State of the Art Treatment for Relapsed Mantle Cell Lymphoma Jonathon - - PDF document

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

Disclosures

• Consulting fees from:

Pharmacyclics, and Seattle Genetics

• Contracted Research from:

Bristol‐Myers Squibb, and Janssen Pharmaceuticals, Inc.

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Outline

• Current Responses to Front‐line Therapy
• Evaluation of the Relapsed Patient
• Approved Therapies

– Ibrutinib – Bortezomib – Lenalidomide

• Investigational Agents
• Stem Cell Transplantation
• Conclusion/Recommendations

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

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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

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

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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

Salvage Options

Dreyling, ASCO 2014 Educational Book

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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

Ibrutinib ‐ Efficacy

• Median Duration of Response: 17.5 month
• Median Overall Survival: Not Reached

Wang et al, NEJM 2013

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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

Mechanisms for Ibrutinib Resistance

Woyach et al, NEJM 2014

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FDA Approved Therapies: Bortezomib

• Phase II Study: 1.3mg/m2 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

Bortezomib

• Peripheral Neuropathy

– 13% Grade ≥ 3 in Phase II Study

• GI Side Effects
• Thrombocytopenia

– 11% Grade ≥ 3

• Zoster Reactivations

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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

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

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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

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

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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

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.

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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

Stem Cell Transplantation

• Allo transplant has increased rate of non‐

relapse 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

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Relapsed MCL Proposed Algorithm 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

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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.

THANK YOU

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