic
  • Gahérová L
  • Móciková H
  • Marková J
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P021 (P021)

Difficulties in distinguishing syncytial variant of nodular sclerosis classical Hodgkin’s lymphoma from diffuse large B-cell lymphoma and complete remission after intensive chemotherapy

Case report: A 31-year-old woman presented at a primary care physician with a dry cough and a sore throat that had persisted for one month. A cold was diagnosed, but dyspnea gradually developed. A chest X-ray and computed tomography (CT) revealed a bulky mediastinal mass and several enlarged lymph nodes. Positron emission tomography/computed tomography (PET-CT) imaging showed increased 18-fluoro-deoxyglucose uptake in the bilateral supraclavicular, axillary, mediastinal, hilar, and paraaortic lymph nodes (maximum standardized uptake value [SUVmax], 13.4). A lymph node biopsy showed destruction of the basic structure, hyperplastic fibrous connective fibrous tissue and cohesive clusters and sheets of large malignant cells with a clear, vacuolated cytoplasm and sharply-defined borders. Flow cytometry could not determine the phenotype of the tumor cells. Immunostaining at our hospital showed that the tumor cells expressed CD15, CD30, and CD79a but not CD2, CD3, CD10, or CD20. We initially diagnosed clinical stage 3, CD20-negative diffuse large B-cell lymphoma (DLBCL) and started the patient on the original intensive treatment protocol for advanced, aggressive lymphoma (ML5 protocol). The patient partially responded to the first CHOP-like regimen (doxorubicin 40mg/m2 day1,5,9, vindesine 3mg/body day1,5,9, cyclophosphamide 1000mg/m2 day2,6,10, prednisolone 60mg/m2 day1-10) and then an etoposide-based second regimen(etoposide 100mg/m2 day1-3, 8-10, mitoxantrone 8mg/m2 day1, 8, cyclephosphamide 400mg/m2 day2, 9, prednisolone 60mg/m2 day1-3, 8-10, procarbazine 100mg/m2 day1-10) resulted in a complete response (CR) on PET-CT images. The Department of Pathology, Okayama University, Japan found that the tumor cells were CD79a-, Bob.1-, Oct.2-, indicating a syncytial variant of nodular sclerosis classical Hodgkin lymphoma (NSCHL). Discussion: A syncytial variant of NSCHL has been described in Cancer (1990), and this disease is statistically more advanced at diagnosis and often accompanied by huge mediastinal masses that require treatment after diagnosis. We applied the intensive chemotherapy used for DLBCL to our patient, but seven of eight other patients achieved CR after the administration of MOPP (mechlorethamine, vincristine, procarbazine, prednisolone) or ABV (doxorubicin, bleomycin, vinblastine) regimens. Therefore, awareness of this variant is needed at initial diagnosis to ensure appropriate treatment.
  • Okatani T
  • Asaoku H
  • Fujiwara M
  • Sato Y
  • Seto M
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P022 (P022)

Systemic Hodgkin's Disease with osseal involvement

Hodgkin’s Disease most commonly presents with progressive painless enlargement of peripheral lymph nodes. At diagnosis, osseous involvement is rare (<2%) and even in refractory or relapsing disease only 1/3 of the patients have any bony involvement. Systemic Hodgkin’s Disease with skeletal involvement is considered to have worse prognosis. We present a 26-year-old female, who admitted to our orthopedic department with complaints of deformity and pain in the left shoulder. Upon examination, mild local tenderness was noted with no neurological findings. Patient also had involvement of adjacent axillary and supraclavian nodes. Regarding laboratory tests, mild anemia and leukocytosis along with increased ESR and CRP were noted. Left shoulder X-Ray showed osteolytic lesion of capita arm extended to the upper third of diaphyseal humeral. Magnetic resonance imaging (MRI) showed lesions of the capita arm and diaphyseal humeral (low T1/high T2) with surrounding soft tissue mass. CT scanning revealed left axillary/supraclavian and mediastinal lymphadenopathy. Lymph node and bone mass biopsies confirmed the diagnosis of Hodgkin’ Disease (nodular sclerosis).The patient received 8 courses of ABVD with PET positivity after completion in left humerus (18FDG suv max : 3.8). Subsequently involved field radiotherapy (4000cGy) was given with no additional treatment benefit. The patient was then deferred to transplantation unit and underwent ASCT, resulting in long term complete remission (PET negative-4,5 years). Osseous involvement in systemic Hodgkin’ Disease is rare but warrants intensive treatment in order to achieve sustained remission.
  • Banti A
  • Papadakis E
  • Kioumi A
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P023 (P023)

Brentuximab Vedotin Alone and in Combination With Dacarbazine or Bendamustine in Patients Aged ≥60 Years With Newly Diagnosed Hodgkin Lymphoma: Interim Results of a Phase 2 Study

Background. Treatment-related mortality and inferior responses to chemotherapy lead to poorer outcomes for patients aged ≥60 years with newly diagnosed Hodgkin lymphoma (HL). This phase 2, frontline, open-label study is evaluating safety, efficacy, and durability of response to treatment with brentuximab vedotin (BV) as monotherapy and in combination with dacarbazine (DTIC) or bendamustine. The primary endpoint is objective response rate (ORR) (NCT01716806). Methods. Patients with classical HL who were ineligible for or declined initial conventional chemotherapy and had ECOG ≤3 were eligible. The study evaluated cohorts of 1.8 mg/kg BV (16 cycles), 1.8 mg/kg BV + 375 mg/m2 DTIC (12 cycles), and 1.8 mg/kg BV + 90 or 70 mg/m2 bendamustine (starting dose reduced to improve tolerability after 10 patients treated) (6 cycles). Patients with clinical benefit could subsequently continue BV treatment. Responses were assessed per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results. Enrollment was completed sequentially (treated patients: n=27 BV; n=22 BV+DTIC; n=20 BV+bendamustine), all patients are off treatment, and 44 remain in long-term follow-up (n=16 BV; n=18 BV+DTIC; n=10 BV+bendamustine). Overall, median age was 76 years (range, 62–92). At baseline, 70% of patients had Stage III-IV HL, 13% presented with bulky disease, 41% had B symptoms, 25% had ECOG 2-3, and 72% were ineligible for frontline chemotherapy. Treatment was discontinued for adverse events (n=35; mostly peripheral neuropathy, n=24), progressive disease (PD; n=15), or other reasons (n=19). Although no specific safety signal was identified, the sponsor suspended treatment with bendamustine because the tolerability did not meet the study goal of defining a low toxicity regimen for this patient population (Table). Median number of treatment cycles, median observation time, ORR, complete remission (CR) rate, median progression-free survival (PFS), and overall survival (OS) are presented by cohort (Table). Conclusions. Both BV monotherapy and BV+DTIC appear tolerable and yield high response rates (ORR 92-100%) in this fragile patient population. Furthermore, the combination with DTIC appears to increase the durability of response without increasing toxicity; and therefore, may represent a reasonable frontline treatment option for elderly HL patients. Other treatment combinations are being considered.
  • Friedberg JW
  • Forero-Torres A
  • Cline-Burkhardt VJM
  • Bordoni RE
  • Patel-Donnelly D
  • Flynn PJ
  • Chen R
  • Fong A
  • Yasenchak CA
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T001 (T001)

BEACOPP escalated followed by radiotherapy of initial bulk or residual disease in advanced-stage Hodgkin Lymphoma: long-term follow-up of the GHSG HD9 and HD12 trials

abstract talk Abstract Talk in Advanced Stages (Tuesday, 25.10. 10:30)

Introduction: The HD9 trial had established 8xBEACOPPescalated followed by radiotherapy (RX) of initial bulk or residual tumors as standard of care for advanced Hodgkin Lymphoma (HL) at that time. The successor study of HD9, HD12, evaluated a reduction of chemotherapy and RX. Since the long-term safety and efficacy of BEACOPPescalated and RX has been debated, we report the HD9 and HD12 long-term follow-up. Patients and methods: All patients had advanced HL. 1,282 HD9-patients were randomized between 8xCOPP/ABVD, 8xBEACOPPbaseline, and 8xBEACOPPescalated. 1,670 HD12-patients were randomized between 8xBEACOPPescalated, and 4xBEACOPPescalated followed by 4xBEACOPPbaseline (“4+ 4”), both with or without RX to initial bulk and residual disease. Results: In HD9-patients treated with COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, the 15-year progression-free survival (PFS) was 57%, 66.8%, and 74% with overall survival (OS) rates of 72.3%, 74.5%, and 80.9%, respectively. BEACOPPescalated remains significantly better than COPP/ABVD in terms of PFS (P<0.0001) and OS (P=0.02). A total of 123 second malignancies corresponding to 15-year cumulative secondary malignancy incidences of 7.2%, 13%, and 11.4% were reported for COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, respectively, without a difference between COPP/ABVD and BEACOPPescalated (p=0.5). Standardized incidence ratios (SIR) with 95%-CI were 2.0[1.2-3.2], 2.6[1.9-3.4] and 2.6[1.9-3.4]. The 10-year PFS and OS rates in the two HD12 chemotherapy groups were not significantly different with 82.6% and 87.3% in the BEACOPPescalated group and 80.6% and 86.8% in the 4+4 group, respectively. However, omitting RX resulted in an significantly inferior 10-year PFS of 83.5% in no RX patients with initial bulk/residual disease compared to RX (88.6%, difference -5.1%; 95%-CI,-9.9% to -0.4%, hazard ratio [HR] 1.47; figure 1) and a trend towards inferior OS in no RX patients (RX 93%; no RX 90.2%; difference -2.7%; 95%-CI,-6.5% to 1%). Patients with residual lesions without RX had an inferior OS as compared to patients with RX (as treated comparison: RX 94.4%; no RX 88.4%; difference -6%; 95%-CI,-11.4% to -0.5%). Conclusions: The superiority of BEACOPPescalated to COPP/ABVD is confirmed by this HD9 long-term analysis. The HD12 long-term analysis shows an inferior PFS and trend towards inferior OS in patients in the no RX groups, particularly in patients with residual lesions.
  • von Tresckow B
  • Kreissl S
  • Haverkamp H
  • Sasse S
  • Diehl V
  • Engert A
  • Borchmann P
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T002 (T002)

Overall survival (OS) impact of BEACOPP versus ABVD in advanced Hodgkin Lymphoma: a pooled analysis of 4 randomized trials

abstract talk Abstract Talk in Advanced Stages (Tuesday, 25.10. 10:30)

Introduction. In 4 individual randomized trials comparing ABVD and BEACOPP in advanced HL, BEACOPP significantly improved disease control but not OS. We explored the potential OS benefit of BEACOPP in a pooled analysis of these 4 trials. Methods. The primary objective was to assess the impact of BEACOPP on OS by one-stage individual patient data meta-analysis stratified for trial. Secondary endpoints were PFS, early toxicities, second malignancies and use of hematopoietic stem cell transplantation (HSCT). Results. Four trials representing a total of 1227 patients (622 ABVD and 605 BEACOPP) were included (IIL Viviani 2011, LYSA H34 Mounier 2014, EORTC 20012 Carde 2016, HD2000 Merli 2016). Patients characteristics: median age: 32 yrs, male 64%, nodular sclerosis 78%, stage II-III-IV: 13-32-55%, B symptoms: 77%, Bulky disease: 38%, IPS>3: 66%. With a median fup of 4.9 yrs, the 5-yrs OS is 86.59% for ABVD (95%CI=83.0-89.3) vs 90.8% for BEACOPP (95%CI=88.0-93.0). The data indicated that the HR is not constant over time (P<0.05) preventing the use of a simple Cox model. Per analysis plan, two time periods (< and ≥ 18m) were defined from the observed survival and hazard curves. In the first 18 months (N=1227, 54 events), no difference was detected (HR:0.75, 95%CI=0.41-1.23). After 18 months (N=1083, 68 events), the risk of death appeared higher in patients in ABVD arm than in BEACOPP arm (HRABVD vs BEACOPP=2.52, 95%CI=1.48-4.28, p<0.001). Further adjustment for IPS showed that both treatment (p<0.001) and IPS group (p=0.0326) effects are significant. The 5-yr PFS was 72.0% for ABVD (95%CI=67.3-76.1) vs 82.9% for BEACOPP (95%CI=78.7-86.4) (p<0.001). Grade 3-4 toxicities (ABVD vs BEACOPP): anemia: 4.3% vs 24.2%; leukopenia: 23.2% vs 76.8%; thrombocytopenia: 1.7% vs 26.4%; infection: 7.9% vs 34.2%. After ABVD, 17 second malignancies (0 AML) (2.7%) were reported and 21(7 AML)(3.6%) after BEACOPP. After ABVD, 86 patients (13.8%) received HSCT vs 39 (6.4%) after BEACOPP. Conclusions. This pooled analysis of 4 studies with increased power, indicated a non-constant treatment effect over time. A statistically significant OS benefit of BEACOPP was observed from 18 months after randomization. Frontline use of BEACOPP increased PFS, early hematological toxicity, secondary leukemia incidence but halved the need of HSCT. Further follow-up is needed to explore the impact of BEACOPP on fertility, second malignancies and long term survival.
  • André M
  • Fortpied C
  • Viviani S
  • Bellei M
  • Carde P
  • Hutchings M
  • Gianni A
  • Brice P
  • Casasnovas O
  • Gobbi P
  • Zinzani PL
  • Dupuis J
  • Iannitto E
  • Rambaldi A
  • Brière J
  • Perrot A
  • Heczko M
  • Valagussa P
  • Douxfils J
  • Joubert C
  • Federico M
  • Mounier N
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T003 (T003)

Long-term follow-up of SWOG S0816: response-adapted therapy of advanced stage Hodgkin Lymphoma using early interim FDG-PET imaging

abstract talk Abstract Talk in Advanced Stages (Tuesday, 25.10. 10:30)

S0816 was the first US intergroup clinical trial using early interim FDG–PET imaging to determine the utility of response-adapted therapy for adults with stage III–IV classical Hodgkin Lymphoma. After 2 initial cycles of ABVD, PET2-negative patients (Deauville 1-3) received an additional 4 cycles of ABVD, while PET2+ patients (Deauville score 4-5) switched to eBEACOPP for 6 cycles. Among 336 eligible and evaluable patients, the median age was 32 (18-60), with 52% stage III, 48% stage IV, and 49% IPS 0-2, 51% IPS 3-7. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2+. Of 60 eligible PET2+ patients, 49 switched to eBEACOPP as planned and 11 declined. The median follow-up of patients last known alive now exceeds 45 months (range 2.1-76 months). Eighty-two patients have either progressed or died, for an estimated 2-year progression-free survival of 79% (95%CI: 73.8%-82.7%). There were 61 failures in the PET2-negative group (2-year PFS 82%) and 20 failures in the PET2+ group (2-year PFS 64%), see figure. In the entire trial, only 19 patients died, for estimated 2-year overall survival of 98%. Long-term or late (post therapy) grade 3 adverse events on ABVD arm were uncommon including 1 case each of neuropathy, heart failure, DVT, diarrhea and prolonged neutropenia. There was one case of late grade 3 osteonecrosis on the eBEACOPP arm. Six patients (1.4%) have developed secondary malignancies, including 3 cases (1%) on ABVD (non-Hodgkin lymphoma, renal cell carcinoma, and melanoma) and 3 cases (6%) on eBEACOPP (non-Hodgkin lymphoma, renal cell carcinoma and skin cancer). We conclude that response-adapted therapy based on interim PET imaging after two cycles of ABVD appears promising and durable with a high 2-year PFS for PET2+ patients (64%), and outstanding overall survival. However, surprisingly, with prolonged follow-up, the majority of failures have occurred in PET2-negative patients, indicating the limitations to a PET-adapted approach. To further improve ABVD using precision medicine, we need to further refine predictive markers of failure at the time of Hodgkin lymphoma diagnosis. Support: National Cancer Institute (NCI), National Clinical Trials Network (NCTN) grants CA180888, CA180819, CA180821, CA180820, CA121947
  • Friedberg JW
  • Li H
  • Schöder H
  • Straus DJ
  • Moskowitz CH
  • LeBlanc M
  • Rimsza LM
  • Bartlett NL
  • Evens AM
  • Mittra ES
  • LaCasce AS
  • Sweetenham JW
  • Barr PM
  • Fanale MA
  • Knopp MV
  • Noy A
  • Hsi ED
  • Cook JR
  • Lechowicz MJ
  • Gascoyne RD
  • Leonard JP
  • Kahl BS
  • Cheson BD
  • Fisher RI
  • Press OW

Immunotherapy (Basic Science)

Selected for Oral Presentation

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    T007 (T007) Hodgkin Lymphoma infiltrating T cells: considering various means of tumor evasion

    • Wein F
    • Stock K
    • Hartmann S
    • Hansmann ML
    • Küppers R
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    T008 (T008) Award winning CCR5 blocking by Maraviroc inhibited recruitment, proliferation and pro-tumor effects of mesenchymal stromal cells and monocytes in 2D and 3D models of Hodgkin Lymphoma microenvironment

    • Casagrande N
    • Borghese C
    • Celegato M
    • Aldinucci D
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    T009 (T009) Award winning Disturbed antigen presentation in classical Hodgkin Lymphoma: implications for immune checkpoint inhibitor therapy?

    • Nijland M
    • Visser L
    • Veenstra R
    • Kushekhar K
    • van Imhoff G
    • van den Berg A
    • Diepstra A

Posters

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    P059 (P059) Tumor infiltrating HLA-matched CD4+ T cells retargeted against Hodgkin and Reed-Sternberg cells

    • Rengstl B
    • Schmid F
    • Weiser C
    • Döring C
    • Heinrich T
    • Warner K
    • Becker PSA
    • Wistinghausen R
    • Kameh-Var S
    • Werling E
    • Billmeier A
    • Seidl C
    • Hartmann S
    • Abken H
    • Küppers R
    • Hansmann ML
    • Newrzela S
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P059 (P059)

Tumor infiltrating HLA-matched CD4+ T cells retargeted against Hodgkin and Reed-Sternberg cells

Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4+ T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape anti-tumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong anti-tumor potential of allogeneic CD4+ T cells against HL cell lines. HRS and CD4+ T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4+ T cells from MHC-II compatible donors did not develop any anti-tumor potential in case of HL cell line L428. However, gene expression profiling of co-cultured HRS cells as well as tumor infiltration of matched CD4+ T cells indicated cellular interactions. Moreover, matched CD4+ T cells could be activated to kill CD30+ HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4+ T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.
  • Rengstl B
  • Schmid F
  • Weiser C
  • Döring C
  • Heinrich T
  • Warner K
  • Becker PSA
  • Wistinghausen R
  • Kameh-Var S
  • Werling E
  • Billmeier A
  • Seidl C
  • Hartmann S
  • Abken H
  • Küppers R
  • Hansmann ML
  • Newrzela S
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T007 (T007)

Hodgkin Lymphoma infiltrating T cells: considering various means of tumor evasion

abstract talk Abstract Talk in Immunotherapy (Basic Science) (Monday, 24.10. 10:30)

The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only one or a few percent of Hodgkin and Reed/Sternberg (HRS) tumor cells. HRS cells orchestrate this infiltrate by the secretion of a multitude of chemokines and direct cell–cell interactions. T cells are usually the largest population of cells in the HL tissue, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Helper and regulatory T cells presumably provide essential survival signals for the HRS cells, and the regulatory T cells also play an important role in rescuing HRS cells from cellular immune response. Here, we investigate the significance of the cHL-specific T cell infiltrate in regard to its role in tumor evasion. Comparing the global gene expression profiles of T cells isolated from cHL lymph nodes (LN) and reactive human tonsils revealed substantial phenotypical differences. Performing gene expression profiling, the T cell compartment in the cHL microenvironment featured an activated, highly proliferative and yet immunosuppressive phenotype. However, the nature of the regulative phenotype in both cHL CD4+ T cell subsets (Th: CD25- and CD127+; Tregs: CD25+ and CD127-) differs to the corresponding tonsillar Treg subset that comprises a purer population of natural FOXP3+ T cells. The ability of HRS cells to induce suppressive T cells was analyzed with an in vitro model system using human CD4+ peripheral blood (PB) T cells that were co-cultured with cHL cell lines. Co-cultured, naive T cells displayed an induced, CD25+ subpopulation and upregulated levels of FOXP3, CTLA4 and IRF4. Moreover, the exposure to HRS cells caused a dampened Th1 specific immune response. As for specific means of tumor evasion, the purinergic pathway seems an attractive co-factor. In vitro observations support a HRS dependent generation of environmental adenosine. Additionally, we observed an increase expression of the surface molecules BTLA and CD200R in cHL-infiltrating T cell subsets. Regarding their corresponding binding partners, typically expressed on tumor cells, most cHL cell lines were positive for HVEM and CD200. Taken together, we provide a novel perspective on the complex HRS - T cells interaction, verify its immunosuppressive nature and provide further insights into various means of tumor evasion in cHL.
  • Wein F
  • Stock K
  • Hartmann S
  • Hansmann ML
  • Küppers R
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T008 (T008)

CCR5 blocking by Maraviroc inhibited recruitment, proliferation and pro-tumor effects of mesenchymal stromal cells and monocytes in 2D and 3D models of Hodgkin Lymphoma microenvironment

abstract talk Abstract Talk in Immunotherapy (Basic Science) (Monday, 24.10. 10:30)

Award winning Young Investigator Award

In classical Hodgkin Lymphoma (cHL), the tumor microenvironment (TME) is dominated by an extensive mixed cellular inflammatory infiltrate that plays a decisive role in the pathobiology of the disease. CCL5 and its main receptor CCR5, expressed by cHL cells and by bystander cells including stromal cells and macrophages, are increased in cHL lymph nodes respect to normal lymph nodes. Recently, CCL5 and CCR5 have been implicated in cancer progression. Our hypothesis is that CCL5 secreted by cHL cells could recruit Mesenchymal Stromal cells (MCS) and monocytes, which in turn educated by tumor cells may affect tumor progression. To demonstrate the involvement of CCL5 in the cross-talk of cHL cells with the TME we used neutralizing anti-CCL5 antibody and the CCR5 antagonist Maraviroc. We found that CCL5 secreted by L-1236, L-428, KM-H2 and HDLM-2 cHL cell lines, recruited and increased the proliferation of MSCs from Bone Marrow and Adipose Tissue. In turn, tumor-educated MSCs (E-MSCs) secreted higher amounts of CCL5, which increased the proliferation, the clonogenic growth and the movement/spread of cHL cells. Both E-MSCs and cHL cells by secreting CCL5 were able to recruit monocytes purified from Peripheral blood, suggesting that monocytes may be recruited directly by tumor cells and indirectly by E-MSCs. Treatment of monocytes with L-1236-conditioned medium (CM) enhanced the surface expression of CCR5, the proliferation and induced the secretion of CCL5. In turn, tumor-educated monocytes, by secreting CCL5, increased the proliferation and the clonogenic growth of L-1236 and HDLM2 cells. Only CM from tumor-educated monocytes inhibited the proliferation of PHA activated peripheral blood mononuclear cells. Finally, using a new tridimensional (3D) approach (mixed organoids) to mimic the TME, we found that the cocultivation of L1236 and HDLM-2 cells with monocytes, MSCs and especially the combination cHL/monocytes/MSCs increased the survival/proliferation of tumor cells. Treatment with Maraviroc not only decreased cHL cell survival/proliferation due to the cocultivation with MSCs and monocytes, but also disrupted the 3D mixed organoids. Taken together our results suggest that CCL5 secreted by cHL cells, as well as by tumor-educated MSCs and monocytes, may build the protective TME and suggest a potential for Maraviroc as adjuvant therapy to block TME formation and tumor cell proliferation due to CCR5 ligands.
  • Casagrande N
  • Borghese C
  • Celegato M
  • Aldinucci D
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T009 (T009)

Disturbed antigen presentation in classical Hodgkin Lymphoma: implications for immune checkpoint inhibitor therapy?

abstract talk Abstract Talk in Immunotherapy (Basic Science) (Monday, 24.10. 10:30)

Award winning Karl Musshoff Prize: Best Basic Science Abstract

Immune checkpoint inhibitors are being tested in clinical trials and show great promise in the treatment of classical Hodgkin lymphoma (cHL). The proposed mechanism of action of these inhibitors consists of reactivating T lymphocytes that have become unresponsive as a consequence of inhibitory mechanisms exerted by the tumor cells. These reactivated T cells are expected to kill tumor cells after recognizing tumor cell derived antigens that are presented by Human Leukocyte Antigens (HLA) at the tumor cell surface. Consequently, lack of tumor cell surface expression of HLA may be one of the explanations why immune checkpoint inhibitor therapy does not always result in a complete remission in cHL. We evaluated expression of HLA class I, HLA class II and HLA-DM in primary diagnostic tissue in a large population based cohort of cHL, by using immunohistochemistry. HLA class I cell surface expression was lacking in tumor cells in 229 out of 361 cases (63.3%), more often in EBV- cHL (83.2%) than in EBV+ cHL (27.4%). HLA class II cell surface expression was missing in 147 out of 361 cHL cases (40.8%; EBV- 46.8% and EBV+ 29.7%). In addition, we scored lack of cytoplasmic expression of the non-polymorphic HLA-DM. This molecule is essential in the intracellular assembly of HLA class II-antigenic peptide complexes. HLA-DM displaces the invariant chain peptide CLIP from the antigen binding groove of HLA class II molecules, to make this groove accessible for loading of antigens. We show that in the absence of HLA-DM, CLIP is not displaced and is aberrantly expressed on the cell surface of Hodgkin tumor cells in frozen sections (n=8). We found that in HLA class II cell surface expressing tumor cells, HLA-DM expression was lacking in 44 out of 89 cases of cHL (49.4%), indicating that no immunogenic peptides are being presented. Combined results for HLA class I, class II and DM show that only 12.4% of cHL cases show HLA expression that is compatible with normal antigen presentation. In conclusion, antigen presentation is often disturbed in cHL. It is expected that this will influence the success of immune checkpoint inhibitors. We therefore propose to take tumor cell HLA expression into account in the evaluation of (lack of) clinical response to these inhibitors.
  • Nijland M
  • Visser L
  • Veenstra R
  • Kushekhar K
  • van Imhoff G
  • van den Berg A
  • Diepstra A

MRD and Prediction

Selected for Oral Presentation

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    T013 (T013) Plasma vesicle-associated miRNAs as therapy response biomarkers in Hodgkin Lymphoma

    • Pegtel DM
    • Drees E
    • van Eijndhoven MAJ
    • Groenewegen NJ
    • van Niele S
    • Prins R
    • Baglio SR
    • van der Voorn H
    • Libregts SFWM
    • Wauben MH
    • de Menezes RX
    • van Weering JRT
    • Nieuwland R
    • Diepstra A
    • van den Berg A
    • de Jong D
    • Zijlstra JM
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    T014 (T014) Award winning Mid-treatment TARC and mid-treatment FDG-PET predict for progression free survival in classical Hodgkin Lymphoma

    • Plattel WJ
    • van den Berg A
    • Visser L
    • Glaudemans A
    • Diepstra A
    • van Imhoff GW
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    T015 (T015) A comprehensive analysis of Hodgkin Lymphoma seasonality across various geographic regions

    • Borchmann S
    • Müller H
    • Engert A

Posters

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    P060 (P060) Evaluation of Serum TARC Levels in Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma: Results from the AETHERA Trial

    • Bachanova V
    • Carella A
    • Masszi T
    • Holowiecki J
    • Viviani S
    • Huebner D
    • Hunder N
    • Larsen E
    • Odegard J
    • Onsum M
    • Moskowitz C
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    P061 (P061) Validation of a clinical/biological prognostic model in a large cohort of elderly patients with a classical Hodgkin lymphoma

    • Safar V
    • Morelle M
    • Brice P
    • Rossi C
    • Dupuis J
    • Perrot A
    • Stamatoulas A
    • Garciaz S
    • Carras S
    • Lazarovici J
    • Ghesquieres H
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    P062 (P062) Outcomes and prognostic factors in Hodgkin lymphoma – a single center experience

    • Pinto A
    • Mota D
    • Santos M
    • Guilherme R
    • Gomes M
    • Ribeiro L
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    P063 (P063) Combined prognostic role of TARC protein and PET/CT in patients with Hodgkin lymphoma

    • Husi K
    • Illés A
    • Jóna A
    • Nagy B
    • Fejes Z
    • Barna S
    • Miltényi Z
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P060 (P060)

Evaluation of Serum TARC Levels in Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma: Results from the AETHERA Trial

Background: In patients with Hodgkin lymphoma (HL), serum concentrations of thymus and activation-regulated chemokine (TARC) and other cytokines may have prognostic significance in both the front-line and salvage therapy settings. The potential utility of TARC to predict relapse or progression of HL following autologous hematopoietic cell transplant (AHCT) is unknown. AETHERA (NCT01100502) is a phase 3, randomized, placebo-controlled trial that demonstrated improved progression-free survival (PFS) in patients with high risk HL who received post-AHCT consolidation treatment with brentuximab vedotin (BV) (hazard ratio [HR]=0.57, P=0.001), and an acceptable safety profile. Methods: In this exploratory analysis, we measured baseline serum TARC levels in patients enrolled in AETHERA, and evaluated impact of TARC on outcomes after AHCT with or without BV consolidation therapy. Additional serum biomarkers under analysis include sCD30, sCD163, IL-6, sIL-2R, and sCD68. Descriptive statistics were used to characterize baseline TARC concentrations as a function of baseline clinical characteristics, and Kaplan-Meier analysis was used to assess PFS over 24 months of follow-up. Results: Among 329 patients enrolled, 312 (156 BV and 156 placebo) had available serum samples collected between days 28-45 post-AHCT. The median (range) baseline TARC concentration was 472 (18-18,092) pg/mL, and was similar among patients in the BV (481 [18-18,092] pg/mL) and placebo (446 [43-9,756] pg/mL) arms. Median TARC levels were higher among patients with (vs without) established risk factors for progression; these included B symptoms (537 vs 414 pg/mL), extranodal involvement (501 vs 450 pg/mL), FDG-avid PET status (543 vs 433 pg/mL), and incomplete response to salvage therapy (532 [stable disease] vs 474 [partial remission] vs 404 [complete remission] pg/mL, respectively). The median TARC level was also higher among patients with ≥2 risk factors vs those with 1 risk factor (487 vs 410 pg/mL). PFS at 12 months decreased progressively with increasing TARC among patients who received placebo, but not among those who received BV consolidation (Figure). PFS at 24 months was more similar across TARC levels within each treatment arm. Conclusions: Overall, these data suggest that serum TARC may help to identify HL patients at increased risk of disease progression following AHCT.
  • Bachanova V
  • Carella A
  • Masszi T
  • Holowiecki J
  • Viviani S
  • Huebner D
  • Hunder N
  • Larsen E
  • Odegard J
  • Onsum M
  • Moskowitz C
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P061 (P061)

Validation of a clinical/biological prognostic model in a large cohort of elderly patients with a classical Hodgkin lymphoma

Introduction: Our goal is to investigate the external validity of two previously developed prognostic models for overall survival (OS) and progression free survival (PFS) using a scoring system counting unfavorable risk factors (age, performans status, bone marrow involvement, gamma globulin level and fibrinogen level) in elderly patients with a classical Hodgkin lymphoma (cHL) Methods: The performance of the prediction models was evaluated on a retrospective cohort of patients ≥ 59 years with newly diagnosed cHL treated in eight hospitals in France. Model discrimination was evaluated by computing hazard ratio (HR) across risk groups. A comparison with the International Prognostic Score (IPS) was performed using ROC curves. Results: 288 patients were included (November 1990 –June 2015): median age at diagnosis was 70 years (range, 59-93), 55% were male, 53% presented with B symptoms, 25% had a PS>2, 61% had Ann Harbor stage III/IV, 26% had at least one comorbidity scored 3 or 4 on CIRS. Median follow up is 64 months (0-232). 25% of patients have progressed or relapsed and 103 patients died, 40% within the first year of treatment. OS and PFS at 36 months were 72.1% [95% CI: 66.2%; 77.1%] and 63.5% [57.5%; 68.9%], respectively. On 188 evaluable patients, HR for PFS were 8.2, 7.9, and 9.6 for the presence of 1, 2, and 3/4 factors respectively (reference=absence of factor). On 215 evaluable patients, HR for OS were 1.3, 2.2 and 4.0 for the presence of 1, 2 and 3 factors respectively. Patients with 0, 1, 2 and 3 factors had a 3 years OS of 82.3, 77.3, 69.5 and 38.1% respectively (p=0.001). The areas under the curve were not significantly different (p=0.9754) for OS between our score and IPS. Conclusion: These results provide evidence of a satisfactory discrimination ability of the prediction model for OS, with a predictive power similar to IPS. A larger evaluable cohort is required to have a better prognostic model for PFS. This study is a first step in establishing the external validity of these models before use in clinical practice, together with geriatric assessment, in order to offer adequate treatment to patients.
  • Safar V
  • Morelle M
  • Brice P
  • Rossi C
  • Dupuis J
  • Perrot A
  • Stamatoulas A
  • Garciaz S
  • Carras S
  • Lazarovici J
  • Ghesquieres H
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P062 (P062)

Outcomes and prognostic factors in Hodgkin lymphoma – a single center experience

Background: Identification of patients with Hodgkin lymphoma (HL) at risk of treatment failure remains an important unsolved question. Several prognostic models have been proposed to define risk-adapted therapeutic strategies, avoiding overtreatment and identifying in whom standard treatment is not sufficient. Aims: To test validated prognostic factors and identify other predictors of survival in a cohort of patients with classical HL (cHL) in a tertiary health institution. Methods: Retrospective analysis of patients with cHL treated between 1990 and 2015. Univariate analysis was performed and significant predictors at the level of 0.05 were used to adjust a multivariate Cox regression model. Results: We included 355 cHL patients, mainly males (55.2%) with a median age at diagnosis of 29 years (12-80). The most prevalent histological subtype was nodular sclerosis (78.3%). Ann Arbor stage III/IV was observed in 41.1% (n=146) patients, B symptoms in 54.6% (n=194) and bulky disease in 22.8% (n=81). According to GHSG criteria, 50.1% (n=178) had advanced disease of which 49.4% (n=88) had an IPS≥3. Among the 344 patients treated, ABVD was performed in 210 (59.2%); MOPP/ABVD in 78 (21.9%); MOPP/MOPP like in 30 (8.5%); BEACOPP in 25 (7.0%); other regimens in 17 patients (4.8%) and radiotherapy alone in 11 (3.1%). Overall response rate was 83.9% (77.2% of complete responses). With a median follow-up of 100.1 months (0.3-316.0), overall survival (OS) at 5, 10 and 20 years was 84.3%, 78.1% and 67.8% and progression free survival (PFS) was 71.6%, 67.3% and 57.9%, respectively. We analyze the prognostic significance of several factors accepted previously with regard to survival. On multivariate regression analysis only 3 factors were associated with impact on OS: age (HR 1.04; 95%CI 1.02-1.06, p<0.001); hemoglobin level (HR 0.78; 95%CI 0.66-0.93, p=0.005) and LDH>2xULN (HR 2.13; 95%CI 1.06-4.28, p=0.034). Four factors were predictors of PFS: age (HR 1.02; 95%CI 1.01-1.04, p<0.004); lymphocyte count (HR 0.60; 95%CI 0.39-0.92, p=0.02), LDH>2xULN (HR 2.55; 95%CI 1.31-4.97, p=0.006) and Ann Arbor stage III/VI (HR 2.40; 95%CI 1.18-4.86, p=0.015). Conclusion: This data provides evidence for age, hemoglobin and LDH as independent predictors of OS and age, lymphocyte count, LDH and Ann Arbor stage as predictors of PFS in patients with cHL. Further work in larger groups is warranted to create an accurate predictive model for adequate stratification of newly diagnosed patients.
  • Pinto A
  • Mota D
  • Santos M
  • Guilherme R
  • Gomes M
  • Ribeiro L
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P063 (P063)

Combined prognostic role of TARC protein and PET/CT in patients with Hodgkin lymphoma

Introduction: It is well known that long-term survival of Hodgkin lymphoma (HL) patients is very favourable, that is why we have to detect those high-risk patients in time who don’t respond to first-line therapy on a desirable way. Nowadays interim and restaging PET/CT is widespread, but there are some biomarkers in addition, which may help us to choose the best way of therapy and to avoid undertreatment. Patients and methods: We examined HL patients who were treated in our institute from September 2013 to March 2016. Our aim was to detect whether serum TARC (Thymus and Activation- Regulated Chemokine) protein alone or combined with PET/CT is appropriate for being a helpful biomarker in HL patients or not. Results: During this period we collected serum samples from 39 patients treated with Hodgkin lymphoma. We have got samples from 3 different times (before treatment, after 2 cycles of chemotherapy and after 6 cycles of chemotherapy) in the case of 20 patients. The mean age of the 20 patient ( 11 males and 9 females) was 42,4 years (18-75 years) at the time of the diagnosis. Three of them were in an early stage and 17 of them were in advanced stage. According to our results the activity of TARC protein measured before treatment is fit for indicating extranodal manifestations, the presence of bulky disease, and the extension of the disease, but neither it’s activity after 2 cycles of chemotherapy, nor at the end of treatment indicated refractory disease nor alone, neither combined with interim PET/CT. Conclusion: Nevertheless, Hodgkin lymphoma is one of the best curable malignancies; there are no methods except PET/CT which may help us to identify high-risk patients in time. The exact role of biomarkers needs further investigations.
  • Husi K
  • Illés A
  • Jóna A
  • Nagy B
  • Fejes Z
  • Barna S
  • Miltényi Z
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T013 (T013)

Plasma vesicle-associated miRNAs as therapy response biomarkers in Hodgkin Lymphoma

abstract talk Abstract Talk in MRD and Prediction (Sunday, 23.10. 10:30)

Cure rates for classical Hodgkin Lymphoma (CHL) patients are generally high. CHL patients that are cured remain at risk for long-term side effects from the aggressive radiation/chemotherapy regimens and relapses occur. Upcoming treatment strategies aim towards personalized therapy by early assessment of the effectiveness of active treatment by measuring vital tumor tissue with FDG-PET/CT imaging. Apart from radiation burden, imaging is costly and reported positive predictive values are suboptimal. Studies suggest that tumors actively secrete small extracellular vesicles (EVs) that encapsulate tumor-derived nucleic acids, including 22nt non-coding microRNAs (miRNAs). Here we identified with RNAseq, CHL-associated miRNAs in circulating EVs as defined biosource, using size-exclusion chromatography (SEC) as isolation method. Apart from miR-21-5p and miR-155-5p oncomiRs already implicated in lymphomagenesis, we identified let7-a-5p, miR-24-3p and miR-127-3p as circulating CHL biomarkers. Notably, a high abundance of these miRNAs in circulation of CHL patients pre-therapy, correlated with a high concentration of 100nm EVs, as determined with tunable-resistive pulse sensing (TRPS). Using logistic regression modeling we determined that EV-associated miR-127-3p levels alone can distinguish primary and relapse CHL patients from healthy controls. Importantly, the calculated AUC for miR127-3p in vesicles outperform ROC calculations using unfractionated (total) plasma. Finally, in serial samples of individual CHL patients, during- and after treatment but also in long-term follow up, we measured robust and consistent decreases in EV-miRNA levels that corresponded with FDG-PET/CT outcome . Thus defined EV-miRNAs in circulation reflect the presence of vital tumor tissue. This liquid biopsy method may proof suitable for early respsonse and relapse monitoring, MRD detection and guiding therapy decisions. Upcoming studies in serial samples are ongoing to determine whether RNAseq-generated small RNA signatures are useful for diagnosis, prognosis and prediction in CHL.
  • Pegtel DM
  • Drees E
  • van Eijndhoven MAJ
  • Groenewegen NJ
  • van Niele S
  • Prins R
  • Baglio SR
  • van der Voorn H
  • Libregts SFWM
  • Wauben MH
  • de Menezes RX
  • van Weering JRT
  • Nieuwland R
  • Diepstra A
  • van den Berg A
  • de Jong D
  • Zijlstra JM
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T014 (T014)

Mid-treatment TARC and mid-treatment FDG-PET predict for progression free survival in classical Hodgkin Lymphoma

abstract talk Abstract Talk in MRD and Prediction (Sunday, 23.10. 10:30)

Award winning Young Investigator Award

BACKGROUND Plasma or serum CC-chemokine ligand 17 (CCL17) / Thymus and Activation Regulated Chemokine (TARC) is a highly specific biomarker for classical Hodgkin lymphoma (cHL) disease activity. Serial TARC levels correlate with treatment response as early as after one cycle of chemotherapy. In the current study we compared predictive value of mid-treatment TARC with mid-treatment FDG-PET for modified progression free survival (mPFS) in primary cHL patients. PATIENTS AND METHODS: Serial serum or plasma samples were prospectively obtained from 112 newly diagnosed (65 early stage and 57 advanced stage) cHL patients. Patients were mainly treated with ABVD or eBEACOPP based treatment regimens. TARC levels were quantified using ELISA. FDG-PET results were quantified and reassessed according to the Lugano classification including Deauville five point score. Events for mPFS were scored in case of death due to any cause, progression of cHL or start of second line treatment. Patients without elevated TARC at pre-treatment and patients with active atopic dermatitis were excluded for survival analysis on TARC. RESULTS Median follow-up was 45 months for the entire cohort. Out of 112 patients, 103 (92%) achieved a complete remission, 8 patients (7%) had a partial response and one patient (1%) had progressive disease. Of 92 patients with a mid-treatment FDG-PET scan 16 (17%) were positive (Deauville ≥4). Mid-treatment FDG-PET positive patients had significantly reduced mPFS compared to mid-treatment FDG-PET negative patients (56% versus 93% at 3 years, p<.001, Figure 1A). Pre-treatment TARC levels were elevated in 100/112 patients (89%) of which two patients had active atopic disease. Of 92 patients with a mid-treatment plasma or serum sample, TARC was elevated (>900 pg/ml) in 8 (9%). mPFS at 3-years was 25% for patients with high mid-treatment TARC and 92% for patients with low mid-treatment TARC levels (p<.001, Figure 1B). Elevated mid-treatment TARC levels were associated with mid-treatment Deauville score of 5. In multivariate analysis both mid-treatment FDG-PET and mid-treatment TARC independently predicted for mPFS. CONCLUSION Elevated levels of TARC at mid-treatment are highly predictive for inferior mPFS. Both negative and positive predictive value of mid-treatment TARC are at least as good or even better than mid-treatment FDG-PET imaging. TARC might serve as a substitute for mid-treatment FDG-PET imaging in future response evaluation.
  • Plattel WJ
  • van den Berg A
  • Visser L
  • Glaudemans A
  • Diepstra A
  • van Imhoff GW
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T015 (T015)

A comprehensive analysis of Hodgkin Lymphoma seasonality across various geographic regions

abstract talk Abstract Talk in MRD and Prediction (Sunday, 23.10. 10:30)

Introduction: Seasonal variations in incidence and mortality after a Hodgkin lymphoma (HL) diagnosis have been previously described with partly conflicting results. The goal of this study is to comprehensively analyze seasonal variation in incidence and mortality risk of HL with a focus on geographic differences. Methods: HL cases diagnosed between 1973 and 2012 in the 18 Surveillance, Epidemiology, and End Results (SEER) registries were eligible (n=50,179). Cases with missing data for at least one of the analyzed variables (n=8,700) and from the two SEER registries “Alaska natives” (n=17) and “Rural Georgia” (n=57) were excluded, leaving 41,405 cases for the study. Seasonality of incidence was analyzed using cosinor analysis. The risk of overall mortality within 3 years following a HL diagnosis in winter (Sep.-Feb.) vs. summer (Mar.-Aug.) was analyzed by employing a Cox proportional-hazards model with correction for known risk factors. Results: HL shows a seasonal incidence pattern with a peak in March and a trough in September (p<0.001). In predefined subgroup analyses, cases of the mixed cellularity (p<0.001), nodular sclerosis (p<0.001) and lymphocyte depleted subtype (p=0.002) showed a seasonal incidence pattern. Seasonality was particularly pronounced in the age groups 20-29, 30-39 and 60-69, coinciding with age groups of increased HL incidence. Cases from lower (<38.05°N) latitudes showed a decreased seasonality of incidence (amplitude=0.055) compared to cases from higher (≥38.05°N) latitudes (amplitude=0.102) (p(diff.)=0.023). The risk of dying in winter vs. summer is increased at higher latitudes (HR: 1.082[1.009;1.161], p=0.027), whereas no seasonal difference in mortality was observed for cases from lower latitudes (HR: 0.990[0.926;1.059], p=0.772). A multiplicative interaction term showed interaction between the latitude and a diagnosis in winter on mortality risk (HR(interaction): 1.119[1.009;1.241], p=0.033). Conclusions: HL exhibits a seasonal incidence and mortality pattern in this most comprehensive analysis performed to date. The seasonal effect on incidence is exacerbated at and the effect on mortality restricted to higher latitudes. As latitude is closely linked to seasonal variations in Vitamin D serum levels, a protective effect of Vitamin D in HL is a possible explanation. Evidence on the direct association between Vitamin D levels and the clinical course of HL should be collected to improve the understanding of Vitamin D in HL.
  • Borchmann S
  • Müller H
  • Engert A

Pediatric Hodgkin Lymphoma

Selected for Oral Presentation

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    P065 (P065) Joint pediatric Hodgkin and Non-Hodgkin lymphoma study group on grey zone lymphoma in children and adolescents

    • Burkhardt B
    • Makarova O
    • Koerholz D
    • Zimmermann M
    • Mueller S
    • Knoerr F
    • Oschlies I
    • Klapper W
    • Woessmann W
    • Mauz-Koerholz C
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    T016 (T016) Whole body functional and anatomical MRI: accuracy in staging and treatment response monitoring in childhood and adolescent Hodgkin’s Lymphoma compared to conventional multimodality imaging (CRUK C23580/A12707)

    • Daw S
    • Punwani S
    • Latifoltojar A
    • Humphries PD
    • Menezes LJ
    • Neriman D
    • Shankar A
    • Popova B
    • Smith P
    • Condne KM
    • Lopes A
    • Taylor SA
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    T017 (T017) Phase III study of response adapted therapy for the treatment of children with newly diagnosed very high risk Hodgkin Lymphoma (Stages IIIB/IVB) (AHOD0831): a report from the Children’s Oncology Group

    • Kelly KM
    • Cole PD
    • Chen L
    • Roberts KB
    • Hodgson DC
    • McCarten K
    • Cho SY
    • Schwartz CL
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    T018 (T018) Outcomes in adolescents and young adults (AYA) with Hodgkin Lymphoma (HL) treated on US cooperative group protocols: an adult intergroup (E2496) and Children’s Oncology Group (COG AHOD0031) comparative analysis

    • Henderson TO
    • Parsons SK
    • Wroblewski K
    • Chen L
    • Hong F
    • Smith S
    • McNeer J
    • Advani R
    • Gascoyne RD
    • Constine LS
    • Horning S
    • Bartlett NL
    • Shah B
    • Connor JM
    • Leonard J
    • Kahl BS
    • Kelly K
    • Schwartz CL
    • Friedman D
    • Gordon LI
    • Evens AM

Posters

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    P066 (P066) Hodgkin lymphoma in children, adolescents and young adults – a comparative study of clinical presentation and treatment outcome

    • Englund A
    • Glimelius I
    • Rostgaard K
    • Eloranta S
    • Molin D
    • Kuusk T
    • de Nully Brown P
    • Kamper P
    • Smedby KE
    • Hjalgrim H
    • Ljungman G
    • Hjalgrim LL
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    P067 (P067) Pharmacokinetics, Immunogenicity and Safety of Weekly Dosing of Brentuximab Vedotin in Pediatric Patients with Hodgkin Lymphoma

    • Flerlage J
    • Metzger M
    • Panetta JC
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    P068 (P068) Approach and Feasibility of Patient-Reported Outcomes (PROs) in a Phase III clinical trial for advanced stage classical Hodgkin Lymphoma (cHL) in children and adolescents

    • Castellino SM
    • Henderson TO
    • Keller FG
    • Kelly K
    • Curtis R
    • Conti RM
    • Parsons SK
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    P069 (P069) Prediction of primary treatment response and outcome in pediatric Hodgkin lymphoma using digital gene expression profiling

    • Mottok A
    • Johnston RL
    • Chan FC
    • Scott DW
    • Friedman DL
    • Schwartz CL
    • Kelly KM
    • Horton TM
    • Steidl C
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    P070 (P070) Does involved field radiotherapy improve survival rates in pediatric Classic Hodgkin’s Lymphoma?: A retrospective study of 694 children

    • Zaghloul MS
    • Akoush H
    • El Haddad A
    • Attia E
    • Taha H
    • El Wakeel M
    • Omar W
    • El Sayed S
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    P071 (P071) CHIPS as a Predictor of Outcome in Radiated vs. Unradiated HL

    • Schwartz CL
    • Wolden S
    • Constine LS
    • Chen L
    • Friedman DL
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    P073 (P073) Hodgkin lymphoma (HL) in AYA (adolescents and young adults): Results from a single-tertiary-center prospective cohort of 349 patients

    • Bigenwald C
    • Galimard JE
    • Amorim S
    • Thieblemont C
    • Boissel N
    • Resche-Rigon M
    • Brice P
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    P074 (P074) Prognostic value of ‘interim’ positron emission tomography among children with Advanced Hodgkin lymphoma in developing countries; Children Cancer Hospital Egypt experience

    • Khedr R
    • Hamouda A
    • Naguib S
    • Khalaf M
    • Fikry S
    • El Sayed A
    • Taha H
    • Zaghloul MS
    • Attia I
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    P075 (P075) Long-lasting remission in an adolescent with refractory Hodgkin lymphoma after brentuximab vedotin-containing treatment – a case report

    • Fedorova A
    • Markavets A
    • Hushchina L
    • Aleinikova O
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    P076 (P076) Overview and Survival of Pediatric Advanced stage Hodgkin Lymphoma treated in Developing countries; Children Cancer Hospital Egypt Experience

    • Hamouda A
    • Khedr R
    • Naguib S
    • Khalaf M
    • Fikry S
    • El Sayed A
    • Taha H
    • Zaghloul MS
    • Attia I
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P066 (P066)

Hodgkin lymphoma in children, adolescents and young adults – a comparative study of clinical presentation and treatment outcome

Hodgkin lymphoma (HL) treatment protocols for adolescents and young adults traditionally vary by age, but the biological and clinical rationale for this remains uncertain. Our aim was to investigate clinical presentation and outcome in different age groups (0-9, 10-17, 18-24 years) and to compare prognosis among patients treated in pediatric or adult departments. PATIENTS AND METHODS 1345 classical HL (cHL) 0-24 years were diagnosed in Denmark 1990-2010 and Sweden 1992-2009. Disease characteristics and treatment outcome were available for 1083 cHL patients treated in pediatric (n=325) or adult departments (n=758). Outcome was estimated as event free survival (EFS) and overall survival (OS) and using Cox regression. Patients treated in adult departments were mainly treated with ABVD (doxorubicine, bleomycin, vinblastine, dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicine, cyclophosphamide, vincristine, procarbazine, prednisone) +/- radiotherapy (RT) and the majority of the pediatric patients with OPPA/OEPA (vincristine, etoposide vs procarbazine, prednisone, doxorubicine) and COPP/COPDAC (cyclophosphamide, vincristine, prednisone, procarbazine vs dacarbazine) +/- RT. RESULTS Children0-9yrs had male predominance and presented with lower stage disease and lower frequency of B-symptoms and extra nodal disease. Five-year EFS was lower among Danish paediatric patients (0-14 years) [0.81 (95% confidence interval (95%CI):0.72-0.88)] than among Danish adults [0.85 (0.81-0.88)], Swedish pediatric patients (0-17 years) [0.89 (0.85-0.93)] and adults [0.90 (0.86-0.92)] (Figure 1A). There was no difference in 5- or 10-year OS (Figure 1B). Danish pediatric patients received RT (32%) less frequently than Swedish pediatric patients (71%), p<0.002, while in adults the difference was not as pronounced (Denmark 67%, Sweden 56 %). In analyses adjusted for sex, stage and country, EFS and OS did not vary among patients treated in pediatric compared to adult departments. CONCLUSION Children0-9yrs had a different clinical presentation in several aspects, whereas adolescents10-17yrs and young adults18-24yrs shared similar features. There was no difference in treatment outcome between pediatric and adult departments overall. Patients in Denmark treated in pediatric departments had lower EFS than patients in Swedish pediatric departments and Swedish and Danish adult departments. This correlated to a lower use of RT in primary treatment. OS was equal between the groups.
  • Englund A
  • Glimelius I
  • Rostgaard K
  • Eloranta S
  • Molin D
  • Kuusk T
  • de Nully Brown P
  • Kamper P
  • Smedby KE
  • Hjalgrim H
  • Ljungman G
  • Hjalgrim LL
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P067 (P067)

Pharmacokinetics, Immunogenicity and Safety of Weekly Dosing of Brentuximab Vedotin in Pediatric Patients with Hodgkin Lymphoma

Background: To improve the success of treatment for Hodgkin Lymphoma (HL) the novel agent brentuximab vedotin (anti-CD30 agent) was developed as CD30 is highly expressed in both HL and anaplastic large cell lymphoma. Based off the success of phase 1 and II trials it is now used as a frontline agent in a high-risk pediatric HL trial HLHR13. Purpose: The primary goal of this study was to evaluate the variability of pharmacokinetics for weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data for the recommended 1.8 mg/kg every 3 week dosing and evaluate toxicity with this novel agent in the pediatric population. Methods: Serum samples for brentuximab vedotin levels were collected at day 1 pre and post infusion, 48 hours and day 8 pre-infusion for 16 patients. A compartmental pharmacokinetic model was fit to the data using non-linear mixed effects modeling methods. Serum concentration of anti-therapeutic antibody was measured prior to the first 3 courses and at the end of therapy. Results: Brentuximab vedotin and MMAE clearance and volume were significantly correlated with weight (p<1e-10) and accounting for weight explained 75%, 84%, 61%, and 94% of the inter-individual variability in the ADC clearance, ADC volume, MMAE apparent clearance, and MMAE apparent volume respectively. The ADC clearance and volume differed by gender; clearance and volume were higher in male vs female patients (17%; p=0.08, and 17%; p=0.03, respectively) and explained an additional 11% and 36% of the inter-individual variability in the ADC clearance and volume respectively compared to the weight-normalized model. The ADC AUC and Cmax in our pediatric study were lower compared to those reported in adult studies (25% and 11%, respectively at 1.2 mg/kg and 35% and 16%, respectively at 1.8 mg/kg). Toxicity was comparable to that published for the standard of care backbone. All 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy. Conclusion: As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin pharmacokinetic variability in pediatric patients. Exposure with weekly dosing appeared safe and tolerable in pediatric patients. Given the promising clinical results of brentuximab vedotin, more studies are warranted to demonstrate safety and allow for increased use in the pediatric population.
  • Flerlage J
  • Metzger M
  • Panetta JC
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P068 (P068)

Approach and Feasibility of Patient-Reported Outcomes (PROs) in a Phase III clinical trial for advanced stage classical Hodgkin Lymphoma (cHL) in children and adolescents

Objectives: We describe the feasibility of embedding PROs for chemotherapy-induced peripheral neuropathy (CIPN) and cost effectiveness (CEA) in a randomized, multi-institutional Phase III study (NCT02166463), evaluating the efficacy of the novel agent, Brentuximab vedotin, for advanced cHL in children and adolescents. Methods: Recruitment for PROs of interest is targeted for 250 of the planned 600 trial participants. Participation in the trial includes prospective collection of patient- and parent proxy-reported outcomes. CIPN is evaluated with the 11- item FACT-GOG-NTX and paired with the 9-item CHRIs-Global to serially evaluate health-related quality of life (HRQL) consequences of CIPN from initial diagnosis to 12 months off therapy. For CEA, US-based participants are queried from diagnosis through 36 months off therapy with the 4-item Stanford Healthcare Utilization Questionnaire (parent-report), the Health Utilities Index (HUI) 2/3, and the 23-item Caregiver Work Limitations Questionnaire (parent-report) as a measure of productivity loss. A study-designated research assistant is charged with contacting site personnel at study entry and at each scheduled assessment. All data are tracked for completion and uploaded into a web-based relational database for future analysis. Units of healthcare utilization will be monetized with unit costs from US-based administrative databases, including claims from public and private payers, based on site of care and diagnostic and/or procedure codes. Total costs will be calculated by study arm and expressed as cost per quality-adjusted life year, derived from the HUI 2/3. Results: The clinical trial, activated in March 2015, has enrolled 137 participants; accrual is ongoing at 170 participating institutions. Among participants 95% have completed the baseline CIPN and CEA assessments and > 90% have completed subsequent measures. Monetization of significant adverse events and utilization is in progress. Discussion: We demonstrate feasibility of embedding PROs evidenced by high acceptance and completion rates of assessments for prospective evaluation of CIPN, HRQL, and healthcare utilization in a multi-institutional trial of children with advanced HL. Our experience serves as a proof of principle to cooperative groups regarding the resources and the feasibility of incorporating necessary PRO and health utilization outcomes into Phase III clinical trials as a component of cancer care delivery research.
  • Castellino SM
  • Henderson TO
  • Keller FG
  • Kelly K
  • Curtis R
  • Conti RM
  • Parsons SK
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P069 (P069)

Prediction of primary treatment response and outcome in pediatric Hodgkin lymphoma using digital gene expression profiling

Introduction: Hodgkin lymphoma (HL) is a common pediatric malignancy, and although considered highly curable, treatment success comes at a high cost in the form of long-term toxicity and morbidity. To overcome this challenge clinical trials have evaluated risk-adapted treatment regimens aiming to maintain high survival rates and reduce treatment-related toxicity. However, risk stratification is currently limited to the use of clinical factors as there are no validated molecular biomarkers that can be employed as predictors for treatment outcome in pediatric HL. Therefore, we aimed to perform gene expression profiling (GEP) to uncover disease biology underlying treatment response and develop a prognostic model to tailor first-line therapy in pediatric HL. Methods: We selected specimens from patients enrolled in a phase 3 clinical trial (AHOD0031) of the Children’s Oncology Group (COG) randomizing patients dependent on CT imaging-based early response criteria (slow early response, SER; rapid early response, RER). We performed intermediate density GEP (784 genes) using NanoString on RNA extracted from pre-treatment formalin-fixed, paraffin-embedded tissue biopsies. Results: Of the 206 tissue samples obtained, 185 (89.8%) passed quality assurance testing. We applied our previously published 23-gene predictor - developed to predict OS in adult HL patients - to the pediatric cohort. This assay failed to predict outcomes, with patients in the “high-risk” group, as assigned by the assay, trending to have superior outcomes than the “low risk” patients. Therefore, we sought to develop a novel EFS predictive model for pediatric patients. Using penalized Cox regression, we developed a 16-gene model to predict EFS in a training cohort. This model was applied to an independent cohort of 117 specimens from the same clinical trial which were enriched for treatment failure (no EFS event to EFS event ratio = 1:1). Using this validation cohort, the 16-gene model separated high-risk and low-risk groups with significantly different EFS in the SER (p=0.034), but not in the RER group (p=0.81). Conclusions: Failure of the GEP-based model developed in adult HL suggests distinct biology underlies treatment failure in the pediatric age group, although differences in therapy may also be a contributing factor. We describe the development of a novel predictive model for EFS in intermediate-risk pediatric HL patients which successfully risk-stratifies patients in the SER subgroup.
  • Mottok A
  • Johnston RL
  • Chan FC
  • Scott DW
  • Friedman DL
  • Schwartz CL
  • Kelly KM
  • Horton TM
  • Steidl C
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P070 (P070)

Does involved field radiotherapy improve survival rates in pediatric Classic Hodgkin’s Lymphoma?: A retrospective study of 694 children

Background: Pediatric Hodgkin’s lymphoma represents survival success story, however late toxicity remains as a big consideration issue. Patients & Methods: During the period July 2007 and December 2014, 694 pediatric classic Hodgkin’s lymphoma patients were treated according to risk-adapted protocol consisted of 4-8 ABDV chemotherapy courses and involved field radiotherapy (IFRT). Out of them 543 (78.2%) received IFRT with a dose of 19.8 Gy, while the other 151 (21.8%) did not receive radiotherapy for different reasons. Results: The 5-year overall (OS) and event-free survival (EFS) for the low risk patients were 99.7% and 92.6% respectively. These rates were 93.1% and 83.9% for the intermediate risk and 95.4% and 75.3% for the high risk respectively. The 5-year OS and EFS for those received IFRT were 98.0 % and 86.9 % respectively, while those who receive chemotherapy only were 92.9% and 77.8 % respectively (p˂0.001 for each). Radiotherapy could improve the 5-year EFS in the advanced (intermediate and high-risk) patients from 76.6 % to 79.4 % with marginal statistical significance (0.073). On the other hand, the OS improved from 94.5 % to 96.0 % though this difference did not reach the level of significance. Only one out of 318 low-risk patients died and 14 relapsed and could be salvaged. Only 25 low-risk patients did not receive IFRT and those did not show OS nor EFS differences from the 293 patients who received IFRT. Two patients developed acute myeloid leukemia & one developed thyroid cancer as second primary (0.43%). All of them received chemotherapy and IFRT. Conclusion: Involved field radiotherapy marginally improved the EFS in intermediate and high-risk pediatric Hodgkin’s lymphoma significantly, while its improvement in OS in such patients did not reach the significant statistical level. Low-risk patient needs prospective randomized trial to thoroughly investigate this issue.
  • Zaghloul MS
  • Akoush H
  • El Haddad A
  • Attia E
  • Taha H
  • El Wakeel M
  • Omar W
  • El Sayed S
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P071 (P071)

CHIPS as a Predictor of Outcome in Radiated vs. Unradiated HL

Purpose: To evaluate the CHIPS (Childhood Hodgkin International Prognostic score) in patients with intermediate risk (IR) Hodgkin Lymphoma (HL) randomized to +/- 21 Gy of involved filed radiation (IFRT) after completing 4 cycles of ABVE-PC. These patients had achieved a rapid early response (RER) to 2 cycles of ABVE-PC (RER) and complete response (CR) at the end of chemotherapy. Methods: Patients enrolled on COG AHOD were <21 years with IR HL. The CHIPS score was derived from clinical data on 1103 patients who had received 4 ABVE-PC and radiation. Four factors (fever, low albumin, large mediastinal adenopathy, stage 4) were identified as independent predictors of EFS. CHIPS was then examined in the cohort of RER who achieved CR and were randomized to receive or not receive IFRT. Results: There were 664 RER/CR patients with CHIPS scores available; 329 were randomized to no RT and 335 were randomized to RT. 4 year EFS was similar between CHIPS cohorts except for CHIPS 1. CHIPS 1 patients showed an advantage to the addition of IFRT (p=0.035). CHIPS 0 patients did well with or without IFRT. CHIPS 3 patients had poor outcomes with or without RT. Conclusion: CHIPS was derived based on patients treated on COG protocol AHOD0031 who received IFRT after ABVE-PC chemotherapy. For this report, we compared CHIPS in the RER/CR cohort randomized to IFRT vs. no IFRT. Although the overall randomization to +/- RT (Friedman, JCO 2015) did not detect any advantage to the addition of IFRT, this sub-analysis shows that 1) CHIPS was predictive of outcome in both the radiated and the un-irradiated cohort and 2) there may be a benefit for IFRT in the CHIPS 1 cohort. As in the overall cohort, CHIPS 2 and 3 patients should be considered for augmented therapy.
  • Schwartz CL
  • Wolden S
  • Constine LS
  • Chen L
  • Friedman DL
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P073 (P073)

Hodgkin lymphoma (HL) in AYA (adolescents and young adults): Results from a single-tertiary-center prospective cohort of 349 patients

Background: Adolescents and young adults (AYA) represent one third of patients affected with Hodgkin lymphoma (HL). Clinical presentation at diagnosis differs among some subgroups of patient: children, adults, elderly, and patients with immunodeficiency. However, specific features of HL in AYA remain unclear. We conducted a single-center study to describe the characteristics of HL in AYA and to define associated factors with disease progression and/or death. Methods: All consecutive patients newly diagnosed with HL were prospectively recruited before the initiation of treatment from one tertiary academic center (Saint Louis Hospital, Paris, France). Clinical characteristics and outcomes of patients aged from 15 to 25 years old were retrospectively computed. The primary endpoint was the occurrence of an event defined as progression of the disease or death from any cause. June 2005 was chosen as threshold for the analysis as it constitutes the advent of TEP-TDM in current practice. Uni- and multivariate survival analyses were performed using a Cox model. Results: 349 patients were included between 1979 and 2013, with a median follow-up of 7 years. Nodular sclerosis was the most representative histologic subtype (86.3%). According to Ann Arbor classification, patients had a disseminated disease in 45 % of cases. 289 (83%), 97 (28%) and 140 patients (56%) had a mediastinal lymph node, a bulky mediastinum and an extra-nodal involvement, respectively. No significant difference in terms of clinical presentation was noticed between patients younger than 21 year-old compared to older, except a more frequent EBV association after 21. Patients diagnosed after June 2005 presented more frequently a disseminated disease (36 % vs. 46.2 %, p = 0.04). 10 year-event free survival rate was estimated at 81% (95CI [76,7-85,5]). The first cause of mortality was HL. In multivariate analysis, stage 3 and 4 according to Ann Arbor classification were independently associated with the occurrence of event. Conversely, nodular sclerosis subtype was associated with a favourable outcome. Conclusion: Our large prospective cohort revealed interesting features of HL in AYA. Considering data from the literature, our study suggests a more frequent mediastinal involvement and a more advanced stage of disease in AYA compared to children and adults. Despite these pejorative features, relapse rate and mortality rates remain low.
  • Bigenwald C
  • Galimard JE
  • Amorim S
  • Thieblemont C
  • Boissel N
  • Resche-Rigon M
  • Brice P
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P074 (P074)

Prognostic value of ‘interim’ positron emission tomography among children with Advanced Hodgkin lymphoma in developing countries; Children Cancer Hospital Egypt experience

  • Khedr R
  • Hamouda A
  • Naguib S
  • Khalaf M
  • Fikry S
  • El Sayed A
  • Taha H
  • Zaghloul MS
  • Attia I
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P075 (P075)

Long-lasting remission in an adolescent with refractory Hodgkin lymphoma after brentuximab vedotin-containing treatment – a case report

Background: Despite the high cure rate of childhood Hodgkin lymphoma (HL) patients with refractory HL remain incurable with standard therapies. Autologous or allogeneic heamotopoietic stem cell transplantation (HSCT) is considered the most effective method of consolidation in relapsed or refractory HL treatment. Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate that has become the preferred therapy option for adults with HL who have relapsed after or are ineligible for auto HSCT, but data relating to pediatric patients are very limited. Objectives: We aimed to report a case of effective and tolerable BV-containing treatment in an adolescent with refractory HL. Case report: A 17-year-old female with enlarged cervical, supra-/subclavicular, axillary, mediastinum lymph nodes and multiple lesions in both lungs was admitted to our hospital. FDG-PET/CT and lymph node biopsy were performed and nodular sclerosis HL stage IVA was diagnosed. Treatment was administered according to modified DAL-HD-95 protocol, and consisted of 6 courses of chemotherapy (2OPPA/4COPP) plus radiation therapy of the involved fields (20 Gy). Partial response was achieved after the 2nd cycle OPPA and stable disease was observing during the all remaining treatment. One month after the end of treatment the patient showed disease progression in mediastinum and lungs, confirmed by FDG-PET/CT and lung biopsy. Positive response was obtained after the two courses (IEP, ABVD) of second-line therapy, but patient remained PET-positive. Treatment was continued with 3 cycles VV (BV 1.8 mg/kg/bendamustine/dexamethasone), PET-negative complete remission was achieved and autoHSCT (conditioning regimen consisted of BEAM) with allogeneic bone marrow-derived mesenchymal stem cells cotransplantation was subsequently performed. Further the patient received adjuvant monotherapy with BV 1.2 mg/kg every 3 weeks (a total of 12 doses). The only evident side effect seen in BV treatment was deteriorating peripheral neuropathy. Patient remains in PET-negative complete remission for 14 months after autoHSCT and 4 months after the last dose of BV. Conclusion: Our experience should encourage to use BV in combination with chemotherapy or even alone in pediatric patients with refractory HL.
  • Fedorova A
  • Markavets A
  • Hushchina L
  • Aleinikova O
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P076 (P076)

Overview and Survival of Pediatric Advanced stage Hodgkin Lymphoma treated in Developing countries; Children Cancer Hospital Egypt Experience

Background & aim of the study: The major challenge in advanced stage Hodgkin Lymphoma is to optimize the balance between overall survival and treatment related toxicity. The aim of the study was to describe the pediatric population with advanced Hodgkin lymphoma (HL) in our country and their treatment outcome. Patients and methods:   This is a retrospective single center study. Data analysis for children with advanced stage HL (IIB or IIIB with bulk disease, or stage IV) as done. Demographic data, staging, number of cycles (doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)) received and whether or not consolidation radiotherapy (RTH) was administered. Positron emission tomography (PET) was performed baseline and after the second cycle to detect early response without any change to treatment plan. Results: Three hundred and eighty-one patients with newly diagnosed Hodgkin lymphoma were enrolled in the data analysis. Male (283) to female (98) ratio 3:1. B-symptoms was present in 60% of patients. Ann Arbor staging distribution was as follows; 68 (17.8%) IIB, 97 (25.5%) IIIA, 96 (25.2%) IIIB, 55 (14.4%) IVA, 65 (17.1%) IVB. the prevalent pathological subtype was the nodular sclerosis accounting for 54% (203/381) followed by the mixed cellularity 148/ 381 ( 39%) .One hundred sixty-five patients with early unfavorable and 216 with advanced-stage disease were treated with ABVD ± RTH. One hundred twenty- nine (34%) patient did not receive RTH. The Five-years Overall survival (OS) and the Event free survival (EFS) in these patients was 90.7 (95% CI: 85.4-95.9 and 71.9% (95% CI: 63.6-76.1) (p value 0.006) respectively. The OS and EFS of patient with advanced stage HL in the whole study population was 94.1 (95% CI: 91.5-96.6) and 79.4 (95% CI 74.3-84.4) respectively. Conclusion: More than 90% of patients are cured with risk-based combined-modality therapy, yet these therapies are frequently associated with risks for significant long term toxicities; innovative approaches are needed for those patients who have a high risk of failure with current therapies.
  • Hamouda A
  • Khedr R
  • Naguib S
  • Khalaf M
  • Fikry S
  • El Sayed A
  • Taha H
  • Zaghloul MS
  • Attia I
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P065 (P065)

Joint pediatric Hodgkin and Non-Hodgkin lymphoma study group on grey zone lymphoma in children and adolescents

abstract talk Abstract Talk in Grey Zone Lymphoma (Sunday, 23.10. 14:00)

Background In the current version of the WHO classification of lymphoid tumors the term ‘grey zone lymphoma’ (GZL) was introduced for the first time. The cases of GZL with characteristics of Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) are poorly characterized in children and adolescents and need further improvement of diagnostic and treatment approaches. Patients and methods We evaluated patient’s characteristics, treatment and outcome of young GZL patients reported to the German Pediatric Hodgkin lymphoma study center and/or to the NHL-Berlin-Frankfurt-Muenster study center. Results Between 2003 and 2015, 27 children and adolescents with GZL, comprised of 22 boys and 5 girls, with a median age of 15 years, were identified. The GZL was identified at the time of initial diagnosis in 19 patients, in six patients the diagnosis was established at the time of relapse by comparing initial and relapse samples, and in two patients by a reference pathology panel which reviewed primary mediastinal B-cell lymphoma (PMLBL) cases. GZL between classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) was diagnosed in eleven patients, GZL between cHL and PMLBL in three cases, GZL of lymphocyte predominant Hodgkin (LPHL) and T-cell rich B-cell lymphoma (TCBCL) in eleven and in two cases grey zone between LPHL and DLBCL. Fifteen patients received frontline treatment according to protocols for HL, te