Stratifizierte Therapie aggressiver Non-Hodgkin-Lymphome ( B- und T-Zell)

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org Stratifizierte Therapie aggressiver Non-Hodgkin-Lymphome ( B- und T-Zell) Lorenz Trümper, Klinik für Hämatologie und Medizinische Onkologie, UniversitätsKrebszentrum Göttingen (G-CCC), Georg-August-Universität Göttingen Für die Deutsche Studiengruppe Hochmaligne Lymphome DSHNHL Marita Ziepert, Markus Loeffler, Bertram Glass, Norbert Schmitz, Gerald Wulf, Andreas Rosenwald, German Ott, Gerhard Held, Michael Pfreundschuh

Immunchemotherapie Standard beim DLBCL LN98-5 (elderly) MInT (young good risk) Coiffier et al., N Engl J Med 2002 Pfreundschuh et al., Lancet Oncol 2006

Risikoadaptation Stage I No bulk Stage I Bulk IPI=0,1 aaipi=2,3 Elderly IPI=0, n.b. Elderly IPI=0 IPI=1 aaipi=2,3 Elderly 0/I Elderly IPI=1,2 II-IV,3 Limited aaipi=2, 3 Elderly II-IV DSHNHL France (LYSA) U S A (SWOG) U S A (CALBG) U N F I T Elderly aaipi=0 U K (NCRI) U N F I T I,noBulk Stage I Non-Bulk Limited Therapieempfehlung (Evidenz fehlt (noch)) No Bulk: (4)-6 x R CHOP 21 Bulk: 6 x R-CHOP-(14)21 + Bulk Rx (PET Adaptiert) High IPI: 6 x R-CHOEP-14 (! Keine random. Studie) Elderly low (4)- 6 x R CHOP 14 + Rx Elderly High 6 x R CHOP 14 Elderly non fit: R-Mini-CHOP oder BR Japan (JCOG)

Fragen zur Therapie GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.lymphome.de/en/groups/dshnhl 1. R-CHOP gibt es etwas besseres? 2. Brauchen wir noch die Strahlentherapie? 3. Molekulare Diagnostik prognostische Faktoren - Zielgerichtete Therapie? 4. Periphere T-Zell Lymphome nur CHOP?

NCRI: R-CHOP-14 vs. R-CHOP-21 Cunningham et al. Lancet 2013

R-CHOP-14 oder 21? GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.lymphome.de/en/groups/dshnhl R-CHOP-14 vs R-CHOP-21 (>60): - Gleich wirksam - Gleiche Akuttoxizität (G-CSF!) - Weniger Langzeittoxizität (kardial: ja; Zweitneoplasien: steht aus) - Kürzere Therapiedauer(10 vs 21 Wochen)

HOP oder CHOEP? GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.lymphome.de/en/groups/dshnhl Comparison Of R-CHOP14 and R-CHOEP14 As First Line Treatment In Young Patients With High-Risk (aaipi 2-3) Diffuse Large B-Cell Lymphoma (DLBCL): A Joint Analysis Of Two Prospective Phase III Randomized Trials Conducted By The Fondazione Italiana Linfomi (FIL) and The German High-Grade Lymphoma Study Group (DSHNHL

Event-free survival (A), progression-free survival (B), and overall survival (C) for all patients. Overall survival for the 192 patients with age-adjusted IPI 2 (D). Schmitz et al. The Lancet Oncology Volume 13, Issue 12 2012 1250-1259

CALGB/Alliance 50303: Event-Free Survival and OS EFS OS EFS (%) 80 60 40 20 0 R-CHOP DA-EPOCH-R 0 1 2 3 4 5 Yrs *Median follow-up 5 yrs Wilson WH, et al. ASH 2016. Abstract 469. HR: 1.14 (95% CI: 0.82-1.61; P =.4386) Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP 233 64 0.81 (0.75-0.85) 0.69 (0.62-0.75) DA-EPOCH-R 232 70 0.79 (0.73-0.84) 0.66 (0.59-0.72) OS (%) 80 60 40 20 0 R-CHOP DA-EPOCH-R HR: 1.18 (95% CI: 0.79-1.77; P =.42) 0 1 2 3 4 5 Yrs Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP 233 44 0.85 (0.80-0.89) 0.80 (0.74-0.85) DA-EPOCH-R 232 50 0.85 (0.79-0.89) 0.76 (0.70-0.71) Slide credit: clinicaloptions.com

UNFOLDER Study OS Patients randomised with reference pathology, according to pathology (n=269) GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.lymphome.de/en/groups/dshnhl 1 0.9 0.8 0.7 Proportion 0.6 0.5 0.4 0.3 0.2 PMBCL, CHOP14/21 +/- Radiotherapy (n=69) 0.1 0 all other with existing pathology, CHOP14 (n=200) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 DSHNHL 01.07.12 Months

SWOG-9706 vs. R-CHOEP-14 82% 68% 51%

GOYA Final Analysis GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org

DSHNHL 2009-1/OPTIMAL>60 Study Trial design - Favourable Patients RANDOMIZATION 4/6 x CHOP-14 + 8xR -14 + 8xR 4/6 x CHLIP-14 + 8xR DSHNHL 17.10.2016

DSHNHL 2009-1/OPTIMAL>60 Study Trial design - Less Favourable Patients RANDOMIZATION 6 x CHOP-14 + 8xR -14 + 8xR 6 x CHLIP-14 + 8xR 6 x CHOP-14 + 12xOptiR 6 x CHLIP-14 + 12xOptiR DSHNHL 17.10.2016

Treatment-related Deaths: OPTIMAL>60 vs. RICOVER-60 6xCHOP-14 + 8xR 6xCHLIP-14 + 8R 6xCHOP-14 + Opti-R 6xCHLIP-14 + 12xOptiR Total Favourable 1/60 (1.6%) 0/60 (0%) 1/120 (0.8%) Less Favourable 1/95 (1.1%) 2/96 (2.1%) 1/96 (1.0%) 2/98 (2.0%) 6/385 (1.6%) OPTIMAL>60 7/505 (1.4%) RICOVER-60 17/306 (5.6%) 92/1222 (7.5%)

Favourable Patients: OPTIMAL>60 vs. RICOVER-60 1.0 Progression-free Survival 0.9 0.8 0.7 Proportion 0.6 0.5 0.4 RICOVER-60-6xCHOP-14+8xR (n=74) 0.3 0.2 0.1 0.0 DSHNHL 17.10.2016 p=0.407 OPTIMAL>60-4/6xCHOP-14+8xR (n=58) (n=58) 0 10 20 30 40 50 60 70 80 90 100 110 120 Months

Favourable Patients: OLD (OPTIMAL>60) vs. YOUNG (FLYER) OPTIMAL (71 years) FLYER (47 years) 1.0 1.0 0.9 0.9 P F S Proportion 0.8 0.7 0.6 0.5 Proportion 0.8 0.7 0.6 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0 10 20 30 40 50 60 Months 0.0 0 10 20 30 40 50 60 70 80 90 100 Months 1.0 1.0 0.9 0.9 O S Proportion 0.8 0.7 0.6 0.5 0.4 Proportion 0.8 0.7 0.6 0.5 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0 10 20 30 40 50 60 Months 0.0 0 10 20 30 40 50 60 70 80 90 100 Months

Less Favourable Patients: OPTIMAL>60 vs. RICOVER-60 1.0 Progression-free Survival 0.9 Proportion 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 RICOVER-60-6xCHOP-14+8xR (n=232) OPTIMAL>60 (n=385) p=0.155 DSHNHL 17.10.2016 0.0 0 10 20 30 40 50 60 70 80 90 100110 120 Months

Supportive Care in Elderly DLBCL No prophylaxis mandatory Prophylaxis mandatory: Aciclovir & Cotrimoxazole

28% 7% 18% 6% 4% 2%

R-CHOP +? GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org Verbesserte Rituximab Applikation (Smarter) Vitamin D Substitution Bessere Antikörper? GA 101 Nein Polatuzumab (CD79), Mor208 (CD 19) im Rezidiv? Bessere Chemotherapie? DA-R-EPOCH Nein

DSHNHL Study Group Meeting 19. November 2016 München supported by

Bulky Disease: OPTIMAL>60 vs. RICOVER-60 Proportion 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 PROGRESSION-FREE SURVIVAL p=0.602 79% 75% 1: RICOVER 6xCHOP-14+8xR (n=117) 2: OPTIMAL 6xCHOP-14+8xR (n=47) 3: OPTIMAL 6xCHLIP-14+8xR (n=45) 4: OPTIMAL 6xCHOP-14+12xOptiR (n=46) RICOVER-6xCHOP-14+8xR (n=117) 5: OPTIMAL 6xCHLIP-14+12xOptiR (n=49) OPTIMAL-6xCHOP-14+8xR (n=47) 0 10 20 30 40 50 60 70 80 90 100 110 120 Months median time of observation: 24 months

Patients with Bulky Disease: OPTIMAL>60 vs. RICOVER-60 Radiotherapy received OPTIMAL>60 (n=187) RICOVER-60 (n=117) 65 (34.7%) 67* (57.3%) * Reasons fro norx: progressive disease, toxicity, medical reasons, protocol violation DSHNHL 17.10.2016

Bulky Disease: OPTIMAL>60 vs. RICOVER-60 Prognostic Significance of PET-Positivity P F S O S Start of radiotherapy after 6xR-CHOP-14 by day 100

Strahlentherapie DLBCL GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org Indiziert: 1. Bulky disease (PET gesteuert???) 2. Extranodal-Befall (z.b. Knochen) 3. Mediastinales Lymphom Exzellentes Outcome mit R-CHOP-21 + Rx

Risiko: Molekular GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org Myc Bruch / Double & Triple Hit Double Expressors ABC und GCB

Lymph2Cx-based COO Classification and Survival Analysis Ricover60 R-CHOP R-MegaCHOEP Staiger et al., in press JCO 2017 37

Study design Powered to detect a 10% improvement in 30 month PFS (α=0.05; power 0.9). n=688 ABC and GCB randomised. ABC 260 Amendment 2 nd May 2014 Bortezomib 1.6 mg/m 2 day 1+8 sub cut

Progression-free survival according to molecular classification 30 month PFS GCB: 74.3%: HR=0.774, p=0.079 Unc: 68.2%: HR=0.884, p=0.480 ABC: 68.1%: HR=1 (Reference category) Median follow-up of surviving patients: 28.4 months No difference in OS either

Salvage therapy in elderly patients : R-GemOX Mounier et al. Haematologica 2013; 98:1726

G-CCC 2014

Molekulare Prognostik bei agg. B-NHL ABC vs. GCB beschreibt biologisch distinkte und relevante Subgruppen des DLBCL-NOS Prognostisch/prädiktive Ergebnisse verschiedener Techniken noch nicht vergleichbar (Methodik)! NUR deswegen: Prognostische Bedeutung von GCB/ ABC, MYC, BCL2 und BCL6 Bruch/Expression in grossen prospektiven Studien nicht konsistent! Wir brauchen molekulare Daten in allen prospektiven Studien

B-Zell Rezeptor Mutationen Wilson, Hematology 2013, ASH EDU Wilson, Nat Med 2015

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.lymphome.de/en/groups/dshnhl Phase II single arm study: R-CHOEP14 + Ibrutinib DLBCL aaipi 2 / 3 Age 18-60 yrs GCB and ABC subtypes 0 +14 +28 +42 +56 +70 +86 +100 +121 Ibrutinib 560 mg PO,die (Day 1-121) CHOEP 14 (8 courses) Cyclophosphamide 750 mg/ sqm d 1 Doxorubicine 50 mg /sqm d 1 Etoposide 100 mg/ sqm d 1, 2, 3 Vincristine 1,4 mg/ sqm d 1 Prednisone 100 mg d 1, 2, 3, 4, 5 Rituximab

T-cell WHO Classification lymphoma: WHO classification Mature T-/NK-cell Neoplasms 2008 WHO Classification NHL Neoplasm of Major Subtypes 2,3 Grouping B-cell Neoplasms WHO 2016: Precursor Lymphoid Neoplasms T-Lymphoblastic Leukemia/Lymphoma Cutaneous Mycosis Fungoides (MF) Transformed MF Sézary Syndrome Primary Cutaneous CD30+ T-cell Disorders Primary Cutaneous Gamma/Delta TCL new: follicular T-cell lymphoma (FTCL) Non-Hodgkin Lymphoma T-/NK-cell Neoplasms Extranodal NK/TCL Nasal Type Enteropathyassociated TCL Hepatosplenic TCL Subcutaneous Panniculitis-like TCL Mature T-/NK-cell Neoplasms aggressive Nodal Peripheral TCL-NOS Anaplastic Large Cell Lymphoma (ALK +/-) Angioimmunoblastic TCL ~ 5% of all NHL Leukemic Adult T-cell Leukemia/ Lymphoma Aggressive NK-Cell Leukemia T-cell Prolymphocytic Leukemia T-cell Large Granular Lymphocytic Leukemia adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008 new (provisional): indolent T-cell lymphoproliferative disorder (LPD) of the GI tract and primary cutaneous acral CD8 + TCL renamed: EATL-2: monomorphic epitheliotropic intestinal TCL (MEITL) 49

CHOP as back-bone chemotherapy in aggressive lymphoma: still valid in PTCL PTCL-NOS/AITL n=191 Mayo Clinic 1994-2009; U Michigan 1988-2011 Briski et al., Blood Cancer Journal 2014; 4; e214 Schmitz et al., Blood 2010;116(18):3418-3425 McKelvey et al. Cancer 1976 Oct;38(4):1484-93 Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma n ORR [%] CRR [%] Morabito 297 76 56 Savage 199 76-90 55-70 Lee 84 59 47 Lopez-G. 174 64 49 Sung 52 63 17 Delmer 57 46

ptnhl very few data Clinical data sets? retrospective analyses (subgroups) phase I/II clinical trials (relapse) Few true phase III clinical trials ACT-1 (NLG) DSHNHL 2006 1A (in coop w. LYSA) ACT-2 / DSHNHL 2006 1B ( w. NLG) GEM-P (UK) vs CHOP Ro-CHOP (LYSA) Petrich et al., Br.J.Hematol. 168:708-718, 2014 2 large international registries 51

p TNHL: Targets & Drugs HDAC-I kinase inhibitor pralatrexate bendamustin gemcitabine anti-cd52 anti-cd4 anti-cd30 denileukin diftitox bortezomib mtor I Graft v. Lymphoma IMID molecular targets & companion diagnostics: CD30 brentuximab vedotin ALK crizotinib etc. CD52 alemtuzumab 52

ptnhl: treatment approaches beyond CHOP Novel regimens NK/T: L-asparaginase,ifosfamide, etoposide, dexamethasone, methotrexate (SMILE); Gemcitabine, Platinum GEM-? 6 x CHOP14 6-8 x CHO/E/P-14 (dose density, etoposide) Maintenance (?) First line addition of novel agents: antibodies, HDAC-I, vedotin, prala Addition of cellular immunotherapy: allogeneic SC transplantation DHAP FBC12 Dose escalation: HD therapy / autologous tx Mega CHOEP BEAM 53

Stand PTCL Studien national Primärtherapie ptnhl Studie Stand Publikation Perspektive DSHNHL2006-1B/ACT-2 abgeschlossen ASCO 2016 keine Vollpublikation in Vorbereitung DSHNHL 2006-1A /AATT im Follow-up ASCO 2015 offen Auswertung 17/18 Ro-CHOP (LYSA) rekrutierend noch nicht offen BV-CHOP (Seattle Genetics) im Follow-up noch nicht ja

1.0 0.9 ACT-2 trial OS according to treatment arm Median observation time: 43 months Proportion 0.8 0.7 0.6 0.5 6xCHOP-14 (n=58) 6xCHOP-14 + A (n=58) p=0.120 0.4 0.3 0.2 0.1 DSHNHL 07-DEC-2015 0.0 0 10 20 30 40 50 60 70 80 90 100 Months

CHOP versus CHP with Brentuximab vedotin as first line therapy: ECHELON2 DSHNHL: http://www.dshnhl.org/ O Connor OA, et al. ASCO 2013; Chicago, US (Abstract #TPS8611)

CHOP plus x - etoposide: Swedish registry data for CHOEP 5-y OS (%) Ellin et al., Blood 2014; 124; 1570-1577

ALCL ALK neg: benefit of planned upfront autologous SCT (NLG-T-01) 6x CHOEP-14/CHOP-14, BEAM + auto tx n 160 90 9 relapse > 2 years: 5 PTCL NOS 2 Alk neg ALCL 1 AILT 1 EATL D Amore et al. 2013, Hematol Oncol 31(suppl.1): 176 d Amore et al. J Clin Oncol. 2012: 30(25):3093-9

NK/T cell lymphoma: current treatment algorithm 06/2014 Yamaguchi Int J Hematol 2012 59

140 Fälle aus Register Mean PFS 33 m. Mean OS 46 m. 5-yr OS 56/34 % für Nasal/Extra-nasal NK/T

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) www.dshnhl.org Aktuelle Studien und Empfehlungen: www.dshnhl.org

German Lymphoma Alliance GLA e.v. Gegründet am 28.03.2017 Studientreffen ULM 16.-18. November 2017