Lymphoma. André Bosly M.D.,Ph.D. Post ASH meeting 10/01/2014 Sheraton Brussels National Airport

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1 Lymphoma André Bosly M.D.,Ph.D. Post ASH meeting 10/01/2014 Sheraton Brussels National Airport

2 Lymphoma Hodgkin Lymphoma (HL) Indolent Lymphoma (inhl) Diffuse Large B Cell Lymphoma (DLBCL)

3 Hodgkin Lymphoma Role of radiotherapy in early stages Novel therapies Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

4 Overall results of therapy for early disease Up to 90% cures with first line therapy About 95% alive at 5 years Primary focus of research is to maintain (? improve) this result minimise toxicity Risk-adapted and response-adapted approaches Johnson P Educational

5 EORTC/LYSA/FIL H10: Interim analysis for futility: PET negative groups F group U group Progression-free survival Favorable - PET2 negative 1-yr PFS: 94.9% vs % HR = 9.36 (79.6% CI: ) P-value=0.017< (months) O N Number of patients at risk : Group ABVD+RT ABVD Progression-free survival Unfavorable - PET2 negative 1-yr PFS: 94.7% vs. 97.3% HR = 2.42 (80.4% CI: ) P-value=0.026< (months) O N Number of patients at risk : Group ABVD+RT ABVD Futility is concluded. M Andre et al, Haematologica 2013,

6 UK NCRI RAPID - trial design Initial treatment: ABVD x 3 Re-assessment: if response, PET scan performed PET +ve PET -ve 4 th cycle ABVD then IFRT Randomisation 30 Gy IFRT No further treatment

7 PFS in the randomised PET negative population (per protocol analysis, n=392) 3 year PFS 97% (94.5%, 99.6%) vs 90.7% (86.7%, 94.7%) HR 2.39 in favour of IFRT, p=0.03 Radford et al, Blood 2012; 120: a547

8 Mechanism of action of novel agents in HL A.Younes Educational

9 Idelalisib:12%ORR A.Younes Educational

10 Prospective trials ongoing with Brentuximab vedotin 1 st line ABVD vs AVD + BV 2 nd line R/R:BV and ICE + ASCT Young. Educat. ASH

11 Impact of reduction of Bleomycin and Vincristine in patients with advanced Hodgkin lymphoma treated with BEACOPP : German Hodgkin study group Less cycles given than planned Bleomycin 17.0 % Etoposide 1.1 % Adriamycin 0.4 % no impact on PFS Cyclophophamide 0.3 % Vincristine 32.6 % Procarbazine 3.1 % Prednison 1.3 % von Tresckow B. Cologne - # 637

12 Phase I panobinostat with ICE in R/R chl Pan-deacetylase inhibitor + ICE 23 pts (ABVD) 9 primary refractory No grade ¾ non haematological toxicity ORR 86 % CR 71 % auto SCT Oki, Houston, # 252

13 NLPHL:Approach to Frontline Treatment M.Fanale Educational

14 HL Take home message Omission of radiotherapy after a negative early FDG- PET scan will slightly increase the rate of recurrence (about 5%).but probably not affect survival;most patients will not therefore benefit from unselected irradiation Novel therapies in Hodgkin are promising Brentuximab vedotin is not only effective in R/R but could probably replace bleomycin and vincristine in first line NLPHL could be treated with IFRT(localized);R- CHOP(advanced)and R-CHOP+IFRT(intermediate stages)

15 Lymphoma Hodgkin Lymphoma (HL) Indolent Lymphoma (inhl) Diffuse Large B Cell Lymphoma (DLBCL)

16 Indolent Lymphoma (inhl) Target BCR signal (Idelalisib,Ibrutinib) Lenalidomide Rituximab (R2) R2-CHOP PRIMA long time results Zevalin

17 N.Fowler Education program

18 PI3Kδ Inhibition Impacts Multiple Critical Pathways in inhl

19 Phase II Idelalisib in refractory(alkalating and rituximab) inhl Study :Response Rate Characteristic N=125 Overall Response Rate, n (%) 95% CI Complete Response Partial Response Minor Response 1 Stable Disease Progressive Disease Not Evaluated 71 (57%) (48%, 66%) 7 (6%) 63 (50%) 1 (1%) 42 (34%) 10 (8%) 2 (2%) Time to response, months (N=71) Median (Q1, Q3) 1.9 (1.8, 3.7) 1 -LPL/WM patients Gopal #85

20 Study Waterfall Plot Lymph Node Response SPD of Measured Lymph Nodes, Best % Change from Baseline a % had improvement in lymphadenopathy 57% had 50% decrease from baseline Individual Patients (N=125) a Criterion for lymphadenopathy response [Cheson 2007] b 3 subjects no post baseline evaluation: 2 subjects NE 1 subject PD by Lymph Node biopsy

21 Study : Duration Of Response (DOR) % Continued Response (71) 3 (54) 6 (34) 9 (17) Median DOR = 12.5 months 12 (9) 15 (0) Time from Response, Months (N, Patients at Risk) 18 (0) Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments

22 Ibrutinib in Waldenström 67 pts(17 refractory) Prior therapy 2(1-6) Best overall response:81% Major response:57% VGPR:4,PR:32,MR 15 Response greater in wild-type CXCR4: 77% vs 30% (mutated) S.P.Treon #251

23 Phase II trial with lenalidomide+rituximab in inhl (Yamshon #249): Results 45 patients enrolled to date Cohort 1; previously treated: 30 patients Cohort 2; previously untreated: 15 patients Median follow-up Cohort 1: 43 months 6 patients continue at cycle 20, 33, 40, 52, 61, and 66 Cohort 2: 16 months *8 of 13 (4 CR/CRu) rituximab refractory patients responded CRu, CR unconfirmed; NR, not reached; PR, partial response; SD, stable disease; DOR, duration of response. Yamshon S, Qi L, Yu C, et al. Correlative Analysis and Clinical Update of a Phase 2 Study Using Lenalidomide and Rituximab in Patients With Indolent Non-Hodgkin Lymphoma. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2013; December 7-10; New Orleans, LA. 23

24 R2 Phase II multicentric first line in MCL (Ruan #247) Results 12-month PFS: 93.2 (95% CI = 75.5%, 98.3%) Median follow-up: 16 months (range 7-26) Overall survival: All subjects remain alive at last follow-up PFS, Progression-free survival Ruan J, Martin P, Shah B, et al. Combination Biologic Therapy Without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase 2 Study of Lenalidomide Plus Rituximab. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2013; December 7-10; New Orleans, LA. 24

25 R2+CHOP in untreated high tumour burden FL Response N=80 (%) CR 35 (44) CRu 24 (30) PR 16 (20) SD 1 PD 2 Not evaluated 2 CR: 74% ORR: 94% H.Tilly #248

26 Exploratory analysis: matched with PRIMA trial R-CHOP PRIMA n=80 R2-CHOP n=80 Response at the end of induction (IWG 1999) Age > Sex M/F 40/40 40/40 100% FLIPI Stage III-IV Hb <12 g/dl LDH > N % 60% 40% 65% 74% SD/PD PR CRu CR 20% 0% PRIMA R2-CHOP Salles G et al. Lancet 2011;377: Morschhauser F et al. ICML 2011

27 PRIMA 6 years follow-up Progression free survival from randomization (G.Salles #509) 6 years = 59.2% HR= 0.57 P< years = 42.7% Median follow-up since randomization : 73 months

28 PRIMA 6 years follow-up Response to second line treatment ORR CR/CRu PR 10 0 Observation Maintenance Responses reported by the investigators (percentage)

29 ZAR: Patient disposition Patients registered N=146 R-CHOP x 6 Patients randomized N=126 (PR 57; CR 69) Not randomized (N=20): - Incomplete induction treatment or Response <PR (N=8) - Low platelet or neutrophil counts (N=5) - BM infiltration>25% (N=1) - Patient decision (N=2) - Other (N=4) 90 Y-Ibritumomab Tiuxetan (N=64) Rituximab (N=62) A Lopez-Guillermo #369

30 Primary endpoint: Progression-free survival (PFS) 77% Rituximab (N=62; failed 14) 63% 90 Y Ibritumomab Tiuxetan (N=64; failed 25) HR=0.517 (95%CI: ) P=0.044

31 Progression-free survival (PFS) by arm Patients in CR after R-CHOP Patients in PR after R-CHOP 90 Y Ibritumomab Tiuxetan Rituximab P=NS P=0.01

32 inhl Take home message Inhibitors of BCR signaling pathway are effective in R/R (idelalisib i.e.) and Waldenström(ibrutinib) Lenalidomide+rituximab are effective in FL or MCL and will be challenged with R2-CHOP in FL Maintenance rituximab efficacy is confirmed with longer follow-up and is superior to Zevalin consolidation in PR patients.

33 Lymphoma Hodgkin Lymphoma (HL) Indolent Lymphoma (inhl) Diffuse Large B Cell Lymphoma (DLBCL)

34 Diffuse large B cell lymphoma(dlbcl) Epigenetic regulation of Germinal center Enzastaurin Best regimen for GCB DLBCL Novel therapies : GA- 101,Ibrutinib,Lenalidomide with R-CHOP Rituximab maintenance Treatment of failures after salvage (CORAL)

35 Role of epigenetic changes in the formation of germinal center and in B-cell lymphoma Ag + B-cell apoptosis Memory Plasma cell Proliferation and Ig gene editions EZH2 expression:histone methyl transferase BCL-6 expression BCL-6 B-cell diff. DNA damage apoptosis Béguelin W. ( Cornell NY) Plenary session #1

36 Role of epigenetic changes in the formation of germinal center and in B-cell lymphoma EZH2 is required for germinal center formation. Mutant EZH2 induces germinal center hyperplasia and lymphomagenesis throught aberrant silencing of bivalent promoter genes. Silencing of germinal center bivalent genes requires cooperation between EZH2 and BCL-6/BCOR complex. EZH2 and BCL-6 cooperate to induce lymphomagenesis. EZH2-BCL-6 combination inhibition therapy synergistically suppresses DLBCLs and may be a new target for therapy of GCB-DLBCL

37 PKC inhibitor (ENZASTAURIN) in 758 DLBCL pts - Prelude Trial Conclusions Enzastaurin did not improve DFS, EFS or OS vs placebo in patients with CR after initial treatment for DLBCL and an IPI score of 3 Safety results of Prelude were consistent with the established safety profile of enzastaurin when used as a single-agent therapy in lymphoma and other cancers. Cell of origin (GCB vs non GCB) was not prognostic for DFS in patients with CR. Crump. Toronto # 371 The prelude trial

38 What Works is a Work in Progress R-ACVBP improves outcome in younger patients with intermediate IPI. Higher toxicity limits age tolerance Efficacy in molecular subtypes of DLBCL unclear R-CHOP-14 is not superior to R-CHOP-21 DA-EPOCH-R may improve outcome of GCB DLBCL Manageable toxicity allows all age ranges Infusional topoisomerase II agents may decreased BCL-6 W.H.Wilson Educational ASH2013

39 DA-EPOCH-R in Untreated DLBCL PFS in Molecular Subtypes Non-GCB (ABC) DLBCL (67%) Enrolled-68 patients HI/H IPI: 40% Median follow-up 5.4 years Wilson et al. Haematologica 2012

40 What Works is a Work in Progress Ibrutinib may modulate sensitivity in ABC DLBCL Randomized study of R-CHOP ± Ibrutinib in ABC ongoing Lenalidomide and IRK4 Inhibitors may modulate MYD88 in ABC DA-EPOCH-R may overcome the adverse prognosis of MYC and BCL-2 expression Multicenter phase II trial of DA-EPOCH-R in MYC rearranged DLBCL (including t(14;18)

41 Phase II Ibrutinib:Outcome by Molecular Subtype Response in ABC and GCB DLBCL Survival in ABC and GCB DLBCL P=0.007! " #$ %#" $ &' ' $( ) *+,-. ) /$ 01$ 02$ /$7189 $#&:$) ;$< =$7> ) /?@A:$ 1BCD$7EBFFG$HI :$ EBE8$7J B00G$HI :$

42 Impact of induction and consolidative SCT in patients with Double Hit Lymphoma 106 RA MYC/BCL 2 77 % RA MYC/BCL6 or + BCL 2 23 % R-CHOP (33 %) R-EPOCH (31 %) R-Hyper CVAD or CODOX M/IVAC (36 %) 14 % SCT Ccl : poor outcome specially primary refractory R-EPOCH best regimen Gandhi,Chicago #640

43 GA 101 +CHOP Phase II in first line DLBCL (Gather Study) 6 G-CHOP 21+2G G : 1000 mg (fixed dose) 80 pts ORR:83% CR:55% PR:28% Rationale for phase III : G vs R A.Zelenetz # 1820

44 IBRUTINIB + R-CHOP Phase I b study in first line B cell lymphoma Results in DLBCL (22 pts) ORR:100% CR:64% PR:36% Rationale for phase III : I-R-CHOP vs R-CHOP A.Younes # 852

45 R2 CHOP in elderly DLBCL pts (Chiappella #850) Primary results Patient responses, % Overall population (N = 49) ORR 92 CR 86 PR 6 Non-responders 6 Unrelated death 2 Median follow-up: 28 months 2-year OS: 92% 2-year PFS: 80% 2-year PFS for low-intermediate IPI: 89% 2-year PFS for intermediate-high/high IPI: 74% 2-year EFS: 70% 2-year EFS for low-intermediate IPI: 84% 2-year EFS for intermediate-high/high IPI: 61% EFS, event-free survival. Chiappella A, Franceschetti S, Castellino A, et al. Final Results of Phase 2 Study of Lenalidomide Plus Rituximab-CHOP21 In Elderly Untreated Diffuse Large B-Cell Lymphoma Focusing on the Analysis of Cell of Origin: REAL07 Trial of the Fondazione Italiana Linfomi. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2013; December 7-10; New Orleans, LA. 45

46 R2 CHOP in elderly DLBCL pts (Chiappella #850) Primary results GCB (n = 16) Patient vs. responses, % non-gcb (n = 16) ORR 88 vs. 88 CR 81 vs year OS 88 vs year PFS 71 vs year EFS 61 vs non-gcb patient with MYC/BCL2 coexpression and 95% Ki-67 expression achieved CR as final response Follow-up: CR at 24 months off therapy Grade 3/4 adverse events (AEs), % Hematologic AEs by % of treatment cycles (N = 277) Neutropenia 32 Thrombocytopenia 13 Anemia 5 Febrile neutropenia 4 Non-hematologic AEs by % of patients (N = 49) Thrombosis 4 Neurological 4 Infections 2 Cardiac 2 BCL2, B-cell lymphoma 2; GC, germinal center. Chiappella A, Franceschetti S, Castellino A, et al. Final Results of Phase 2 Study of Lenalidomide Plus Rituximab-CHOP21 In Elderly Untreated Diffuse Large B-Cell Lymphoma Focusing on the Analysis of Cell of Origin: REAL07 Trial of the Fondazione Italiana Linfomi. Oral presentation at: Annual Meeting and Exposition of the American Society of Hematology 2013; December 7-10; New Orleans, LA. 46

47 Rituximab maintenance in DLBCL: EFS by Treatment Arm:ITT population 100% 90% 80.1% 80% 70% 76.5% Rituximab maintenance 60% 50% 40% 30% 20% All patients A (treatment) N=338 B (observation) N=345 Relapses 100 (14.7%) 36 (10.7%) 64 (18.7%) Observation 10% 0% p = HR: % CI: Time [months] N at risk A: RITUXIMAB B: OBSERVATION Rituximab Observation U.Jaeger #851 1 Jäger U, et al. IMCL 2013; Hematol Oncol 2013; 31 (Suppl. 1): (abstr. 119);

48 Event Free Survival by Treatment Arm and Sex ITT Population 100% 90% 80% Rituximab 70% 60% 50% 40% Male & R 84.1% Female & Obs 78.7% Female & R 76.8% Male & Obs. 74.4% Rituximab Observation Observation 30% 20% 10% 0% Female R vs. Obs.: HR: %CI: p= Male R vs. Obs.: HR: %CI: p= Time [months] Rituximab male A: RITUXIMAB/ female A: RITUXIMAB/ 132 male B: OBSERVATION/ 16 8female 7 7B: OBSERVATION/ 1 male 0 Rituximab female Observation male Observation female

49 DLBCL pts failing second line treatment Included in the Coral trial Design of the CORAL study 1 n = 243 n = 481 Relapsed/ refractory DLBCL <65 y R R-ICE x 3 n = 234 PR, CR CD34+ >2M n = 255 BEAM/ ASCT R Rituximab q2m x 6 R-DHAP x 3 n = 222 Observation FAIL In total, 145 patients were included in the analysis Eric Van den Neste #764 1 Gisselbrecht et al, J Clin Oncol 2010 & 2012

50 Response to 3 rd line regimen N = 145 Response (%) Complete remission (CR) Unconfirmed CR (ucr) Partial response (PR) No response Not evaluated CR/uCR by 3 rd line regimen (%) ICE-type DHAP-type Gemcitabine-containing CHOP-like Dexa-BEAM ORR: 43% In the initial CORAL study report, ORR after 2 d line R- DHAP/R-ICE was 63% (37% CR/CRu)

51 OS according to transplantation Overall Survival according to transplantation With number of Subjects at Risk and 95% Confidence Limits Median OS: 11.1 m (95%CI: ) 1-y OS: 41.6% HR = 2.2 Median OS: 5.0 m (95%CI: ) 1-y OS: 19.2% Months

52 DLBCL Take Home Message Epigenetic changes in the formation of germinal center could be in the future a target for GCB- DLBCL. DA-EPOCH-R may be the best regimen for GCB and double hit DLBCL (?) GA-101,Ibrutinib and Lenalidomide (both for ABC- DLBCL)may improve R-CHOP results Maintenance rituximab is not very useful except for males? In third line SCT can obtain prolonged remission

53 Aknowlegments M.Fanale U.Jäger P.Johnson A.Lopez-Guillermo G.Salles H.Tilly E.Van Den Neste W.Wilson M.André C.Bonnet S.Buyle L.De Vos V.Libotte A.Serck

54 Many thanks for your attention New Orleans is not only ASH