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An Update on the Treatment of Lymphoma

An Update on the Treatment of Lymphoma. Ted Wun, M.D., F.A.C.P. Professor of Medicine and Chief In consultation with Joseph Tuscano, M.D. Professor of Medcine Division of Hematology Oncology, UC Davis SOM. Objectives.

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An Update on the Treatment of Lymphoma

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  1. An Update on the Treatment of Lymphoma Ted Wun, M.D., F.A.C.P. Professor of Medicine and Chief In consultation with Joseph Tuscano, M.D. Professor of Medcine Division of Hematology Oncology, UC Davis SOM

  2. Objectives • To have a better understanding of the role of maintenance Rituximab after initial induction therapy for indolent lymphoma • Elucidate the role of dose dense chemotherapy in the management of diffuse large cell lymphoma • Examine the role of Lenalidomide in the management of lymphoma • Have a better understanding of the up-front management strategies for indolent lymphoma-answer the question “is there a new standard of care?”

  3. The Role of Rituxan for Induction and Maintenance of Indolent Lymphoma

  4. Unresolved questions • How does Rituximab maintenance compare with retreatment at progression? • Will newer, more effective induction regimens eliminate the need for Rituximab maintenance? • What are the best endpoints for Rituximab maintenance trials? • ORR, PFS, OS, QOL ?

  5. What is the Role of Rituxan for Purging Prior to Auto PSCT and Maintenance After

  6. EBMT-Lym-1Conclusions Rituximab maintenance significantly prolongs PFS post AutoPSCT for relapsed indolent NHL Rituximab purging does not have a significant effect on PFS Consistent with prior studies, AutoPSCT produces durable remissions in patients with relapsed indolent NHL and may be curative in some patients

  7. Maintenance rituximab for FL Richard Fischer ASCO 2010

  8. The role of Lenalidomide for the treatment of lymphoma

  9. Back to TOC Relapsed/Refractory Diffuse Large B-Cell Lymphoma With Nongerminal Center B-Cell Phenotype Is Associated With a Higher Response to Lenalidomide Monotherapy or in Combination With Rituximab Francisco Hernandez-Ilizaliturri, MD,1 George Deeb, MD,2 Pier Luigi Zinzani, MD,3 Stefano A. Pileri, MD,3 Farhana Malik, MD,4 William R. Macon, MD,5 Andre Goy, MD,6 Thomas E Witzig, MD,5 and Myron S. Czuczman, MD1 American Society of Clinical Oncology June 2010 1. Medical Oncology and Immunology, Roswell Park Cancer Institute, Buffalo, NY; 2. Pathology, Roswell Park Cancer Institute, Buffalo, NY; 3. Department of Haematology and Oncological Sciences Lorenzo and Ariosto Seràgnoli (DHOS-S), University of Bologna, Bologna, Italy; 4. Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY; 5. College of Medicine, Mayo Clinic, Rochester, MN; 6. The John Theurer Cancer Center at the Hackensack University Medical Center, Hackensack, NJ.

  10. Lenalidomide Response in Rel/Ref DLBCL: NFκB Target Genes Are Highly Expressed in Activated B-Cell–Like DLBCL Rel/Ref=relapsed/refractory; DLBCL=diffuse large B-cell lymphoma; NFKB=nuclear factor kappa B; ABC=activated B-cell–like; GCB=germinal center B-cell–like. Courtesy of L. Staudt. Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  11. Lenalidomide Response in Rel/Ref DLBCL: The Stromal-2 Signature Encodes Regulators and Components of Angiogenesis (unfavorable) Courtesy of L. Staudt. Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  12. Lenalidomide Response in Rel/Ref DLBCL: Can We Predict Clinical Response to Lenalidomide in DLBCL Patients? • Retrospective study of patients with DLBCL treated with lenalidomide alone or in combination with rituximab or dexamethasone at 4 academic institutions (N=56) • RPCI (N=19) • Mayo Clinic (N=20) • University of Bologna (N=11) • John Theurer Cancer Center at the Hackensack University (N=6) • Patients divided into GCB and non-GCB cohorts using the criteria proposed by Hans et al • Tumor biopsies are routinely stained for MUM1, CD10, Bcl-6, and Ki67 by the Pathology Department at RPCI or the Mayo Clinic • Responses to lenalidomide assessed by standard and/or revised Cheson criteria1,2 • Differences in RR, response duration to lenalidomide and OS were analyzed using the software program SPSS 14 RPCI=Roswell Park Cancer Institute; RR=response rate; OS=overall survival. Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038. 1. Cheson et al. J Clin Oncol. 2007 Feb 10;25(5):579-86; 2. Cheson et al. J Clin Oncol. 1999;17:1244-1253.

  13. Lenalidomide Response in Rel/Ref DLBCL: Can We Predict Clinical Response to Lenalidomide in DLBCL Patients? • Rel/Ref DLBCL: N=56 • Histological diagnosis • DLBCL=49 • FL and DLBCL (composite)=5 • Transformed NHL=2 • IHC classification of the patients • Non-GCB=28 • GCB=25 • Undetermined=3 • Median age=66 years (range 43-80) • Median number of prior therapies=4 (range 2-13) • Median cycles of lenalidomide=2 (range 1-35) FL=follicular lymphoma; IHC=immunohistochemistry. Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  14. Lenalidomide Response in Rel/Ref DLBCL: Differences in Responses to Lenalidomide Monotherapy in Rel/Ref GCB vs Non-GCB DLBCL (N=40) • The ORR rate for patients with GCB DLBCL was 8.7% vs 53% for patients with non-GCB DLBCL treated with lenalidomide monotherapy • No differences in the median number of treatments, IPI score, histology, stage, or other demographic characteristics were seen at time of lenalidomide Rx between the 2 groups PR=partial response; CR=complete response; ORR=overall response rate. Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  15. Lenalidomide Response in Rel/Ref DLBCL: PFS Following Lenalidomide Monotherapy in DLBCL According to Histological Subtype Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  16. Lenalidomide Response in Rel/Ref DLBCL: CC-5013-DLC-001 Study Schema Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  17. Lenalidomide Response in Rel/Ref DLBCL: Summary • Lenalidomide monotherapy or in combination with rituximab are active salvage therapies in rel/ref DLBCL • These data strongly suggest that 2 previously identified groups of patients with DLBCL (GCB vs non-GCB) appear to have significantly different degrees of responsiveness to lenalidomide in the rel/ref setting • A prospective phase 2/3 randomized clinical trial comparing lenalidomide vs investigator choice of “salvage monotherapy” in patients with rel/ref DLBCL is underway; patients will be stratified according to the Hans algorithm as GCB or non-GCB DLBCL prior to treatment Hernandez-Illizaliturri et al. Abstract and poster presented at: 2010 Annual ASCO Meeting; June 4-8, 2010; Chicago, IL. Abstract 8038.

  18. R2: Preliminary Results of a Phase 2 Study of Lenalidomide and Rituximab in Relapsed/Refractory Indolent NHL Mrinal Dutia,1 Ian DeRoock,2 Karen Chee,3 Robert O’Donnell,2 Christine Quirch,2Christine Reed-Pease,2 Joseph M. Tuscano2 1UC Davis Cancer Center, Sacramento, CA, 2UC Davis Medical Center, Sacramento, CA, 3California Cancer Care, San Mateo, CA American Society of HematologyDecember 2009 Back to TOC

  19. Lenalidomide and Rituximab in Rel/Ref Indolent NHL: Introduction and Objective • Introduction • Lenalidomide is a potent immunomodulatory agent with both antiproliferative and antiangiogenic activity • Lenalidomide monotherapy has clinical activity in patients with rel/ref indolent and aggressive lymphomas • Synergistic activity between lenalidomide and rituximab has been reported in both cellular and animal lymphoma models • Objective • To evaluate the safety and efficacy of the combination of R2 in a phase 2, single-arm study of patients with rel/ref indolent NHL Rel/ref=relapsed/refractory. Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679. Back to TOC

  20. Lenalidomide and Rituximab in Rel/Ref Indolent NHL: Baseline Characteristics (N=16) MZL=marginal zone lymphoma; dx=diagnosis.* Rituximab resistance was defined as no response, or relapse ≤6 months after initiating rituximab.Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679. Back to TOC

  21. Lenalidomide and Rituximab in Rel/Ref Indolent NHL: Grade 3/4 AEs (N=16) After prophylaxis was initiated, TLS was not observed at the 20-mg dose level AE=adverse event.Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679. Back to TOC

  22. Lenalidomide and Rituximab in Rel/Ref Indolent NHL: Response Based on Histology and Prior Therapy * Heavily pretreated, 3 prior therapies; CRu=unconfirmed complete response; PD=progressive disease.Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679. Back to TOC

  23. Lenalidomide and Rituximab in Rel/Ref Indolent NHL: Summary and Conclusions • 75% ORR (31% CR) in all patients with indolent NHL • Particular activity noted among patients with rel/ref FL • 85% ORR in (11 of 13) patients with FL • 38% CR/CRu • Responses appeared to correlate with number of cycles of lenalidomide received • 5 patients with a CR/CRu received a median of 13 cycles • 7 patients with a PR received a median of only 7 cycles • TLS prophylaxis and monitoring are recommended, particularly during the initial cycles of treatment • Further evaluation of this combination is underway • In larger studies of indolent NHL, and particularly in patients with FL • In earlier lines of therapy Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679.

  24. A Biologic Combination of Lenalidomide and Rituximab for Frontline Therapy of Indolent B-Cell Non-Hodgkin’s Lymphoma Nathan Fowler, Peter McLaughlin, Fredrick Hagemeister, Larry W. Kwak, Michelle Fanale, Sattva Neelapu, Louis Fayad, Barbara Pro, Crystal Sergent, Shana White, Felipe Samaniego Department of Lymphoma/Melanoma, MD Anderson Cancer Center, Houston, Texas American Society of HematologyDecember 2009

  25. Phase II Study of Lenalidomide + Rituximab in Indolent NHL: Rationale and Objective • Despite advances, optimal treatment for patients with newly-diagnosed indolent NHL has not been determined • In the rel/ref setting, treatment with lenalidomide has resulted in a response duration 16.5 months • Rituximab has been shown to have clinical activity in indolent NHL • This phase II study evaluates the efficacy and safety of the lenalidomide and rituximab as frontline treatment of indolent NHL • Patients with untreated stage III or IV indolent NHL • Rituximab 375 mg/m2 IV on Day 1 and lenalidomide 20 mg/day on Days 1-21 of a 28-day cycle • A total of 6 cycles administered Rel/ref=relapsed/refractory; IV=intravenous.Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714.

  26. Phase II Study of Lenalidomide + Rituximab in Indolent NHL: Patient Demographics (N=30) FLIPI=Follicular Lymphoma International Prognostic Index; BM=bone marrow; MZL=marginal zone lymphoma. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714.

  27. Phase II Study of Lenalidomide + Rituximab in Indolent NHL: Most Common Grade 3 or 4 AEs Were Rash, Neutropenia, and Myalgia (N=30) AEs=adverse events. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714. Back to TOC

  28. Phase II Study of Lenalidomide + Rituximab in Indolent NHL: Therapy Was Generally Well Tolerated (N=30) • 50% of patients developed rashes (all grades) • Rash was self-limited • Usually did not occur on re-exposure to drug • 1 patient discontinued during cycle 1 due to leukocytoclastic vasculitis • 4 patients required dose reductions due to neutropenia • No patients developed TLS • 1 patient experienced neuropathy (Grade 2) • Most common AEs were myalgia and fatigue (Grade 1/2) TLS=tumor lysis syndrome. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714. Back to TOC

  29. Frontline Therapy With Lenalidomide + Rituximab is Clinically Active in Patients With Indolent NHL • 28 patients received at least 1 post-baseline tumor assessment and were evaluable for response CRu=unconfirmed complete response. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714.

  30. Lenalidomide Plus Rituximab Is Clinically Active as Frontline Therapy in Indolent NHL • 86% ORR (75% CR/CRu) in patients with indolent B-cell NHL treated with lenalidomide + rituximab • 94% ORR (94% CR/CRu) in patients with follicular lymphoma • Treatment was well tolerated with a manageable toxicity profile • Tolerability profile comparable to that observed with studies of lenalidomide monotherapy • The lenalidomide and rituximab combination appears to be clinically relevant for first-line therapy of indolent B-cell NHL • Additional studies are underway to explore the role for lenalidomide + rituximab in the treatment of indolent NHL1,2 1. Ahmadi et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1700; 2. Dutia et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009. Abstract 1679. Fowler et al. Abstract and poster presented at: 51st Annual ASH Meeting and Exhibition; December 5-8, 2009; New Orleans, LA. Abstract 1714.

  31. Does dose dense CHOP-R improve outcomes in patients with DLCL

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