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ASH REVIEW-Lymphoma

ASH REVIEW-Lymphoma. January 31 st , 2014 Kami Maddocks, MD. Overview. Indolent Non-Hodgkin’s Lymphoma Targeting B-cell Receptor Signaling Mantle Cell Lymphoma Is there a role for a non-chemotherapeutic approach? Aggressive Non-Hodgkin’s Lymphoma Can we improve R-CHOP?

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ASH REVIEW-Lymphoma

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  1. ASH REVIEW-Lymphoma January 31st, 2014 Kami Maddocks, MD

  2. Overview • Indolent Non-Hodgkin’s Lymphoma • Targeting B-cell Receptor Signaling • Mantle Cell Lymphoma • Is there a role for a non-chemotherapeutic approach? • Aggressive Non-Hodgkin’s Lymphoma • Can we improve R-CHOP? • OSU Lymphoma Trials

  3. B-cell receptor signalling Stevenson F K et al. Blood 2011;118:4313-4320

  4. Kinase inhibitors Woyach J A et al. Blood 2012;120:1175-1184

  5. Rationale for Targeting PI3K-δ • PI3K-δ expressed primarily in hematopoietic cells • PI3K-δinhibition cells promotes • ↑ Apoptosis • ↓ Proliferation • ↓ Microenvironment • response Herman S et al: Blood 2010 Lanutti B, et al: Blood 2011

  6. Idelalisib/CAL-101/GS-1101 • Selective orally available PI3K-δ inhibitor • Phase 1 Study 61% ORR in indolent NHL and MCL • 150 mg BID Herman S et al: Blood 2010 Kahl et al: ICML 2011

  7. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-cell Non-Hodgkin Lymphoma Gopal A et al. ASH 2013 Abstract 85

  8. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-cell Non-Hodgkin Lymphoma Gopal A et al. ASH 2013 Abstract 85

  9. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-cell Non-Hodgkin Lymphoma Gopal A et al. ASH 2013 Abstract 85

  10. Gopal A et al. ASH 2013 Abstract 85

  11. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-cell Non-Hodgkin Lymphoma Gopal A et al. ASH 2013 Abstract 85

  12. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-cell Non-Hodgkin Lymphoma • Well tolerated, acceptable safety profile • Highly effective in this population of refractory patients • Response rate consistent across all histologies • Responses durable beyond one year Gopal A et al. ASH 2013 Abstract 85

  13. Bruton’s Tyrosine Kinase (BTK)A critical kinase for lymphoma cell survival and proliferation • Bruton’s tyrosine kinase (BTK) is an essential element of the BCR signaling pathway • Inhibitors of BTK block BCR signaling and induce apoptosis • Targeted inhibition of BTK is a novel approach for the treatment of B-cell malignancies 13

  14. Rationale for Targeting BTK in CLL • Inhibition of BTK inhibits PI3K, MAPK, and NF-kB • BTK inhibition promotes • ↑ Apoptosis • ↓ Proliferation • ↓ Chemokines • ↓ Microenvironment response Herman S, et al: Blood 2011 Ponader S, et al: Blood 2012 de Rooij MF, et al: Blood 2002

  15. O N H 2 N N N N N O Ibrutinib (PCI-32765, Imbruvica) • Potent irreversible Btk inhibition • Inhibits BCR signaling • Orally available • Once daily dosing results in 24-hr sustained target inhibition Honigberg LA et al: Proc NatlAcadSci U S A.107:13075-80, 2010

  16. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia • Whole genome sequencing somatic mutations in WM • MYD88 L265P • > 90% pts • Supports malignant growth via signaling involving BTK • Ibrutinib induces apoptosis of WM cells with MYD88 • WHIM-like mutations in CXCR4 • 1/3 pts • Expression induces BTK activity, confers decreased sensitivity to ibrutinib mediated growth suppression in WM cells Treon et al. ASH 2013 Abstract 251

  17. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia • Symptomatic WM with > 1 prior therapy • 420 mg oral daily for 2 years or until progression • Sanger sequencing to determine MYD88 and CXCR4 mutations in BM LPC • 93% MYD88 L265P mutations • 25% WHIM-like CXCR4 Treon et al. ASH 2013 Abstract 251

  18. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia Treon et al. ASH 2013 Abstract 251

  19. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia *At best response Treon et al. ASH 2013 Abstract 251

  20. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia Treon et al. ASH 2013 Abstract 251

  21. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia • 1 non-responder wild type MYD88 L265P • MR impacted by mutations in CXCR4, not MYD88 • 77% MR in wild-type CXCR4 vs 30% in WHIM-like CXCR4 mutations • Improvement in disease parameters associated with wild-type CXCR-4 Treon et al. ASH 2013 Abstract 251

  22. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients with Relapsed or Refractory Waldenstrom’sMacroglobulinemia • Highly active and well-tolerated in R/R WM • Rapid reductions in serum IgM and improved Hgb • WHIM-like CXCR4 mutations impact response Treon et al. ASH 2013 Abstract 251

  23. Phase I 31 patients R/R NHL MTD 75 mg oral BID DLT rash and transaminitis ORR 52% IPI-145 Kahl et al, B Lugano 2013

  24. Upfront Follicular Lymphoma Martin P et al, Lugano Abstract 2013

  25. Combination Biologic Therapy without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase II Study of Lenalidomide Plus Rituximab Ruan J et al. ASH 2013 Abstract 247

  26. Combination Biologic Therapy without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase II Study of Lenaldomide Plus Rituximab Ruan J et al. ASH 2013 Abstract 247

  27. Combination Biologic Therapy without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase II Study of Lenaldomide Plus Rituximab Grade 1-2 infections: URI (29%), UTI (10%), pneumonia (10%), sinusitis (7%) 1 each of DVT and PE resolved with treatment Ruan J et al. ASH 2013 Abstract 247

  28. Combination Biologic Therapy without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase II Study of Lenaldomide Plus Rituximab Ruan J et al. ASH 2013 Abstract 247

  29. Combination Biologic Therapy without Chemotherapy as Initial Treatment for Mantle Cell Lymphoma: Multi-Center Phase II Study of Lenaldomide Plus Rituximab • Chemotherapy-free, combination biologic approach is feasible as initial therapy for MCL • Combination safe in frontline therapy for MCL • Further assessment of response rate and durability with additional follow-up • Combination alone and with addition of novel agents warrants further study in frontline and relapsed setting Ruan J et al. ASH 2013 Abstract 247

  30. The Single-Agent BCL-2 inhibitor ABT-199 (GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Responses Observed in all Mantle Cell Lymphoma Patients Dysregulation of anti-apoptotic protein Bcl-2 in NHL ABT-199 • Selective, potent, orally bioavailable small molecule bcl-2 inhibitor Phase I Dose-Escalation • 200, 300, 400, 600 and 900 mg 32 patients enrolled • Median age 68 • Median prior therapies 3.5 (1-7) Davids MS et al. ASH 2013 Abstract 1789

  31. The Single-Agent BCL-2 inhibitor ABT-199 (GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Responses Observed in all Mantle Cell Lymphoma Patients Most Common Adverse Events ≥ 20% • Nausea • Diarrhea • Vomiting • Fatigue • URI Grade 3/4 Adverse Events • Hematologic • Tumor Lysis (1 MCL, 1 DLBCL) DLT • Grade 3 febrile neutropenia • Grade 4 neutropenia Davids MS et al. ASH 2013 Abstract 1789

  32. *In DLBCL and FL pts, all responses occurred at doses ≥600 mg. **2 pts discontinued due to PD prior to first response assessment (1 MZL and 1 DLBCL) Davids MS et al. ASH 2013 Abstract 1789

  33. The Single-Agent BCL-2 inhibitor ABT-199 (GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Responses Observed in all Mantle Cell Lymphoma Patients • Anti-tumor activity in several NHL subtypes • ORR 53% • ORR MCL and WM 100% across all cohort doses • Response in DLBCL and FL ≥ 600 mg dosing • Dose escalation continues Davids MS et al. ASH 2013 Abstract 1789

  34. A Phase 2 Study of BrentuximabVedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphoma • Anti-CD30 monoclonal antibody conjuaged to microtubule-disrupting agent MMAE • Variable CD30 expression in several types of NHL including DLBCL and PMBCL Bartlett N et al. ASH 2013 Abstract 848

  35. A Phase 2 Study of BrentuximabVedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphoma • Phase 2 single-arm • R/R CD30+ NHL by IHC • 1.8 mg/kg IV q3 weeks Bartlett N et al. ASH 2013 Abstract 848

  36. Median Duration of Response: 21.7 weeks (6.1-37.1) Bartlett N et al. ASH 2013 Abstract 848

  37. A Phase 2 Study of BrentuximabVedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphoma Most Common Adverse Events ≥ 20% • Fatigue • Nausea, vomiting • Neutropenia • Fever • Diarrhea • Peripheral sensory neuropathy • Anemia • Constipation Grade 3/4 Adverse Events ≥ 10% • Neutropenia (29%) Bartlett N et al. ASH 2013 Abstract 848

  38. A Phase 2 Study of BrentuximabVedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphoma Anti-tumor activity in refractory NHL CD30 expression in responders < 1% to 90% • No correlation between CD30 expression and RR 40% ORR in DLBCL • Median duration > 8 months Toxicities consistent with known AE’s Bartlett N et al. ASH 2013 Abstract 848

  39. Final Results of Phase II Study of Lenalidomide Plus Rituximab-CHOP21 in Elderly Untreated DLBCL Focusing on Cell of Origin: REAL07 Trial of the FondazioneItalianaLinfomi • 49 patients enrolled • Median age 69 years (range 61-80) • 30 (61%) of patients had high-intermediate to high IPI • 43 (88%) of patients had Stage IV disease R-CHOP21 + 15 mg Lenalidomide Days 1-14 Chiappella A et al. ASH 2013 Abstract 850

  40. Final Results of Phase II Study of Lenalidomide Plus Rituximab-CHOP21 in Elderly Untreated DLBCL Focusing on Cell of Origin: REAL07 Trial of the FondazioneItalianaLinfomi Chiappella A et al. ASH 2013 Abstract 850

  41. Ph1b: ibrutinib-R-CHOP for DLBCL A Younes et al. J ClinOncol 31, 2013 (suppl; abstr 8502)

  42. i-R-CHOP for DLBCL: Outcomes A Younes et al, ASH 2013 Abstract 852

  43. Lack of Clinical Benefit for Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma in First Complete Response DLBCL patients • R-CHOP or similar regimen • Tertiary care centers 2001-2011 • CR to therapy • 1 year + follow up • Followed by routine surveillance imaging vs clinical surveillance • Median follow-up 5 years (1-12) • Baseline characteristics similar Vose J et al. ASH 2013 Abstract 4303

  44. Vose J et al. ASH 2013 Abstract 4303

  45. Lack of Clinical Benefit for Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma in First Complete Response Relapse detected by clinical manifestation • 100% clinical surveillance vs. 43% by routine imaging (p = 0.01) 5-year PFS • 76% clinical surveillance vs. 82% in routine imaging (p = 0.31) 5-year OS • 87% clinical surveillance vs. 92% in the routine imaging (p = 0.15) Vose J et al. ASH 2013 Abstract 4303

  46. Vose J et al. ASH 2013 Abstract 4303

  47. Lack of Clinical Benefit for Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma in First Complete Response • Majority of relapses in DLBCL in CR1 occur when signs or symptoms lead to evaluation as opposed to routine surveillance imaging • Relapses detected by imaging in this cohort did not have a PFS or OS benefit in favor of imaging • Cost, radiation exposure and risk of additional procedures limits clinical utility of imaging surveillance Vose J et al. ASH 2013 Abstract 4303

  48. Abstract 640: Impact of Induction Regimen & Consolidative Stem Cell Transplantation in Patients with Double Hit Lymphoma: Large Multicenter Retrospective Analysis • R-EPOCH increased CR but not OS, Pts achieving CR did not benefit from SCT, Primary refractory disease primary predictor of OS (106 pts, PFS 8.8 mos, OS 12 mos) • Abstract 1776: Double Hit Lymphoma: M.D. Anderson Experience • Improvement in 3 yr OS with CR to initial therapy, in patients achieving CR consolidative transplant had no statistically significant benefit to OS (56 case, PFS 9 mos, OS 18mos)

  49. Abstract 4362: Role of Aggressive Chemotherapeutic Regimens in Double Hit Lymphoma- Can Alternate Aggressive Induction Regimens Overcome the Poor Prognosis of Diffuse Large B Cell Lymphoma? No benefit with aggressive regimens (560 pts, median OS 12.2 mos – actually less with aggressive but not statistically significant) Abstract 2141: Dose Intensive Induction Followed by Allogeneic Stem Cell Transplantation more than Doubles Progression-Free and Overall Survival in “Double-Hit” Lymphoma PFS prolonged with DI regimens as compared to standard therapy (46 vs 8 mos) with added benefit with SCT (46 vs 14.8 vs 4.9 PFS, OS not reached vs 11.1 mos)

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