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CLL : Integrating novel therapies into frontline and salvage regimens Michael Keating M.B.,B.S.

CLL : Integrating novel therapies into frontline and salvage regimens Michael Keating M.B.,B.S. New Treatments for CLL - 2011. Lenalidomide , Flavopiridol , SCH-727965 Ofatumumab , GA-101, Abt-263, etc Bendamustine , Nelarabine CAL 101(PI3-K Delta inhibitor ), BTK Inhibitor, etc

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CLL : Integrating novel therapies into frontline and salvage regimens Michael Keating M.B.,B.S.

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  1. CLL : Integrating novel therapies into frontline and salvage regimens Michael Keating M.B.,B.S.

  2. New Treatments for CLL - 2011 • Lenalidomide, Flavopiridol, SCH-727965 • Ofatumumab, GA-101, Abt-263, etc • Bendamustine, Nelarabine • CAL 101(PI3-K Delta inhibitor), BTK Inhibitor, etc • PEITC (Huang), Sapacitabine (Plunkett) • Immuno-therapy (CARs) • OFAR (Oxaliplatin)—Richter’s • 8. Non –ablative allo transplant.

  3. Frontline therapy for CLL

  4. Response to FC + Rituximab(NCI-WG: 300 Patients) Response # Pts. ( % ) CR 217 (72%) Nodular PR 31 (10%) 95% PR 37 (12%) No Response 13 ( 4%) Early Death2 ( 1%)

  5. FCR-300 Survival and Time to Fail Proportion

  6. Is FCR good for everyone ? Mutation status? 17p– (p53 mutation)? 11q- (ATM deletion)? Age greater than 70 years?

  7. Time to Progression FCR Based responders by Mutation Status and FISH2004-2010 Proportion

  8. Time to Fail Untreated CLL Age <70 by FISH (2004-10) Proportion

  9. ELDERLY CLL

  10. Response to FCR (Front-Line) by Age, Stage, 2M Characteristic Value Pts. %CR P value Age (years) < 65 228 75 65-69 31 77 0.002 ≥70 41 46 Rai Stage 0-II 199 73* 0.002 III-IV 101 59 2Microglobulin < 3 91 86 3-4 78 76 < 0.001 ≥ 4 122 53 Tam CS, et al, Blood. 112(4):975-980, 2008 Aug 15

  11. Survival CLL Patients Age >70 by Rx p=.04 Proportion

  12. First-line Rituximab + Chlorambucil for Elderly: Response after induction Foà, et al. ASH 2011, Abstract 294

  13. Lenalidomide as Initial Treatment of Elderly Patients Phase II, 60 patients • Frontline patients with standard indications for treatment • Age 65 years or older • 5 mg orally daily for 56 days,  5 mg/28 days  max 25 mg daily • Allopurinol 300 mg day 1 -14 as tumor lysis syndrome prophylaxis Badoux, X et al. (submitted)

  14. Lenalidomide in Elderly CLL: Response (2008 NCI-WG Criteria) *4 patients (8%) with flow cytometry negative CR Badoux, X et al. (submitted)

  15. Lenalidomide in Elderly CLL: Serum Immunoglobulins (n=37) Cycles of therapy Cycles of therapy 8/16 (50%) patients with IgG<600mg/dl → normalized serum IgG

  16. Lenalidomide in Elderly CLL: Hematological Toxicity *NCI-working group criteria Badoux, X et al. (submitted)

  17. Lenalidomide in Elderly CLL: Overall and Progression-free Survival Proportion

  18. Lenalidomide + Rituximab in First-line CLL Progression-free Survival • Arm A (< 65 years) • n=40 patients • 16 events • Median PFS: 19 months • Median follow-up: 18 months • Arm B (≥ 65 years) • n=29 patients • 13 events • Median PFS: 20 months • Median follow-up: 17 months Patients (%) 100 Arm A Arm B 80 60 0 2 4 6 8 10 12 14 16 18 20 22 24 40 PFS (months) PFS was defined as the time from when patients started treatment to when the disease progressed or to death, or censored on the last known alive date for patients who are still on study. Patients who went off study due to toxicity or initiated a new therapy were censored on the date they went off study. 20 0 James, et al. ASH 2011, Abstract 291

  19. Lenalidomide+ Rituximabin Relapsed CLLBest Responses Badoux, et al. ASH 2011, Abstract 980

  20. Lenalidomide + Rituximab in Relapsed CLLResponses by Pre-treatment Characteristic Badoux, et al. ASH 2011, Abstract 980

  21. Lenalidomide + Rituximab in Relapsed CLLOverall and Progression-free Survival Median follow-up 31 months: Overall Survival 75% (95%CI: 64-87%) Median PFS 17.4 months (95%CI: 11.9-23.0) Badoux, et al. ASH 2011, Abstract 980

  22. Phase II of Lenalidomide + Ofatumumabfor Relapsed CLL (N=34) Day 9:Lenalidomide 10 mg daily until progression Ofatumumab 300 mg Ofatumumab 1000mg Ofatumumab1000mg Ofatumumab1,000mg Days 1 8 15 22 1 1 8-24(every other month) 1 2-6 Months Concomitant Treatments: • Allopurinol 300 mg day 1 -14 of cycle 1 • No antibiotic or anti-viral prophylaxis, no mandated DVT prophylaxis Ferrajoli, et al. ASH 2011, Abstract 1788

  23. Phase II of Lenalidomide + Ofatumumabfor Relapsed CLL – Responses (N=34) Ferrajoli, et al. ASH 2011, Abstract 1788

  24. NEW AGENTS FOR CLL

  25. Untreated CLL: ChlorambucilvsBendamustineProgression-Free Survival Knauf WU, et al. Blood. 2007:110. Abstract 2043 and poster at American Society of Hematology Annual Meeting 2007.

  26. R R R R R R B B B B B B B B B B B B Bendamustine +Rituximab Treatment Schedule B = Bendamustine 90 mg/m2 day 1-2, cycle 1-6, q4wks R = Rituximab 375 mg/m2 day 0, cycle 1, 500 mg/m2 cycle 2-6, q4wks

  27. Bendamustine + rituximab-- Ph 11 CLL2M Frontline therapy for CLL • Patients 117 • CR (%) 27(23%) • PR (%) 74(63%) • Median EFS 34 months • Fischer et al. ASH 2009; Abstract 205

  28. B CELL RECEPTOR SIGNALING

  29. B Cell Receptor Signaling Pathway • Therapeutic targets for small molecule inhibitors: • PI3K • BTK • LYN • SYK

  30. Single-Agent CAL-101 Resulted in Nodal Shrinkage in All Evaluable Patients with CLL Furman et al. ASH 2010, Abstract 55

  31. CAL-101 (C) Combination Therapies Substantially Increased Overall Response Rate Adverse event profiles were generally consistent wit the known safety profiles of each agent C+R (N=19) C+F (N=7) C+B (N=14) C+R+B (N=14) CAL-101 Mono (N=55) ITT Response Rate Lymph Node Response (LNR)a Overall Response (OR)b LNR OR LNR OR LNR OR LNR O R a Decrease by 50% in the nodal SPD b Response by IWCLL criteria [Hallek 2008] Sharman, et al. ASH 2011, Abstract 1787

  32. Both CAL-101 (GS-1101) Monotherapy and Combination Therapy were Associated with Durable Tumor Control C+R C+B (N=19) (N=14) CAL-101 Mono (N=55) C+F (N=7) C+R+B (N=14) % Progression-free Cycles (4 weeks) Sharman, et al. ASH 2011, Abstract 1787

  33. PCI-32765Novel Small Molecule Btk Inhibitor Forms a specific and irreversible bond with cysteine-481 in Btk Potent Btk inhibition IC50 = 0.5 nM Orally available O N H 2 N N N N N O PCI-32765 Burger et al. ASH 2010, Abstract 57

  34. Cumulative Best Response 420 mg/d cohort (n=27) 67% 59% 56% 56% 48% Response Rate % 41% 34% 33% 22% 19% Cycle 2 Cycle 5 Cycle 8 Cycle 11 Best Response CR NodalResponse PR O’Brien, et al. ASH 2011, Abstract 983

  35. Maximum % Change in LN Disease % Change in LN Dimensions 34 out of 39 evaluable pt had a nodal response = 87% 36

  36. Best Response by Risk Features Best Response by Risk Features O’Brien, et al. ASH 2011, Abstract 983

  37. ALC versus LN Response: Continuous Dosing Absolute Lymphocyte Count pre-treatment 2 months on treatment

  38. NEW ANTIBODIES

  39. Ofatumumab in refractory CLL Objective responses by IRC evaluation 51%* 44%* 95% CI H0: ORR = 15% *P<0.0001 versus H0 (two-sided exact test) CI, confidence interval Wierda et al. ASH 2010, Abstract 921

  40. CLL 5 year + 10 year Time to Fail by Decade Proportion

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