News from EHA. Linfomi. Maurizio Martelli Dip. Biotecnologie Cellulari ed Ematologia Sapienza Università di Roma

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1 News from EHA Linfomi Maurizio Martelli Dip. Biotecnologie Cellulari ed Ematologia Sapienza Università di Roma

2 Outline HD advanced disease first line therapy : intensity of chemotherapy and PET guided radiotherapy New drugs relapsed/refractory HD : Brentuximab Vedotin DLBCL first line therapy : R-CHOP 21 vs R-CHOP 14, role of consolidation radiotherapy New drugs relapsed/refractory ALCL : Crizotinib

3 Comparing intensity of chemotherapy followed PET-Guided radiotherapy in patients with adavanced stage Hodgkin lymphoma: final results of the GHSG HD15 trial A.M. Engert Engert EHA 2012 abs 1108 oral session

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5 GHSG 15 trial: results PTS= BEACOPP esc (%) 6 BEACOPP esc (%) 8 BEACOPP 14 (%) CR yrs FFTF yrs OS Hematol. toxici?es Sec. AML/MDS (29) 19 (2,7%) 2(0.3%) 8((1.1%) More effective and less toxic

6 (n=832) Engert EHA 2012 abs 1108 oral session

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8 GHSG 15 trial: conclusions 6 BEACOPP escaleted followed PET- guided IFRT are more effeclve and less toxic than 8 BEACOPP escaleted In the HD- 15 only 11% of all palents received IFRT as compared to 71% in the prior HD- 9 study PET performed auer chemotherapy can guide the need of addilonal IFRT and reduces the number of pts requiring RT Engert EHA 2012 abs 1108 oral session

9 Long term follow up results of an ongoing PIVOTAL study of Brentuximab vedotin in patients with relapsed or refractory Hodgkin Lymphoma (HL) S.Smith Smith et al EHA 2012 abs 1109 oral session

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12 Smith et al EHA 2012 abs 1109 oral session

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14 Smith et al EHA 2012 abs 1109 oral session

15 Smith et al EHA 2012 abs 1109 oral session

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19 Younes et al EHA 2012 educational

20 Younes et al EHA 2012 educational

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22 Younes et al EHA 2012 educational

23 Younes et al EHA 2012 educational

24 Younes et al EHA 2012 educational

25 Panobinostat

26 D S H N H L RICOVER-60-no-RX Role of Radiotherapy for elderly DLBCL Patients in the Rituximab Era: Final Results of the RICOVER-60-no-RX Study of the German High Grade Non-Hodgkin s Lymphoma Study Group (DSHNHL) Gerhard Held, Niels Murawski, Marita Ziepert, Viola Pöschel, Carsten Zwick, Marcel Reiser, Sibylla Wilhelm, Tobias Gaska, Michael Heike, Joerg Schubert, Norbert Schmitz, Markus Loeffler, Christian Ruebe, and Michael Pfreundschuh for the DSHNHL Held et al EHA 2012 abs 1114 oral session

27 Radiotherapy in the Rituximab Era Objective: To assess the role of additional radiotherapy to bulky disease in elderly patients with DLBCL in the setting of 6xR- CHOP R

28 Radiotherapy in the Rituximab Era RICOVER-60 6 x CHOP Gy (Bulk, E) Response Cheson, JCO, 1999 CD20 + DLBCL Std. I-IV Jahre Random 2x2 Factorial Design 8 x CHOP Gy (Bulk, E) 6 x CHOP Gy (Bulk, E) + 8 x Rituximab RICOVER-60-no-RX 6 x CHOP Gy (Bulk, E) + 8 x Rituximab RICOVER-60-no-RX: 8 x CHOP Gy (Bulk, E) + 8 x Rituximab - 3rd Amendment - Recruitment 08/ / Number of Patients Median Observation 39 Months

29 Radiotherapy in the Rituximab Era D e m o g r a p h y p= p= p= p= p=0.024 RICOVER-60 RICOVER-60- no-rx Age (years) Stage III/IV IPI=3-5 Extranodal disease Bulky Disease

30 Bulky Disease: Tx according Protocol EFS PFS OS 80% [95%CI: 71-89] 88% [95%-CI: 80-95] 90% [95%-CI: 84-97] 54% [95%-CI: 38-71] 62% [95%-CI: 46-78] 65% [95%-CI: 49-81] p=0.001 p<0.001 p=0.001 months RICOVER-60 RICOVER-60-no-RX (n=78) (n=35)

31 Bulky Disease: Tx according Protocol PFS: Multivariate analysis adjusted for strata Factor Relative risk p-value 95% CI Rx vs. no Rx (1.8; 10.6) LDH > UNV (0.2; 1.7) ECOG > (0.5; 4.9) Extranodal involvement > (0.3; 2.4) Stage III/ IV (0.5; 3.4) Age > 70 years (0.7; 3.9)

32 Bulky Disease: CR/CRu after R-CHOP-14 EFS PFS OS p=0.439 p=0.430 p=0.839 months RICOVER-60 RICOVER-60-no-RX (n=33) (n=20)

33 Bulky Disease: PR after R-CHOP-14 EFS PFS OS p<0.001 p=0.025 p=0.019 months RICOVER-60 RICOVER-60-no-RX (n=84) (n=27)

34 Radiotherapy in the Rituximab Era Conclusions: Rx of bulk appears not to be beneficial for patients in CR/CRu after 6xR- CHOP-14 Rx to bulk appears to be beneficial for patients in PR after 6xR-CHOP-14 Limitations: No randomized trial Imbalanced demographics Response evaluation according to Cheson 1999 Role of PET remains unclear

35 Radiotherapy in the Rituximab Era Definitive clarification of the role of Rx only by a randomized trial UNFOLDER - Trial R * randomization upfront

36 17th Congress of EHA Amsterdam, the Nederlands, June 2012 R-CHOP21 vs R-CHOP14 IN 712 DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS: RESULTS OF A MULTICENTRIC RETROSPECTIVE STUDY FROM ITALIAN LYMPHOMA FOUNDATION (FIL) Luigi Rigacci Department of Hematology Azienda Ospedaliero Universitaria Careggi Florence EHA 2012 abs 1115 oral session

37 Patient characteristics Retrospective study from Jan 2002 to Dec consecutive DLBCL 7 Italian Hematological Centers R-CHOP21 vs R-CHOP14 R-CHOP21: 478 R-CHOP14: 234 p Median follow-up (months) Age > 60 years Median age < < Systemic Symptoms Stage I-II Stage III-IV Bulky disease Abnormal LDH IPI IPI IPI IPI Bone marrow Lymph nodes >= < Rigacci et al EHA 2012 abs 1115 oral session

38 Recruitment by age R-CHOP21 vs R-CHOP r-chop21 r-chop >79 Rigacci et al EHA 2012 abs 1115 oral session

39 R-CHOP21 vs R-CHOP14 Overall response rate and relapse R-CHOP21 (478) R-CHOP14 (234) p Tot (712) CR/CRu 367 (77%) 187 (80%) 554 (78%) PR 97 (20%) 40 (17%) 137 (19%) NR/PD 14 (3%) 7 (3%) n.s. 21 (3%) Relapse 47/367 (13%) 25/187 (13%) n.s. 72/554 (13%) Rigacci et al EHA 2012 abs 1115 oral session

40 Survival R-CHOP21 vs R-CHOP14 Rigacci et al EHA 2012 abs 1115 oral session

41 R-CHOP21 vs R-CHOP14 Toxicity during treatment Grade >=3 Hematol toxicity R-CHOP21 R-CHOP14 Neutropenia 31.7% 17% Anemia 2.5% 10.2% Thrombocytopenia 2% 0.8% Grade >=3 non-hematol toxicity Infection 3.9% 9.4% Hepatic 0.8% 0.8% Cardiac 0.2% 0.8% Neurological 6.2% 11.1% Rigacci et al EHA 2012 abs 1115 oral session

42 CRIZOTINIB OBTAINS DURABLE RESPONSES IN ADVANCED CHEMORESISTANT ALK+ LYMPHOMA PATIENTS A.Stasia (1), L.Guerra (2), L.Bernard (3), A.Cohen (4), M.King (5), R.Ordemann (6), M.Steurer (7), F.Farina (1), L.Dal Prà (1), M. Ceccon (8), L.Verga (2), E.M.Pogliani (1), R. Piazza (8), C.Gambacorti Passerini (1) 1 University of Milano Bicocca and S. Gerardo, Monza, Italy; 2 S. Gerardo Hospital, Monza, Italy; 3 Maisonneuve-Rosemont Hospital, Montreal, Canada; 4 Trillium Healt Centre, Toronto, Canada; 5 University of Tel-Aviv, Tel-aviv, Israel; 6 University of Dresden, Dresden, Germany; 7 University of Innsbruck, Innsbruck, Austria; 8 University of Milano Bicocca, Monza, Italy University of Milano Bicocca, Monza, Italy EHA 2012 abs 1153 oral session

43 ALK+ LYMPHOMAS: background ALK: 43% of Anaplastic Large Cell Lymphomas (ALCL) and 7 % non ALCL cases are NPM-ALK+ (Drexler H. et al. Leukemia 2001) ALCL ALK+ are responsive to cytotoxic drugs BUT relapses occur and bear a poor prognosis, given the intrinsic aggressiveness of this disease. University of Milano Bicocca, Monza, Italy N K El-Mallawany et al Nature 2012

44 Crizotinib: background is an ATP-competitive molecule inhibitor of c-met/hgfr rec tyrosine kinases with cellular IC50 values between 24 and 60 nm in NPM-ALK+ cells recommended dose in ALK+ lung adenocarcinoma is 250 mg BID; no study has been performed in ALK+ lymphomas. Crizotinib University of Milano Bicocca, Monza, Italy The structure of ALK in complex with Crizotinib

45 PTs UPN AGE N LINES of PRIOR CT Crizotinib: results Alk break BM % LDH, time to normalization FEVER time to normalization RESPONSE 01/SM 27 3 Y 3 > 0 29 days 2 days CR, /KK ABMT Y 8 > 0 22 days 10 days CR, 5 GG ABMT Y 65 > 0 35 days na PR, 2 SL 23 3 Y 0 na 3 days CR, +18 ZD 40 5 Y na 30 days na PR, 1 PR ABMT Y 15 -> 0 na 10 days CR, 2 JS 56 3 Y 0 30 days na CR, +13 RF 28 3 Y 0 na na PRO SI allobmt Y 0 na na CR, +8 ORR 89 % (95% C.I.: 60-99%) Durable (> 6 months) responses: 44% (95% C.I.: 19-73%) University of Milano Bicocca, Monza, Italy Stasia et al EHA 2012 abs 1153

46 Crizotinib: results Day 0 Day + 16 KK University of Milano Bicocca, Monza, Italy Stasia et al EHA 2012 abs 1153

47 Crizotinib: results Day 0 Day + 28 University of Milano Bicocca, Monza, Italy SL Spleen

48 Toxicity Ocular flashes grade 1-2 9/9 Peripheral Edema grade 1-2 1/9 Neutropenia grade 3 1/9 LFT elevation grade 2 1/9 University of Milano Bicocca, Monza, Italy 48

49 Crizotinib : conclusions Well tolerated over a long period of time (up to 2 years) Exerted a potent antitumor activity: ORR 89 % (95% C.I.: 60-99%) Durable (> 6 months) responses in 4/9 patients (44%, 95% C.I.: 19-73%) Crizotinib is being evaluated in a phase I B open label study (81013) in relapsed ALK+ lymphomas. Crizotinib in combination with other agents for first line treatment is under discussion. University of Milano Bicocca, Monza, Italy Stasia et al EHA 2012 abs 1153

50 Final queslons BEACOPP esc x 6 and PET guided IFRT should be considered the standard therapy of advanced HD? When Brentuximab Vedotin in advanced HD? R-CHOP 21 should be considered the standard therapy in all subgroups of DLBCL? Does local radiotherapy in DLBCL provide some benefit or add only toxicity?

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53 Statistical analysis: multivariate R-CHOP21 vs R-CHOP14 Hazard Ratio R-CHOP21 1 R-CHOP (C.I. 95% ) Age > (C.I. 95% ) IPI (C.I. 95% ) IPI (C.I. 95% ) IPI (C.I. 95% ) Bulky 1.43 (C.I. 95% ) Rigacci et al EHA 2012 abs 1115

54 100 Overall survival Percent survival Time (months) University of Milano Bicocca, Monza, Italy