Mantle Cell Lymphoma: Approach to Induction Therapy Mitchell R. Smith M.D., Ph.D. Director, Lymphoid Malignancy Program Cleveland Clinic

Small subset cyclin D1-ve overexpress cyclin D2, D3 Mantle Cell Lymphoma IMMUNOPHENOTYPE CD19/20/22+ CD5+ Negative for CD10, CD23 DETECTION t(11;14) FISH > 95% Cytogenetics 70% PCR 40% Small subset cyclin D1-ve overexpress cyclin D2, D3 Wlodarska I, et al. Blood. 2008;111:5683-5690. Fu K, et al. Blood. 2005;106:4315-4321. Herens C, et al. Blood. 2008;111:1745-1746. 2 2

Mantle Cell Lymphoma: Clinical Summary High response rate to chemotherapy, but short duration Better response duration, but not curable, even with R- HyperCVAD/R-MA or HDC/ASCT Optimal treatment regimen remains unclear Promising recent advances in biology and treatment Goals and selection of treatment depend on: Is MCL aggressive, since it has “short” median survival? Is MCL indolent, since not curable with CHOP-like regimens? 3

What is expected survival in MCL? 1990s Data Median OS ~ 3yr Armitage and Weisenburger JCO 1998

What is expected survival in MCL? GLSG Data (1996-2004) MEDIAN OS ~ 5 yr Herrmann et al. ASH, 2006: A2446

Proliferation correlates with MCL outcome KI-67 Katzenberger et al Blood 2006

Proliferation correlates with MCL outcome Proliferation Gene Expression Signature Lowest quartile Rosenwald, A et al Cancer Cell 2003

MCL IPI = MIPICLINICAL CLINICAL FACTORS Age PS (0,1 vs 2-4) LDH WBC BIOLOGIC FACTOR Ki67 adds additional prognostic value 44% of Pts 35% 21% Hoster et al Blood 2008;111:558-565

R-CHOP vs CHOP for Untreated MCL: TTF and OS Time to Treatment Failure Overall Survival 100 75 50 25 100 75 50 25 R-CHOP (52/62) R-CHOP (35/62) Percent Alive CHOP (49/60) Percent Failure-Free P=.93 CHOP (24/60) 4 3 2 1 4 3 2 1 Years Years Data confounded by post-induction IFN or SCT Lenz et al. JCO 23: 1984-1992, 2005.

Rituximab Effect on MCL Overall Survival: Meta-analysis Schultz et al. J Natl Can Inst. 2007 10

To improve on (R)-CHOP in MCL Intensify induction therapy R-HyperCVAD/R-MA Rituximab + High Dose Cytarabine Add “Novel” agents to CHOP e.g. antibody, bortezomib, temsirolimus, lenalidomide As response rate already high, add consolidation Rituximab maintenance Radioimmunotherapy High dose therapy/autologous stem cell rescue Allogeneic stem cell transplant “Novel” agents: e.g. target other surface markers, proteosome, mTOR, immunomodulation, BCR signaling

NCCN GUIDELINES: MCL Frontline therapy CHOP  rituximab older patients who cannot tolerate more intensive therapy R-HyperCVAD/R-HDMtx+Ara-C (< 60-65?) R-EPOCH Modified R-HyperCVAD (part A) + rituximab maintenance in patients > 65 yrs Nordic regimen (R-Maxi-CHOP alt R-HiDAC → autoSCT) Cladribine + rituximab Clinical trial Observation for selected stage III-IV patients CONSOLIDATION HDC/auto SCT

“Aggressive” Therapy

HDC/SCT prolongs remission, but does not cure, MCL Dreyling M, ASCO Educ Book 2006

R-HyperCVAD/MA in MCL FFS and OS in 97 patients at MDACC 5 toxic deaths + 3 MDS + 1 AML Romaguera et al JCO 2005

R-HyperCVAD/MA in MCL FFS by Age Months from start of treatment  . > 65 yrs - 32 pts, 19 failed <= 65 yrs - 65 pts, 24 failed p = 0.03 <= 65 yrs > 65 yrs R-HyperCVAD/MA in MCL FFS by Age 1.0 0.8 0.6 Survival probability 0.4 <65 24 “failed” of 65) >65 19 “failed” of 32) 50 % of Patients 0.2 P=0.03 10 20 30 40 50 60 70 80 Months from start of treatment For patients >65 years old vs patients ≤65, P=0.03. Updated from Romaguera et al. J Clin Oncol. 2005;23:7013.

R-HyperCVAD/R-MA initial treatment of MCL Gruppo Italiano Studio Linfomi Median Age 57 (29-66) MIPI Low 60% Int 31% High 9% Completed all Rx = 22 (37%) Deaths on RX = 3 Merli et al Brit J Haematology 156)3): 346-353, 2012

Phase 2 R- HyperCVAD/R-MA Front-Line MCL: SWOG 0213 Median age: 57 yrs (eligible if < 70) 88% RR (58% CR/CRu; 30% PR) Grade 3 or 4 ANC 85%; platelets 87% 100% 80% 60% 40% Progression 1-Year At Risk or Death Estimate 20% HCVAD MTX/Ara-C + rituximab 49 13 89% 0% 1 2 3 4 5 Years from Registration Epner et al. ASH, 2007. Abstract 387 Courtesy of Dr. Epner

Initial therapy for MCL patients < 65: NCCN NHL Database Analysis PROGRESSION-FREE SURVIVAL ©2012 by American Society of Hematology LaCasce A et al BLOOD 2012; 119:2093

Initial therapy for MCL patients < 65: NCCN NHL Database Analysis OVERALL SURVIVAL ©2012 by American Society of Hematology LaCasce A et al BLOOD 2012; 119:2093

MCL Younger Trial: Study Design Myeloablative Regimen TBI 12 Gy Cyclophosphamide 60 mg/kg × 2 Control Arm R-CHOP × 6 Stem cell mobilization R A N D O M I Z E Eligibility criteria: Treatment naive Ann Arbor stage II-IV MCL Age < 65 years Eligible for high-dose therapy ECOG PS < 2 ASCT Experimental Alternating (2 + 1) R-CHOP/R-DHAP→ Stem cell mobilization Myeloablative Regimen TBI 10 Gy Cytarabine 1.5 g/m2 × 4 Melphalan 140 mg/m2 ASCT Primary endpoint: TTF R-CHOP R-CHOP/R-DHAP Median age (yrs) 55 56 Male 78% 79% Stage 4 85% MIPI Lo/Int/Hi 61/25/14% 62/23/15% % Transplanted 72% 73% Hermine et al. ASH 2010; abstract 110. 21

MCL Younger Trial: Efficacy R-CHOP (n = 206) R-CHOP/R-DHAP (n = 199) P Response Rates After Induction Complete response/CRu 83 (40%) 111 (55%) P = .0028 Complete response/CRu/PR 186 (90%) 188 (94%) P = .14 Response Rates After ASCT (CR) 97% (63%) (n = 131) 97% (65%) (n = 129) Molecular CR (MRD- by RQ-PCR)* After Induction 29% 76% After ASCT 65% 88% Time to Treatment Failurea (n = 212) (n = 208) Relapse events after CR/CRu/PR 49 22 Median 49 months Not reached HR 0.68; P = .0382 Remission Duration After ASCTb 48 months (n = 133) P = .0059 Overall Survivalc P = .37 a Median follow-up: 32 months b Median follow-up: 30 months c Median follow-up: 33 months, median OS not reached in either arm Hermine et al. ASH 2010; abstract 110. Pott et al ASH 2010; abstract 965. 22

Nordic Lymphoma study group Maxi-CHOP/R-HiDAC → ASCR → R Age  65 Median age 56 Geisler CH et al Blood 2008

“Less Aggressive” Therapy

Less Intense Regimens for MCL Bendamustine is active

R-CHOP vs R-bendamustine in MCL German Study Group Indolent Lymphomas (StiL) Progression- free survival 1.0 0.9 N = 93 0.8 0.7 0.6 Probability 0.5 B-R Bendamustine 90 mg/m2 days 1, 2 Rituximab 375 mg/m2 day1, q 28d 0.4 0.3 CHOP-R 0.2 0.1 0.0 12 24 36 48 courtesy of Dr. M. Rummel

Less Intense Regimens for MCL R-CHOP followed by Radioimmunotherapy

R-CHOP Followed by 90Y-Ibritumomab in Untreated Mantle Cell Lymphoma (E1499) Patients with previously untreated MCL, stage II-IV (N=56) CR PR SD R (250 mg/m2) + imaging with 111In-Ibritumomab tiuxetan R (250 mg/m2) + 90Y-Ibritumomab tiuxetan (0.4 mCi/kg or 0.3* mCi/kg) R-CHOP 3-5 weeks 1 week Primary end point: PFS Secondary end points: ORR, toxicity R-CHOP: R (375 mg/m2); CHOP (q21 × 4) *0.3 mCi/kg for patients with platelet 100-149,000. Smith et al. J Clin Oncol 2012 in press.

E1499: R-CHOP → 90Y-Ibritumomab in MCL: PFS (top) and OS (bottom); right panels by age < 65 vs ≥ 65 Median Overall PFS = 28 months PFS Age ≥ 65 Age ≥ 65 OS MEDIAN FOLLOW-UP 41 MONTHS Smith et al J Clin Oncol 2012 in press

Less Intense Regimens for MCL Omitting High dose MTX/ARA-C from R- HyperCVAD/R-MA And adding Rituximab maintenance

R-HyperCVAD Part A + Rituximab Maintenance in Untreated MCL: PFS and OS Progression-Free Survival OS 100 100 Median OS not reached 80 80 median PFS 37 months 60 60 % of patients progression-free % of patients alive 40 40 20 20 10 20 30 40 50 60 10 20 30 40 50 60 Months Months Median follow up 37 months Kahl et al. Ann Oncol. 2006

Less Intense Regimens for MCL Bortezomib is active in MCL Can we incorporate bortezomib in frontline regimens?

VcR-CVAD → R in Untreated MCL: E1405 Add bortezomib to modified R-HyperCVAD (part A) Add maintenance rituximab 90% RR in previously untreated MCL 69% CR or CRu Toxicity manageable Grade 3 or 4 toxicity primarily hematologic Neurotoxicity tolerable Ongoing follow-up to define durability of responses with rituximab maintenance

Cladribine  rituximab in Untreated MCL (CDA 5 mg/m2 d 1-5) Therapy CDA CDA + rituximab Trial Rummel et al Leuk Lymph 1999 Inwards et al Cancer 2008 N 12 26 29 RR 58% 81% 66% CR/PR 42%/39% 52%/14% TTP (mos) 14.6 12.1

Randomized phase II, N ~ 160; 80 eligible per arm Randomized Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients < age 65 Randomized phase II, N ~ 160; 80 eligible per arm R E G I S T A O N ASCT R-Benda x 6 HD Cy SCC R-HCVAD/MTX/AraC X 4* ASCT HD Cy= cyclophosphamide 1.5 g/m2 SCC= stem cell collection * SCC after cycle 3 35

Randomized Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients  age 60 Randomized phase II, N ~ 328; 82 eligible per arm Rituximab R E G I S T A O N BR x 6 Rituximab BVR x 6 Lenalidomide + Rituximab BR x 6 Lenalidomide + Rituximab BVR x 6 B=bendamustine, V=bortezomib 36

Mantle Cell Lymphoma Treatment: 2012 Therapy guided by patient age/comorbidities and pace of disease Watch and wait for selected patients CLINICAL TRIAL ACCRUAL IS CRITICAL! Initial therapy in young/fit patient R-HyperCVAD/R-MA (? X 8 or x4 → HDC/ASCR) R-CHOP (alt with R-DHAP?) → HDC/ASCR ? Role of HiDAC Initial therapy in older/less fit patient R-bendamustine R-C(H)OP (Vc)R-CVAD → R rituximab “maintenance” under investigation New agents promising

Mantle Cell Lymphoma CONCLUSIONS Overall Survival is improving Risk stratification is improving Treatment outcomes are improving Does dose-intense therapy yield best outcomes? Cure remains elusive Better understanding of MCL biology needed to improve targeted therapies: more effective and less toxic