#EBMTLymphoma

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1 11th Educational Course of the EBMT Lymphoma Working Party on "Treatment of Malignant Lymphoma: State-of-the-Art and Role of Stem Cell Transplantation Heidelberg (Germany), September 24-26, 2015 #EBMTLymphoma

2 Autologous Stem Cell Transplantation in Marginal Zone Lymphoma Irit Avivi Tel Aviv medical Center, Tel Aviv, Israel 11th Educational Course of the EBMT Lymphoma WP, Heidelberg, September #EBMTLymphoma

3 Who are the MZLs? A group of lymphomas that originate from memory B lymphocytes, normally present in a distinct micro-anatomic compartment,called the marginal zone of the secondary lymphoid follicles. 3 specific entities: Extranodal marginal zone lymphoma (EMZL) ;MALT Splenic MZL (SMZL) Nodal MZL (NMZL) Despite sharing morphological features, these diseases differ Clinically and Genetically 3 3

4 MZLs Up to 25% of patients with gastric lymphoma but nearly 50% of those with non-gi lymphoma present with disseminated disease #EBMTLymphoma

5 MZL Management Depends whether the patient present with localized Vs disseminated disease and the existence of symptoms MALT- Ab, Local Radiotherapy, Rituximab, with/without chemotherapy smzl WW, Splenectomy, Rituximab, with/without chemotherapy nmzl WW, Rituximab with/without chemotherapy #EBMTLymphoma

6 MZL- Management & Outcome The outcome is considered as Excellent Is it indeed so good??? 6 6

7 Non- Gastric MALT Non Gastric MALT 6 yr OS=71% 7 7

8 Splenic Marginal Zone Lymphoma HB<12 ALB<3.5 High LDH 5 yr OS 1-88% 2-73% 3-50% Vito Franco, Blood

9 What are the options for non localized Disease progression and What is the Outcome? #EBMTLymphoma

10 Case I MR Brown, a 61 yr old man, was diagnosed with disseminated MALT 22 months ago. He was treated with CHOP-R achieving CR. Rituximab maintenance therapy was employed. He remained in CR for almost 2 years, but..., appeared in the clinic few weeks ago with enlarged neck and inguinal lymph nodes. PET-CT showed enlarged, bulky axillary, inguinal and retroperitoneal lymph nodes, with an SUV uptake of about 8-9. Biopsy confirmed the recurrence of MZL 10 10

11 Therapeutic options BR Lenalidomide(R 2 ) Ibrutinib RICE ASCT 11 11

12 Bendamustine First synthesis by the group of W.Ozegowski and D.Krebs at the Institute of Microbiology and Experimental Therapy in Jena (1962): First publication in Journal für Praktische Chemie, Verlag Ambrosius Barth in Leipzig, Vol. 20, issue 3-4,

13 Phase II study with bendamustine in rituximab-resistant NHL Relapsed, indolent, or transformed B-cell NHL, resistant to rituximab 76 patients, median age 63 years Bendamustine 120 mg/m2, days 1 + 2, every 21 days for 6 cycles Friedberg JW et al. J Clin Oncol 2008;26:

14 Bendamustine in rituximab-resistant NHL: progression-free survival No of patients Event % Censored % Overall (55) 28 (21) Indolent (41) 33 (20) Median duration of PFS, months (95% CI) 7.13 ( ) 8.25 ( ) PFS, progression-free survival Time (months) Adapted from Friedberg JW et al. J Clin Oncol 2008;26:

15 Pooled analysis Bendamustine,120 mg/m 2/d,2d,x6-8 in Rituximab Refractory PTs N=176 Median age 61 years Bendamustine 120 mg/m 2, days 1,2 + 2, x 6 8 cycles 81 stage III/IV Median prior chemotherapies- 2 FL (68%), SLL (20%), MZL (11%, n=18), LPL(1%) Median FU=25m ORR: 76%, 23% CRs Median DOR- 10 months 2 yr PFS=23% ORR and DOR were not dependent on age (< or > 65 years), gender, histology, prior chemotherapy ( or >1) Cheson BD et al. Blood 2009;114:Abs 2681 and associated poster

16 Case I ( Cont) Mr Brown relapsed after 25 months, and being symptomatic, additional therapy was considered. What would you do now? 16 16

17 Therapeutic options Relapsed nmzl Relatively young Relatively Early relapse BR Lenalidomide(R 2 ) Ibrutinib RICE ASCT 17 17

18 Lenalidomide at Disease Progression A phase II study of lenalidomide in patients with MALT 11 of 18 patients (61.1%) achieved an objective response 6 patients with CR (33.3%) 5 with PR (27.8%) 3 patients were rated as SD (16.7%). Some pts responded only after the 5th cycle Barbara Kiesewetter, Haematologica March

19 Lenalidomide- Rituximab ( R 2 ) Lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial Nathan H Fowler, et al

20 R 2 for untreated FL, MZL & SLL: Open-label, phase 2 trial lenalidomide 20 mg/day, days 1 21 Rituximab 375 mg/m², day 1/cycle Patients responding after 6 cycles could continue therapy up to 12 cycles. 110 patients FL n=50 ; MZL n=30 ; SLL n=30 MZL Outcome ORR -90% 67% CR 22% PR Nathan H Fowler, et al

21 Therapeutic options BR Lenalidomide(R 2 ) Ibrutinib RICE ASCT 21 21

22 Ibrutinib inhibits BtK 22

23 Ibrutinib in Relapsed/Refractory B-Cell Malignancies 1 out of 4 achieved PR Ranjana H. Advani, JCO.2012.

24 High-Dose Therapy/Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory #EBMTLymphoma

25 ASCT in R/R MZL( n=14) Median FU= 138m (13 yrs) 6-Refractory, 8-Relapse 3-CR, 11-PR 10/14 attained PFS >27m ( ) Clin Ly Leu MM 2011

26 ASCT in MZL- Outcome ( Median FU=138m) Median duration of failure-free survival -108 months, Median duration overall survival -120 months 26 26

27 High Dose Therapy and Autologous Stem Cell Transplantation in Marginal Zone Lymphoma An EBMT-FIL-GITMO Retrospective Study. Irit Avivi, Luca Arcaini, Virginia Ferretti, Ariane Boumendil, Herve Finel,Peter Dreger, Silvia Montoto, and Annarita Conconi 27 27

28 Study Design 295 consecutive patients with nmzl, MALT or smzl Inclusion criteria: Age 18 years First ASCT between July 1994 and February 2013 Reported to the EBMT and/or the FIL and the GITMO registries. Histological report confirming MZL Patients with a history of histologic transformation were excluded

29 Patient Characteristics (n=295)

30 Best response Post ASCT dependent on Disease status at ASCT 30 30

31 Mortality Rate After a median follow-up of 4 years (range, 0-19 years), 58 patients (29%) died, 25 of disease progression. 20 without disease progression, ASCT related in 12 cases, SPMs in 4 cases Car accident-1. Unknown in 3 cases. 5-year NRM= 9% (95%CI:

32 Patient Outcome Median FU-4.1 yrs ( ) RR 5-year progression= 38% (95%CI:30-45%) 5-year NRM= 9% (95%CI:6- PFS OS 32 32

33 Univariate Analysis 33 33

34 Multivariate for OS 34 34

35 Multivariate analysis for EFS 35 35

36 Multivariate analysis for Relapse/Progression 36 36

37 OS Dependent by Age 75% 65% 27% 27% 37 37

38 OS Dependent by MZL Type 77% 70% 60% 30% 38 38

39 Secondary Malignancies Risk of secondary malignancy was 6% 13 cases within a median FU of 4 yrs 3 MDS, 10 solid 5 died of their secondary cancer 39

40 Long-term follow-up of ASCT in 693 patients with FL: an EBMT registry study Median FU=10 yr 63/693 (9%) developed SPMs, resulting in 46 deaths. Most common SPM was MDS/AML. AML/MDS cases were associated with TBI conditioning regimen. Montoto S, JCO

41 Case 2 A 59 year old man, previously treated with R-CVP for MZL, has been recently diagnosed with transformed MZL ( DLBCL), stage 3B. Medical background is unremarkable. What would you do now? 41 41

42 Transformed MZL 373 pts, diagnosed with MZL, MALT, nmzl between Med FU= 5 yr tmzl occurred in 14 patients ( 12 DLBCL, 1 HL, 1 MCL) Risk for transformation in MZL subtypes smzl-6%, NMZL-3%, 4% MALT (P=0.635). Risk for transformation over time - 4% 6% 9% 5yr 10yr 15yr The rate of transformation tended to plateau from that point onward

43 Treatment ad Outcome at Transformation 9 doxorubicin based; 4 High dose ARA-C based; 4 ASCT Med FU=12m since transformation 4/14 died. 2 yr OS=38% 43 43

44 Treatment of Transformed FL 44 44

45 What Do You Recommend ASCT? Seriously consider ASCT, taking into account that results appear better, than CHOP Who are the Auto candidates young Previously exposed to Anthracyclines Developing transformation whilst receiving rituximab Early vs Late Transformation Disseminated vs localized transformation Highly proliferative transformation 45 45

46 Conclusion (1) Relapsed/Refractory MZL Most MZL pts have an indolent course of their disease Patients who experience systemic relapse are often considered for systemic chemotherapy and/or novel agents, similar to patients with FL. However, most of these therapies provide relatively short remissions, especially in advanced recurrences

47 Conclusion (2) Role of ASCT ASCT appears to be highly potent, providing a very long survival, especially in patients younger than 65, and in those, diagnosed with MALT rather than szl. Rituximab exposure though appeared to be associated with a higher Relapse/progression, was not associated with a statically significant shorter EFS or OS. Relapse rate following ASCT is indeed low Only 6% of patients developed SPMAs,and only 3 pts had 2th MDS/AML - an incidence which might be attributed to the rare employment of TBI, or to our short FU Only 4 pts out of the 199 evaluable pts died of secondary malignancy 47 47

48 Conclusions(3) ASCT is one, if not the most effective therapy, in pts with advanced MZL, providing very long remissions and impressive survival duration. It should be therefore considered in young pts with R/R disease. The current therapeutic options, though expanding, and sound sophisticated and novel, provide shorter remissions and survival, and the need for frequent therapies is likely to decrease QQL

49 The incidence of tmzlmight Appear to be lower than in reported in FL. No solid data prospectively comparing Anthracycline based therapy vs ASCT but data from the rituximab era for those who had an ASCT support the adoption of this strategy in Young patients. Transformed MZL Previously exposed to Anthracyclines Developed transformation while receiving rituximab Presented with Early vs Late Transformation and with disseminated vs localized transformation 49 49

50 Thank you 50 50