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

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1 GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) 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

2 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

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6 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)

7 Fragen zur Therapie GERMAN HIGH-GRADE NHL STUDY GROUP (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?

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

9 R-CHOP-14 oder 21? GERMAN HIGH-GRADE NHL STUDY GROUP (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)

10 HOP oder CHOEP? GERMAN HIGH-GRADE NHL STUDY GROUP (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

11 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

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13 CALGB/Alliance 50303: Event-Free Survival and OS EFS OS EFS (%) R-CHOP DA-EPOCH-R Yrs *Median follow-up 5 yrs Wilson WH, et al. ASH Abstract 469. HR: 1.14 (95% CI: ; P =.4386) Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP ( ) 0.69 ( ) DA-EPOCH-R ( ) 0.66 ( ) OS (%) R-CHOP DA-EPOCH-R HR: 1.18 (95% CI: ; P =.42) Yrs Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP ( ) 0.80 ( ) DA-EPOCH-R ( ) 0.76 ( ) Slide credit: clinicaloptions.com

14 UNFOLDER Study OS Patients randomised with reference pathology, according to pathology (n=269) GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) Proportion PMBCL, CHOP14/21 +/- Radiotherapy (n=69) all other with existing pathology, CHOP14 (n=200) DSHNHL Months

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

17 GOYA Final Analysis GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

20 DSHNHL /OPTIMAL>60 Study Trial design - Favourable Patients RANDOMIZATION 4/6 x CHOP xR xR 4/6 x CHLIP xR DSHNHL

21 DSHNHL /OPTIMAL>60 Study Trial design - Less Favourable Patients RANDOMIZATION 6 x CHOP xR xR 6 x CHLIP xR 6 x CHOP xOptiR 6 x CHLIP xOptiR DSHNHL

22 Treatment-related Deaths: OPTIMAL>60 vs. RICOVER-60 6xCHOP xR 6xCHLIP R 6xCHOP-14 + Opti-R 6xCHLIP xOptiR 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%)

23 Favourable Patients: OPTIMAL>60 vs. RICOVER Progression-free Survival Proportion RICOVER-60-6xCHOP-14+8xR (n=74) DSHNHL p=0.407 OPTIMAL>60-4/6xCHOP-14+8xR (n=58) (n=58) Months

24 Favourable Patients: OLD (OPTIMAL>60) vs. YOUNG (FLYER) OPTIMAL (71 years) FLYER (47 years) P F S Proportion Proportion Months Months O S Proportion Proportion Months Months

25 Less Favourable Patients: OPTIMAL>60 vs. RICOVER Progression-free Survival 0.9 Proportion RICOVER-60-6xCHOP-14+8xR (n=232) OPTIMAL>60 (n=385) p=0.155 DSHNHL Months

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

27 28% 7% 18% 6% 4% 2%

28 R-CHOP +? GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) 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

30 DSHNHL Study Group Meeting 19. November 2016 München supported by

31 Bulky Disease: OPTIMAL>60 vs. RICOVER-60 Proportion PROGRESSION-FREE SURVIVAL p= % 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) Months median time of observation: 24 months

32 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

33 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

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

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

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

38 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

39 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

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

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43 G-CCC 2014

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45 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

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

47 GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL) Phase II single arm study: R-CHOEP14 + Ibrutinib DLBCL aaipi 2 / 3 Age yrs GCB and ABC subtypes 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

49 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 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

50 CHOP as back-bone chemotherapy in aggressive lymphoma: still valid in PTCL PTCL-NOS/AITL n=191 Mayo Clinic ; U Michigan Briski et al., Blood Cancer Journal 2014; 4; e214 Schmitz et al., Blood 2010;116(18): McKelvey et al. Cancer 1976 Oct;38(4): Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma n ORR [%] CRR [%] Morabito Savage Lee Lopez-G Sung Delmer 57 46

51 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 A (in coop w. LYSA) ACT-2 / DSHNHL B ( w. NLG) GEM-P (UK) vs CHOP Ro-CHOP (LYSA) Petrich et al., Br.J.Hematol. 168: , large international registries 51

52 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

53 ptnhl: treatment approaches beyond CHOP Novel regimens NK/T: L-asparaginase,ifosfamide, etoposide, dexamethasone, methotrexate (SMILE); Gemcitabine, Platinum GEM-? 6 x CHOP 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

54 Stand PTCL Studien national Primärtherapie ptnhl Studie Stand Publikation Perspektive DSHNHL2006-1B/ACT-2 abgeschlossen ASCO 2016 keine Vollpublikation in Vorbereitung DSHNHL A /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

55 ACT-2 trial OS according to treatment arm Median observation time: 43 months Proportion xCHOP-14 (n=58) 6xCHOP-14 + A (n=58) p= DSHNHL 07-DEC Months

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

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

58 ALCL ALK neg: benefit of planned upfront autologous SCT (NLG-T-01) 6x CHOEP-14/CHOP-14, BEAM + auto tx n 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