Mantle Cell Lymphoma MCL Approach to Upfront Treatment
- Slides: 28
Mantle Cell Lymphoma (MCL): Approach to Upfront Treatment Lauren C Pinter-Brown, MD Director, UCLA Lymphoma Program Clinical Professor of Medicine Geffen School of Medicine at UCLA
Interest in Topics Related to the Treatment of Patients with CTCL or PTCL (Percent Responding 9 or 10) Copyright © 2011 Research To Practice. All rights reserved.
Interest in Topics Related to the Treatment of Patients with MCL (Percent Responding 9 or 10) New agents/ regimens 50% Initial therapy for patients <70 yo 41% Initial therapy for patients >70 yo 40% Treatment of relapsed MCL 33% Maintenance therapy 0% 30% 10% 20% 30% 40% 50% 60% Copyright © 2011 Research To Practice. All rights reserved.
Prognostic Factors: Pathologic • Blastoid and pleomorphic variants connote poor prognosis • Small cell variant may have more indolent course; impact of mantle zone or nodular pattern less clear • Overt peripheral blood involvement with adenopathy appears worse (vs. peripheral blood, marrow and possible splenic involvement without adenopathy) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4 th edition.
Prognostic Factors: Ki-67 Index • Median overall survival, CHOP-treated subgroup: – <10% Ki-67 index = 112 months – 10% - 30% Ki-67 index = 59 months – ≥ 30% Ki-67 index = 30 months – p-value = 0. 0002 • Median overall survival, R-CHOP treated subgroup: – <10% Ki-67 index = not reached – 10%-30% Ki-67 index = not reached – ≥ 30% Ki-67 index = 52 months – p-value = 0. 0126 Determann O et al. Blood 2008; 111: 2385 -2387.
Prognostic Factors: Simplified MIPI § 0 -3 points applied for each prognostic factor § Sum reflects MIPI score § Low risk: 0 -3 points § Intermediate risk: 4 -5 points § High risk: 6 -11 points Points Age, yrs ECOG PS LDH/ULN WBC, cells/mm 3 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 10, 000 -14, 999 3 ≥ 70 — ≥ 1. 5000 ≥ 15, 000 Hoster E et al. Blood 2008; 111: 558 -65.
Frontline Treatment Considerations • Optimal frontline standard of care not yet defined • MCL not yet shown to be curable with currently available frontline treatments • Prolongation of survival by frontline treatment has been definitely shown • May consider treatment options separately for: – Patients for whom a dose intensive approach is an option (65 and under without comorbidities) – Patients for whom a dose intensive approach is not an option (older than 65 or with significant comorbidities) – Median age is around 60
Patients for Whom a Dose-Intensive Approach is Not an Option • In truth… – Will likely need additional treatment earlier than if the patient had an aggressive initial therapy (NCCN database) – ? Similar OS than if the patient had aggressive therapy (Cornell retrospective data, N=97…in selected asymptomatic patients “watch and wait” is acceptable management 1) – Many choices that include: • R-bendamustine vs R-CHOP (Rummel data: BR has stat sig increased PFS, 33 vs 23 mo, and better tox profile than R-CHOP in MCL, N=932) • Modified hyper. CVAD (Vc. R-CVAD) with R maintenance (ECOG-E 1405 shows high CR rate 3) • Rituximab alone, R-CVP, R-fludarabine/CDA 1. 2. 3. Martin P, JCO 2009; 27: 1209 -1213. Rummel MJ, ASH 2009, abs 405. Kahl B, ASH 2009, abs 1661.
Patients for Whom a Dose-Intensive Approach is an Option • NCCN database, prospective cohort study of pts with MCL <65 yo that R-hyper. CVAD or R-CHOP → auto have similar PFS that are better than R-CHOP alone 1 • Nordic regimen: R-Maxi-CHOP/RHDAra. C → auto with consolidation with R in presumptive relapse 2 • GELA: R-CHOP/R-DHAP → auto 3 1. 2. 3. La. Casce A, ASH 2009, abstract 403. Geisler CH, Blood 2008; 112: 2687 -2693. Delarue R, ASH 2010, abstract 581.
Consolidation or Maintenance Strategies • ECOG-E 14991: Single dose of yttrium-90 ibritumomab tiuxetan given 4 -8 weeks after R-CHOP x 4 in responding patients • 16/56 patients experienced improvement in response after RIT • Median failure-free survival: 27 months • Maintenance rituximab: Await presentation of European MCL Consortium randomized trial 1. Smith M et al. ASH 2007, abstract 389.
PTCL/CTCL: Approaches to Relapsed/Refractory Disease Lauren C Pinter-Brown, MD Director, UCLA Lymphoma Program Clinical Professor of Medicine Geffen School of Medicine at UCLA
What’s the difference between PTCL and CTCL? • Both groups are mature T-cell neoplasms • Most nodal and extranodal (excluding skin) PTCLs are aggressive; most CTCLs are indolent • Be aware that the staging system for mycosis fungoides/Sézary syndrome is a totally different staging system from the Ann Arbor system used for other lymphomas
Classification of PTCL Mature T-NK neoplasm Extranodal NK/T cell, nasal type Enteropathy associated (EATL) Hepatosplenic (ϒΔ) Nodal PTCL, NOS ALCL (ALK +) Angioimmunoblastic (AILT) Leukemic Adult T-cell leukemia/ lymphoma (ATLL) Aggressive NK cell leukemia T-prolymphocytic leukemia (T-PLL) T-large granular lymphocytic leukemia (T-LGL)
Classification of CTCL Cutaneous Mycosis fungoides/Sézary syndrome (MF/SS) CD 30+ lymphoproliferative disorders Subcutaneous panniculitic T-cell lymphoma CD 4+ small/medium pleomorphic T-cell lymphoma Cutaneous PTCL, NOS Cutaneous aggressive CD 8+ T-cell lymphoma Cutaneous NK/T cell lymphoma, nasal type
Outlook for patients with PTCL/CTCL • Nodal and extranodal PTCL (excluding CTCL) have a median survival of 1 -3 years with present therapy • 5 -year overall survival is approximately 25% • The exception is anaplastic large cell lymphoma (ALCL) ALK+ where 5 -year overall survival is 65 -95% • No CTCL is curable with conventional medical therapy
Denileukin diftitox is a recombinant DNA derived cytotoxic protein composed of IL-2 protein sequence fused to active portion of diphtheria toxin • Targets tumor cells expressing the high and medium affinity IL-2 receptor (IL -2 R); the IL-2 portion binds to the IL-2 receptor, allowing the diphtheria toxin to enter the cell and induce cell death by inhibition of protein synthesis • Approved for use in patients with relapsed/refractory CTCL with an overall RR=30 -44% (20 -34% PR) with median duration of response (DOR)=6. 9 mo 1, 2 • In relapsed/refractory T-cell malignancies (excluding CTCL), N=27, RR=48% (46% PR) with median PFS=6 mo 3 • Common toxicity includes: – Immediate: allergic, constitutional – Delayed: vascular capillary leak, primarily in first cycle – Lab: reversible liver function test abnormalities 1. 2. 3. Prince HM, JCO 2010; 28(11): 1870 -7. Olsen E, JCO 2001; 19(2): 376 -88. Dang NH, Br J Haematol 2007; 136(3): 439 -47.
HDAC inhibitors • • • Vorinostat (po) and romidepsin (IV) are approved for treatment of relapsed/refractory CTCL Vorinostat in relapsed/refractory CTCL ORR = 30%; estimated median DOR ≥ 185 days 1; there is no data to support use of vorinostat in PTCL Romidepsin in relapsed/refractory CTCL ORR = 34% (31% PR) with median DOR = 15 mo 2 Romidepsin in relapsed/refractory PTCL ORR 38% (20% PR) with median DOR = 8. 9 mo 3 The common toxicities can be classified into 4 symptom complexes: – Gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation) – Constitutional symptoms (fatigue, chills) – Hematologic abnormalities (thrombocytopenia, anemia, neutropenia) – Taste disorders (dysgeusia, dry mouth) Abnormal laboratory values include high glucose, elevated creatinine, abnormal EKGs 1. 2. 3. Olsen EA, JCO 2007; 25(23): 3109 -15. Whittaker SJ, JCO 2010; 28(29): 4485 -91. Piekarz R, Blood 2011 epub.
Pralatrexate • Novel folate antagonist approved for treatment of relapsed or refractory PTCL • In patients with relapsed/refractory PTCL at dose of 30 mg/m 2 six out of seven weeks, ORR = 29% (18% PR) with median DOR = 10. 1 mo 1 • In patients with relapsed/refractory CTCL, the optimal dose was 15 mg/m 2 three out of four weeks with an ORR = 43%2 • Common toxicities include: mucositis, thrombocytopenia, neutropenia, anemia 1. 2. O’Connor OA JCO 2011; 29(9): 1182 -9. Horwitz SM, ASH 2010, abstract 2800.
How would I sequence these drugs? • In relapsed/refractory PTCL (if not using typical salvage chemotherapy): • (1) Pralatrexate • (2) Romidepsin • (3) Denileukin diftitox • In relapsed/refractory CTCL (if inappropriate for topical or other FDA-approved therapies such as bexarotene): • (1) Romidepsin (or vorinostat) • (2) Denileukin diftitox • (3) Pralatrexate
What is your usual preferred initial systemic treatment for MCL in patients older than age 75? Copyright © 2011 Research To Practice. All rights reserved.
Do you generally use rituximab maintenance in MCL? Copyright © 2011 Research To Practice. All rights reserved.
What is your usual preferred initial systemic treatment for MCL in patients older than age 75? Copyright © 2011 Research To Practice. All rights reserved.
Do you generally use rituximab maintenance in MCL? Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, 2011 7: 00 PM – 9: 30 PM Chicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek Copyright © 2011 Research To Practice. All rights reserved.
What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL? Copyright © 2011 Research To Practice. All rights reserved.
What is your perception and experience concerning the side effects and tolerability of romidepsin in patients with TCL? Copyright © 2011 Research To Practice. All rights reserved.
What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL? Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, 2011 7: 00 PM – 9: 30 PM Chicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek Copyright © 2011 Research To Practice. All rights reserved.
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