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RTP TV: An 8-Part Live CME Webcast Series

RTP TV: An 8-Part Live CME Webcast Series. Part VII – Non-Hodgkin Lymphoma/ Chronic Lymphocytic Leukemia Tuesday, July 26, 2011 7:30 PM – 8:30 PM ET. Neil Love, MD Research To Practice Miami, Florida. Stephanie A Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine

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RTP TV: An 8-Part Live CME Webcast Series

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  1. RTP TV: An 8-Part Live CME Webcast Series Part VII – Non-Hodgkin Lymphoma/Chronic Lymphocytic Leukemia Tuesday, July 26, 20117:30 PM – 8:30 PM ET

  2. Neil Love, MDResearch To PracticeMiami, Florida Stephanie A Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center Chicago, Illinois John P Leonard, MD Richard T Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine, Weill Cornell Medical College New York, New York

  3. Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, Astellas Pharma Global Development Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics

  4. Disclosures for Stephanie A Gregory, MD

  5. Disclosures for John P Leonard, MD

  6. Agenda — Non-Hodgkin Lymphoma/Chronic Lymphocytic Leukemia Module 1: Follicular Lymphoma (FL) Module 2: Chronic Lymphocytic Leukemia (CLL) Module 3: Mantle-Cell Lymphoma (MCL) Module 4: Diffuse Large B-Cell Lymphoma (DLBCL) Questions and answers

  7. Dr Gregory (Case A): Follicular Lymphoma • 6/2004: 54 yo man with diffuse supraclavicular, bilateral axillary and inguinal and intra-abdominal adenopathy, largest 2.8 cm • Lab results: All normal, including LDH • Inguinal node bx: Follicular lymphoma Grade II/III • BM bx: Positive for lymphoma (20%) • FLIPI score: 2

  8. Inguinal Node Biopsy Results: Follicular Lymphoma Grade 2 6-15/hpf

  9. 1. If this patient presented to you now in 2011, which first-line therapy would you generally recommend?

  10. CT scan 12 weeks after 4 weeks of rituximab induction Baseline CT of abdomen June 11, 2004 Markedly decreased adenopathy in all areas Multiple intra-abdominal nodes

  11. ECOG 4402 RESORT Trial N = 600+ patients – closed Rituximab maintenance Single 375 mg/m2 IV q12wk Continue to rituximab failure Induction rituximab 375 mg/m2 weekly x 4 Restage- week 12 R A N D O M I Z E R E G I S T E R ≥PR/CR Rituximab re-treatment at progression Single 375 mg/m2 IV q4wk Continue to rituximab failure End study treatment <PR or PD Primary endpoint is time to rituximab failure

  12. Dr Gregory (Case A): Follicular Lymphoma • 6/21/2011: Remains asymptomatic in complete remission • Labs: Normal except for mildly decreased IgG (794), IgA (144) and IgM (21) • Patient has had no infections • CT scans every 6 months – no evidence of disease • Remains on clinical trial w/o Rx interruption

  13. An Intergroup Randomised Trial of Rituximab vs a Watch & Wait Approachin Patients with Advanced Stage,Asymptomatic, Non-Bulky Follicular Lymphoma Kirit M Ardeshna, Paul Smith, Wendi Qian, June Warden, Lindsey Stevens,Christopher FE Pocock, Fiona Miall, David Cunningham, John Davies, Andrew Jack,Jan Walewski, A Burhan Ferhanoglu, Ken Bradstock and David C Linch Ardeshna KM et al. Proc ASH 2010;Abstract 6.

  14. Rituximab (R) vs a Watch and Wait Strategy in Patients with Stage II-IV Asymptomatic, Nonbulky FL • Improved PFS in R arms (P < 0.001) • Time to initiation of new treatment in the R arms: • 33 mo vs not reached at 4 yr (P < 0.001) • No difference in OS (P > 0.5) • Quality of life no worse Ardeshna K et al. Proc ASH 2010;Abstract 6.

  15. Time to Initiation of New Therapy 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion of patients with no new treatment initiated % requiring Rx at 3 yr Watch and wait = 52% Rituximab = 20% Rituximab and maintenance rituximab = 9% 0 1 2 3 4 5 Years from randomisation With permission from Ardeshna KM et al. Proc ASH 2010;Abstract 6.

  16. Preliminary Results of Quality of Life (QOL) Analyses from the Intergroup Phase III Randomised Trial of Rituximab vs a Watch and Wait Approach in Patients with Advanced Stage, Asymptomatic, Non-Bulky Follicular Lymphoma (FL) Ardeshna KM et al. International Conference on Malignant Lymphoma 2011.

  17. PRIMA: Rituximab Maintenance After R-Chemo • Two years of treatment: Every 8 weeks • Three-year progression-free survival R maintenance: 75% Control: 58% • Gr 3-4 infection R maintenance: 24% Control: 17% • Treatment discontinued R maintenance: 4% Control: 2% Salles G et al. Lancet 2011;377(9759):42-51.

  18. PRIMA: Progression-Free Survival Median follow-up of 36 months Salles G et al. Lancet 2011;377(9759):42-51.

  19. PRIMA: Quality of Life • EORTC QLQ-C30 global health status mean scores in rituximab maintenance vs observation: • 75.5 (95% CI 72.8-78.2) vs 75.2 (95% CI 72.0-78.4), p-value = 0.89 • Mean adjusted FACT-G total scores at the end of treatment in rituximab maintenance vs observation: • 86.6 (95% CI 85.0-88.3) vs 87.2 (95% CI 85.3-89.1), p-value = 0.68 Salles G et al. Lancet 2011;377(9759):42-51.

  20. FIT Study Schema Start of study Patients with previously untreated FL 6-12 weeks after last dose of induction Not eligible Hagenbeek A et al. Proc ASH 2010;Abstract 594.

  21. Overall PFS for Treatment Groups The 5-year overall PFS was 29% in the control arm compared to 47% in the 90Y-ibritumomab armHR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001 100 75 90Y-ibritumomab: n = 207Median PFS: 49 mo Cumulative Percentage 50 25 Control: n = 202 Median PFS: 15 mo N F 90Y-ibritumomab 207 108 Control 202 144 0 0 12 24 36 48 60 PFS from Time of Randomization (Months) With permission from Hagenbeek A et al. Proc ASH 2010;Abstract 594.

  22. N = 676 • Rituximab (n = 340) vs bortezomib/rituximab (n = 336) • Progression-free survival: 11.0 vs 12.8 months, HR = 0.82, p-value = 0.039 • ≥Gr 3 AEs: 21% vs 46% • Serious AEs: 11% vs 18%

  23. ECOG-E2408: A Phase II Trial of BR Followed by Rituximab vs Bortezomib-BR (VBR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab Target Accrual = 250 (open) Arm 1 BR q28d x 6 Rituximab d1, 4 wks after completion of induction, q8wk x 2 yrs Eligibility High-risk FL with high tumor burden Stage II-IV disease Grade 1-3a disease FLIPI-1 score of 3, 4 or 5 Arm 2 VBR q28d x 6 Rituximab as in Arm 1 R Arm 3 BR q28d x 6 Lenalidomide q28d x 13 immediately after induction Rituximab as in Arm 1 B = bendamustine, V = bortezomib, R = rituximab www.ClinicalTrials.gov, July 2011.

  24. Dr Leonard (Case B): Follicular Lymphoma • 8/2006: Currently 61 yo otherwise healthy female artist w/2-cm groin node; asymptomatic • Bx: Follicular Grade II/III • Imaging: Diffuse lymphadenopathy (LAN) 2-3 cm range • Observed 3 years, slowly progressive disease • Imaging: Mass over 12 cm • Labs remain normal including LDH

  25. What is currently your usual preferred regimen for a patient with FL who requires initial treatment? Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.

  26. Dr Leonard (Case B): Follicular Lymphoma • Bendamustine/rituximab therapy is initiated • Excellent response, 75% LAN reduction, no symptoms • Tolerated well but dose reduction in last 2 cycles • Mild cytopenias, fatigue, nausea, IV hydration needed • 9/2010: R maintenance initiated every 2 months • Patient doing well

  27. Before BR After BR

  28. RAPID-FIRE QUESTIONS

  29. Follicular Lymphoma • 59 yo man with bulky follicular lymphoma but minimally symptomatic. What is the optimal regimen? • After bendamustine fails, what is the next step? • Does rituximab change the natural history of follicular lymphoma? • Patient with poor performance status whose FL progressed on rituximab monotherapy

  30. Dr Leonard (Case C): CLL • Currently 75 yo married businessman presents with mild lymphoadenopathy and lymphocytosis • PMH: Diabetes, hyperlipidemia • Followed off therapy • Develops progressivelymphocytosis (70k) anemia, splenomegaly, fatigue • Trisomy 12 (intermediate risk)

  31. 2. Which first-line therapy would you generally recommend for this patient?

  32. National Patterns of Care Among Clinical Investigators (N = 25): Preferred Initial Treatment for Younger and Older Patients with CLL (Normal Cytogenetics) Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.

  33. Dr Leonard (Case C): CLL • F-R x 6 cycles (delayed cycle 6) • Tolerated well, mild cytopenias • Patient is active with minimal symptoms

  34. Informative for Prognosis or Therapy Decision-Making? • Cytogenetics and/or FISH • t(11;14) • t(11q;v) • +12 • del(13q) • del(17p) • Molecular Genetic Analysis • Immunoglobulin heavy chain variable gene (IgHV) mutation status • Flow Cytometry or Immunohistochemistry • CD38 • Zap 70

  35. CLL-8: Progression-Free Survival with FC versus FCR Hallek M et al. Lancet 2010;376:1164-74.

  36. Impact of FC versus FCR on Progression-Free and Overall Survival in CLL Hallek M et al. Lancet 2010;376(9747):1164-74.

  37. Phase III Trial of Combined Immunochemotherapy with FCR versus BR in Previously Untreated CLL Target Accrual = 550 (open) Eligibility FCR Untreated Binet C CLL or Binet B or A with ≥ one ofB-symptoms, progressive lymphocytosis, marrow failure; massive, progressive or painful splenomegaly; or massive lymph nodes or nodal clusters No 17p deletion by FISH R BR German CLL Study Group www.ClinicalTrials.gov, April 2011.

  38. RAPID-FIRE QUESTIONS

  39. Chronic Lymphocytic Leukemia • FCR versus BR for up-front therapy: Which agents, when and for whom? • What is the recommended dose of bendamustine for elderly patients? • Is there still a role for single-agent chlorambucil?

  40. Chronic Lymphocytic Leukemia • What is the optimal use of alemtuzumab in CLL? • Role of bone marrow biopsy in CLL • Guidelines regarding re-treatment with rituximab: Role of ofatumumab

  41. Dr Gregory (Case D): Mantle-Cell Lymphoma • 2/2008: 61 yo male w/progressive asymptomatic lymphadenopathy in left neck and right groin • 8/2008: Lymph node bx = MCL • Staging workup • CT CAP: Diffuse cervical, axillary, inguinal and mesenteric adenopathy, largest 4.7 cm in the inguinal area • Labs: Normal including LDH and beta2 microglobulin • BM bx: 10% involvement by lymphoma

  42. Low Power Cross Sectional Lymph Node Biopsy Showing Replacement by MCL

  43. High Power Showing MCL

  44. Immunohistochemistry CD5 CYCLIN D1 CD20 KI-67

  45. Bone Marrow Biopsy Showing Involvement by Lymphoma

  46. Initial Staging CT Scan: 8/2008 Inguinal LN 4.7 x 3.2 cm Mesenteric LN: 4.5 x 3.1 cm

  47. 3. Which treatment would you generally recommend for this patient as first-line therapy? R-CHOP R-CHOP  ASCT R-hyper-CVAD or other Ara-C-containing regimen BR Other

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