1. Strategies in Mantle cell lymphoma: Chemotherapy Jorge E. Romaguera, M.D. Professor of Medicine Department of Lymphoma/Myeloma U.of Texas M. D. Anderson Cancer Center

2. Disclosures Millenium – research Celgene - research

3. Mantle Cell NHL Clinical Characteristics MDACC EMCLN M:F ratio 3:1 3.2:1 Median age (range) 60(41-80) 64(27-86) Age > 65 33% PS (ECOG) 0-1 98% 84% AA Stage IV 99% 92%(III-IV) Bone marrow involved 91% 72% GI tract involved 88% Peripheral blood involved 49% Splenomegaly 40% Elevated LDH 25% 29% IPI score 0-1 12% 17% Histology Diffuse 89% 81% Nodular 11% 18% Blastoid cytology 14% 3% 12 Dec 2004

4. Strategies in the Treatment of Mantle cell lymphoma 1- When to treat a- Stratify 2- What to treat with

5. Conservative management of MCL Martin et al. J Clin Oncol. 2009 95 patients 1997-2007; median follow up 4.5 years Retrospective, single institution, known date of Diagnosis and date of first Tx Observed X 3 months to define 2 groups: observation Vs. early treatment Median time to treatment 1 yr in observation group Mostly treated with CHOP (5 with HCVAD or SCT)

6. Conservative management of MCL Martin et al. J Clin Oncol. March 2009

7. Strategies in the Treatment of Mantle cell lymphoma 1- When to treat a- Stratify 3- What to treat with

8. Mantle cell International Prognostic Index (MIPI) GLSG 1996 CHOP, MCP GLSG CHOP + R, Ifn Vs ASCT 438 patients CHOP – 56% R-CHOP – 31% MCP - 11% Other - 2% ASCT – 80 pts IFN maintenance – 199 pts No therapy in remission – 72 pts Hoster et al. Blood Jan 2008

9. Simplified MIPI prognostic index For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with 6 to 11 points as high risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden (ECOG 2-4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/L, the cutpoints were 180 U/L, 240 U/L, and 360 U/L, for example. Points Age, y ECOG LDHULN WBC, 10 9 /L 0 <50 0-1 <0.67 < 6.700 1 50-59 — 0.67-0.99 6.700-9.999 2 60-69 2-4 1.000 -1.49 1.000-14.999 3 70 — 1.5000 15000

10. Hoster et al. Blood Jan 2008 Overall Survival according to MIPI – GLSG

11. Conservative management of MCL Martin et al. J Clin Oncol. 2009

12. Other prognostic variables Pre- Treatment 1- Lack of adenopathy 2- Early stage 3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-11 5- b2 microglobulin Post- Treatment 1- MRD

13. Other prognostic variables Pre- Treatment 1- Lack of adenopathy 2- Early stage 3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-11 5- b2 microglobulin Post- Treatment 1- MRD

14. Chemotherapy + XRT for Stage I-IIA untreated MCL: 26 pts Leitch et al, Ann Oncol 14:1555-1561, 2003

15. Chemotherapy + XRT for Stage I-IIA untreated MCL: 21 pts Bernard M et al. ICML 2011 62% stage II; 73% head and neck 5 patients with blastoid variant 17 patients with chemotherapy (R-CHOP in 13 )-XRT ORR 95% With median follow up 5 yrs, 5 yr relapse rate 46% Prognostic factors for worse outcome: stage II, blastoid variant

16. Other prognostic variables Pre- Treatment 1- Lack of adenopathy 2- Early stage 3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-11 5- b2 microglobulin Post- Treatment 1- MRD

18. Other prognostic variables Pre- Treatment 1- Lack of adenopathy 2- Early stage 3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-11 5- b2 microglobulin Post- Treatment 1- MRD

20. Other prognostic variables Pre- Treatment 1- Lack of adenopathy 2- Early stage 3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-11 5- b2 microglobulin Post- Treatment 1- MRD

21. 8 x R-CHOP IFN-  maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) PR, CR 6 x R-FC Rituximab maintenance (all 2 months) First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review Kluin-Nelemans et al: ICML 2011 European MCL Network

22. MRD (minimal residual disease) MRD clearance mid-therapy rapid for R-FC 67% vs only 31% for R-CHOP Sustained molecular remission beyond 1 year from end of treatment predicted for improved chances of maintaining clinical remission at 2 years (84% vs. 35%) Pott et al. IMCL 2011

23. Strategies in the Treatment of Mantle cell lymphoma 1- When to treat a- Stratify 3- What to treat with a- conventional b- new non-transplant approaches i- combination with newer drugs ii- consolidation/maintenance

24. Should treatment include Rituximab?

25. Rituximab in Overall Survival of MCL Schultz et al. J Natl Can Inst. 2007 Meta-analysis of seven randomized controlled trials 1990-2005, 1943 patients R- chemotherapy improved OS in MCL But heterogeneity made data less reliable (p = .07)

26. Griffith et al, Blood 2011; SEER data Rituximab improves Survival in the elderly

27. Overall Survival for MCL in 2 periods Abrahamsson et al, ICML 2011 785 patients from 2000-2010 For 2006-2010, 3-yr OS better (62% vs. 47%, p < 0.01) These patients received High dose AraC and rituximab as part of induction regimen OS improvement persisted when groups corrected for prognostic factors (age, PS, B symptoms)

28. Should it be more intense?

29. Improvement in Survival of MCL Herrmann et al. J Clin Oncol. 2008 Kiel Lymphoma Study Group (KLSG) – 1975-1986 German low-grade Study Group (GLSG) – 1996-2004 520 patients (370 from GLSG) Frequency matching for age, LDH, Performance status non-blastoid,advanced stage Median overall Survival improved from 2.7 y to 4.8 y

30. Overall Survival for MCL in 2 periods Herrmann et al J Clin Oncol Dec 2008 A – Initial cohorts B – matched cohorts

32. R-HCVAD/R-MA Overall Survival

34. R-HyperCVAD/R-MA 10 year follow-up

35. R-HCVAD/R-MA Time to Failure

38. Strategies in the Treatment of Mantle cell lymphoma 1- When to treat 2- Stratify 3- What to treat with a- conventional b- new non-transplant approaches i- combination with newer drugs ii- consolidation/maintenance

47. Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line-Treatment of Patients with Follicular, Indolent and MCLs Rummel, ASH 2008 # 2596 StiL: Study Group Indolent Lymphomas Histology Benda-R (ORR / CR) CHOP-R (ORR / CR) FL 94 / 44 94 / 34 MCL 89 / 32 95 / 35 IC / LPL 100 / NE 95 / NE MZL 90 / 52 96 / 36

48. PFS, mantle cell, B-R vs CHOP-R 0 12 24 36 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability CHOP-R B-R

49. Bendamustine Plus Rituximab Plus Cytarabine for MCL 28 patients (15 untreated) Median age 71 yrs, high MIPI 54%; blastoid 18% R 375/m2 day 1; B 70 mg/m2 days 2,3; Cytarabine 800 mg/m2 daily days 2, 3, 4 4-6 cycles every 4 weeks. ORR 96% (92% CR) Median follow up 1 year; 2 patients relapsed Visco et al; ICML 2011

54. R-CHOP alternating with R-Cytarabine X 5 cycles Then Cytarabine-fludarabine cycles 6-8 Then Rituximab q 2 months X 2 yrs 50 untreated patients, median age 74 yrs; high MIPI in 50% ORR 96% (86% CR/Cru) At median follow up 3 yrs, 86% OS, 70% EFS 18% patients (9) improved during cytarabine/fludarabine Toxicity: one MDS, one gr 4 infection, 19 patient with transient gr 4 neutropenia during maintenance. More dose reductions during fludarabine. Raty et al. ICML 2011

55. R-GIFOX q 2 weeks X 6 plus Rituximab q 2 months maintenance 16 untreated patients, median age 66 yrs Gemcitabine 1200 mg/m2 D1, Oxaliplatin 120 mg/m2 D2, Ifosfamide 5 g/m2 D2, R 375 mg/m2 q 2 months ORR 100% (88% CR) 5-year PFS of 56% without plateau Toxicity: Gr 4 thrombocytopenia in 43% patients; Gr 3 infection in 37% patients Corazzelli et al. ICML 2011

56. 8 x R-CHOP IFN-  maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) PR, CR 6 x R-FC Rituximab maintenance (all 2 months) First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review Kluin-Nelemans et al: ICML 2011 European MCL Network

57. MCL Elderly: Baseline Characteristics evaluable patients Kluin-Nelemans et al: ICML 2011 Parameter R-CHOP (%) R-FC (%) Age median (range) 71 (61-87) 70 (60-85) % male 67 72 Stage IV 85 82 % pos. BM 76 74 B-Symptoms 36 38 Performance 0-1 92 92 Elevated LDH 41 42 MIPI low risk 8 11 MIPI intermediate risk 44 40 MIPI high risk 48 50 n 215 216

59. Improvement in survival is also a measure of the effectiveness of salvage therapy, and over the last few years there has been marked improvement in options available.

60. Acknowledgements LYMPHOMA DEPARTMENT LUIS FAYAD, MD FREDERICK HAGEMEISTER, MD NEELAPU, SATTVA, M.D., PH.D. M ALMA RODRIGUEZ, MD FELIPE SAMANIEGO, MD ANAS YOUNES, MD MICHAEL WANG, MD DONNA WEBER, M.D. RAYMOND ALEXANIAN, M.D. QING YI, Ph.D . ROBERT ORLOWSKI, M.D., Ph.D. JATIN SHAH, M.D. NATHAN FOWLER, M.D. Andre Goy, M.D. LARRY KWAK, MD, Ph.D. PAMELA WEAVER, R.N. KIMBERLY HARTIG CHRISTINE SAMUEL MARIA BADILLO SANDY HOROWITZ, PHARM D KATHLEEN SHANNON-MCADAMS, RN, ANP ELLEN MULLEN, RN, ANP MATHAI VARGHESE, PA SHAPATRA PARKER HEMATOPATHOLOGY JEFFREY L MEDEIROS, MD JOHN MANNING, MD JEFFREY JORGENSEN RICHARD FORD, M.D. Ph.D RAJA LUTHRA, MD, Ph.D. CYTOPATHOLOGY RUTH L KATZ, MD NANCY CARAWAY M.D. ABHA KHANNA AMANDA WEDGWOOD, RN, CNS AMYE MOSHIER, PA HONGYAN WANG, PA MARIA GUERRERO, ANP WENDY CHEN, PA PETER LAI, PA SHIRLEY GEORGE, APN BMT DEPARTMENT RICHARD CHAMPLIN, M.D. ISSA F.KHOURI, M.D. CHITRA HOSING, M.D.

61. 12 Dec 2004 Thank you!