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Mantle Cell Lymphoma (MCL): Approach to Upfront Treatment

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).

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Mantle Cell Lymphoma (MCL): Approach to Upfront Treatment

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  1. 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

  2. Interest in Topics Related to the Treatment of Patients with CTCL or PTCL (Percent Responding 9 or 10)

  3. Interest in Topics Related to the Treatment of Patients with MCL (Percent Responding 9 or 10) New agents/regimens 50% Initial therapy for 41% patients <70 yo Initial therapy for 40% patients >70 yo Treatment of 33% relapsed MCL Maintenance 30% therapy 0% 10% 20% 30% 40% 50% 60%

  4. 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, 4th edition.

  5. 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.

  6. 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 Hoster E et al. Blood 2008;111:558-65.

  7. 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

  8. Patients for Whom a Dose-Intensive Approach is Not an Option • Martin P, JCO 2009; 27:1209-1213. • Rummel MJ, ASH 2009, abs 405. • Kahl B, ASH 2009, abs 1661. • 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 management1) • 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 hyperCVAD (VcR-CVAD) with R maintenance (ECOG-E1405 shows high CR rate3) • Rituximab alone, R-CVP, R-fludarabine/CDA

  9. Patients for Whom a Dose-Intensive Approach is an Option • NCCN database, prospective cohort study of pts with MCL <65 yo that R-hyperCVAD or R-CHOP → auto have similar PFS that are better than R-CHOPalone1 • Nordic regimen: R-Maxi-CHOP/R-HDAraC → auto with consolidation with R in presumptive relapse2 • GELA: R-CHOP/R-DHAP → auto3 • LaCasce A, ASH 2009, abstract 403. • Geisler CH, Blood 2008; 112:2687-2693. • Delarue R, ASH 2010, abstract 581.

  10. Consolidation or Maintenance Strategies • ECOG-E14991: 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.

  11. 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

  12. 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

  13. Classification of PTCL Mature T-NK neoplasm Extranodal Nodal Leukemic PTCL, NOS ALCL (ALK +) Angioimmunoblastic (AILT) Adult T-cell leukemia/lymphoma (ATLL) Aggressive NK cell leukemia T-prolymphocytic leukemia (T-PLL) T-large granular lymphocytic leukemia (T-LGL) Extranodal NK/T cell, nasal type Enteropathy associated (EATL) Hepatosplenic (ϒΔ)

  14. Classification of CTCL Cutaneous Mycosis fungoides/Sézary syndrome (MF/SS) CD30+ lymphoproliferative disorders Subcutaneous panniculitic T-cell lymphoma CD4+ small/medium pleomorphic T-cell lymphoma Cutaneous PTCL, NOS Cutaneous aggressive CD8+ T-cell lymphoma Cutaneous NK/T cell lymphoma, nasal type

  15. 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

  16. Denileukin diftitox • 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-2R); 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 mo1,2 • In relapsed/refractory T-cell malignancies (excluding CTCL), N=27, RR=48% (46% PR) with median PFS=6 mo3 • Common toxicity includes: • Immediate: allergic, constitutional • Delayed: vascular capillary leak, primarily in first cycle • Lab: reversible liver function test abnormalities • 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.

  17. 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 days1; there is no data to support use of vorinostat in PTCL • Romidepsin in relapsed/refractory CTCL ORR = 34% (31% PR) with median DOR = 15 mo2 • Romidepsin in relapsed/refractory PTCL ORR 38% (20% PR) with median DOR = 8.9 mo3 • 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 • Olsen EA, JCO 2007; 25(23): 3109-15. • Whittaker SJ, JCO 2010; 28(29): 4485-91. • Piekarz R, Blood 2011 epub.

  18. Pralatrexate Novel folate antagonist approved for treatment of relapsed or refractory PTCL In patients with relapsed/refractory PTCLat dose of 30 mg/m2 six out of seven weeks, ORR = 29% (18% PR) with median DOR = 10.1 mo1 In patients with relapsed/refractory CTCL, the optimal dose was 15 mg/m2 three out of four weeks with an ORR = 43%2 Common toxicities include: mucositis, thrombocytopenia, neutropenia, anemia • O’Connor OA JCO 2011; 29(9):1182-9. • Horwitz SM, ASH 2010, abstract 2800.

  19. 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

  20. What is your usual preferred initial systemic treatment for MCL in patients older than age 75?

  21. Do you generally use rituximab maintenance in MCL?

  22. What is your usual preferred initial systemic treatment for MCL in patients older than age 75?

  23. Do you generally use rituximab maintenance in MCL?

  24. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

  25. What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?

  26. What is your perception and experience concerning the side effects and tolerability of romidepsin in patients with TCL?

  27. What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?

  28. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

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