State of the Art Treatment for Relapsed Mantle Cell Lymphoma

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1 Winship Cancer Institute of Emory University State of the Art Treatment for Relapsed Mantle Cell Lymphoma Jonathon B. Cohen, MD, MS Assistant Professor, BMT Program Emory University- Winship Cancer Institute

2 Outline Current Responses to Front-line Therapy Evaluation of the Relapsed Patient Approved Therapies Ibrutinib Bortezomib Lenalidomide Investigational Agents Stem Cell Transplantation Conclusion/Recommendations

3 Mantle Cell Lymphoma- Background < 10% of cases of NHL Characterized by: CyclinD1 positivity by IHC Immunophenotype: CD5, CD20, CD23+ t(11;14) Frequently Stage IV Bone Marrow Involvement Peripheral Blood Lymphocytosis Spleen GI Tract

4 Prognostic Markers MCL International Prognostic Index (MIPI) WBC Count Age LDH Performance Status Ki67 proliferative index Cytogenetics Complex Karyotype Del(17p) Mutations (ie, NOTCH1) Hoster et al, Blood 2008; Hoster et al J Clin Oncol 2014; Hsi et al Leuk Lymphoma 2008 Sarkozy et al, Genes Chromosomes Cancer 2014; Cohen et al ASH 2012; Kridel et al Blood 2012

5 Front-Line Approaches No Standard of Care Cytarabine-containing regimens and autologous stem cell transplant appear to be important Median Event-free survival 83 months with CHOP/DHAP + Rituximab + Transplant Emory Experience: HyperCVAD + ASCT: 5-year OS 76% Nearly all patients will eventually relapse Delarue et al, Blood 2013; Murali et al, BMT 2008

6 Evaluation of the Relapsed Patient Outcomes for relapsed patients are historically poor Considerations Duration of relapse Prior regimens received Fitness / Motivation for Therapy Appropriateness / Interest in Clinical Trial Feasibility of Allogeneic Transplant Dietrich et al, Ann Oncol 2014

7 Salvage Options Dreyling, ASCO 2014 Educational Book

8 FDA Approved Therapies: Ibrutinib Orally available BTK inhibitor Standard MCL Dose: 560mg daily Toxicities: Diarrhea Rash Fatigue Mild Cytopenias / Increased Risk for Infection Bleeding Complications Generally very well tolerated Peripheral lymphocytosis is expected

9 Ibrutinib - Efficacy Median Duration of Response: 17.5 month Median Overall Survival: Not Reached Wang et al, NEJM 2013

10 Lymphocytosis with Ibrutinib In CLL, peripheral lymphocytosis is not associated with poor response or PFS Responding pts should continue therapy. No apparent risk to patients. Woyach et al, Blood 2014

11 Mechanisms for Ibrutinib Resistance Woyach et al, NEJM 2014

12 FDA Approved Therapies: Bortezomib Phase II Study: 1.3mg/m 2 days 1, 3, 8, and 11 Overall Response Rate: 33% Median Duration of Response: 9.2 months Median Overall Survival: 35.4 months Fisher et al, J Clin Oncol 2006; Goy et al Ann Oncol 2009

13 Bortezomib Peripheral Neuropathy 13% Grade 3 in Phase II Study GI Side Effects Thrombocytopenia 11% Grade 3 Zoster Reactivations

14 FDA Approved Therapies: Lenalidomide Approved for use after bortezomib EMERGE Study: 25mg orally days 1-21 of a 28 day cycle Overall Response Rate: 28% Median Duration of Response: 16.6 months Goy et al, J Clin Oncol 2013

15 Investigational Agents All patients should be considered for eligibility for clinical trials Agents under investigation Idelalisib (PI3δ-kinase inhibitor) mtor inhibitors Novel proteasome inhibitors Novel combinations Others

16 Idelalisib Oral PI3-kinase inhibitor Phase I Study in relapsed/refractory MCL: Overall Response Rate 40% Median duration of response 2.7 months Kahl et al, Blood 2014

17 Idelalisib - Single Agent Toxicities Transaminitis (20% Grade 3) Diarrhea (17.5% Grade 3) Anorexia (15% Grade 3) Pneumonia (10% Grade 3) Nausea, Fatigue, Rash (All 5% or less Grade 3) 18% of patients required discontinuation of therapy due to toxicity Kahl et al, Blood 2014

18 Everolimus/Temsirolimus Phase II Study of Everolimus in Patients Relapsed after Bortezomib 10mg daily dosing Overall Response Rate: 10.3% Median PFS: 5.3 months Temsirolimus Currently studied in a phase III study Phase II Response rates: 38-41% Wang et al, B J Haematol 2014; Dreyling ASCO Educational Book 2014

19 Carfilzomib/Ixazomib Novel proteasome inhibitors May have benefit in bortezomib-resistant cases Lower incidence of neuropathy Ixazomib to be evaluated at Emory in the setting of post-transplant maintenance.

20 Stem Cell Transplantation No standard role for stem cell transplantation in management of relapsed MCL Allogeneic transplant may provide long term remission but is associated with toxicity. CIBMTR: RIC allo v auto: Fenske et al, JCO 2014

21 Stem Cell Transplantation Allo transplant has increased rate of nonrelapse mortality: 17% 1-year NRM for patients undergoing allo transplant after relapse. Among all deaths, leading causes include: Disease (30%) Infection (17%) GVHD (15%) Organ Failure (11%) Fenske et al, JCO 2010

22 Relapsed MCL Proposed Algorithm

23 Conclusions Nearly all patients with MCL will relapse Ibrutinib now standard first option for relapsed patients Bortezomib and Lenalidomide also option Ibrutinib is not curative; clinical trials should be considered Healthy, motivated patients should be referred for consideration of allo transplant

24 Future Directions How to manage patients who received ibrutinib in first line. Identification of patients unlikely to respond to therapies. Optimal integration of transplant into management of relapsed patients.

25 THANK YOU QUESTIONS?