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What’s new in Chronic Lymphocytic Leukemia? Updates from ASCO and ASH 2013 31 January 2014

What’s new in Chronic Lymphocytic Leukemia? Updates from ASCO and ASH 2013 31 January 2014. Jeffrey Jones, MD, MPH Section Chief, CLL/HCL Division of Hematology. Overview. Frontline Therapy Chemoimmunotherapy for young, fit patients GCLLSG CLL10: BR V. FCR

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What’s new in Chronic Lymphocytic Leukemia? Updates from ASCO and ASH 2013 31 January 2014

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  1. What’s new in Chronic Lymphocytic Leukemia?Updates from ASCO and ASH 201331 January 2014 Jeffrey Jones, MD, MPH Section Chief, CLL/HCL Division of Hematology

  2. Overview • Frontline Therapy • Chemoimmunotherapy for young, fit patients • GCLLSG CLL10: BR V. FCR • GCLLSG CLL11: chlorambucil +/- rituximab or obinutuzumab • Emerging agents • Relapsed Disease • Small molecule inhibitors of BCR signaling • PI3K: idelalisib, IPI-145 • BTK: ibrutinib • Small molecule inhibitor of BCL2 (ABT-199) • Cyclin-dependent kinase inhibitors (dinaciclib)

  3. Frontline TherapyChemo-immunotherapy

  4. CLL10: Ph3 FCR v BR in Frontline Primary endpoint: noninferiority of BR vs FCR for PFS FCR Fludarabine 25 mg/m3 IV Days 1-3Cyclophosphamide 250 mg/m2 Days 1-3Rituximab 375 mg/m2 IV Day 0, cycle 1Rituximab 500 mg/m3 IV Day 1, cycles 2-6 ELIGIBILITY Untreated, active CLL No del(17p) Physically fit CrCl ≥70 mL/min(N = 561) BR Bendamustine 90 mg/m3 IV Days 1-2Rituximab 375 mg/m2 Day 0, cycle 1Rituximab 500 mg/m2 IV Day 1, cycles 2-4 Eichhorst B, et al. ASH 2013. Abstract 526

  5. CLL10: Ph3 FCR v BR in Frontline • Median observation time: 27.9 mos • Median PFS: • FCR: NR versus BR: 44.9 mos (P = .04) • 2-yr OS • FCR: 94.2% v. BR: 95.8% (P = .59) Eichhorst B, et al. ASH 2013. Abstract 526

  6. CLL10: Ph3 FCR v BR in Frontline Eichhorst B, et al. ASH 2013. Abstract 526

  7. CLL11 Trial: Obinutuzumab + Chl v Rituximab + Chl Randomized 1:2:2 28-day cycle Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 118) Previously untreatedCLL patients withcomorbidities(CIRS score > 6 and/orCrCl < 70 mL/min)(N = 780) Obinutuzumab 1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 333) Rituximab 375 mg/m2 IVcycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 330) Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014 [Epub ahead of print]

  8. CLL11 Trial: Obinutuzumab + Chl v Rituximab + Chl Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014 [Epub ahead of print]

  9. CLL11 Trial: Obinutuzumab + Chl v Rituximab + Chl *Includes 5 patients randomized to who mistakenly received obinutuzumab-chlorambucil. Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]

  10. CLL11 Trial: Obinutuzumab + Chl v Rituximab + Chl Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]

  11. CLL11 Trial (G-Chl v. R-Chl) PFS Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [E-pub ahead of print]

  12. CLL11 Trial (G-Chl v. R-Chl) OS Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [E-pub ahead of print]

  13. Implications for Practice? • CR more common after FCR v. BR for tx-naïve CLL • ORR are similar • PFS significantly longer with FCR • Acute (and long-term?) toxicity greater with BR • Obinituzumab (now approved) + chlorambucil is an effective, well-tolerated therapy for tx-naïve CLL • Most appropriate for elderly and/or infirm • Begs question of whether obinituzumab is superior to rituximab in other clinical contexts • Frontline clinical trials involving CIT open at OSU? • A041202: A Randomized Phase III Study of Bendamustine Plus Rituximab versus Ibrutinib Plus Rituximab versus Ibrutinib Alone in Untreated Older Patients (≥ 65 Years Of Age) with Chronic Lymphocytic Leukemia (CLL)

  14. Frontline TherapyEMERGING Agents

  15. Ibrutinib in Treatment-Naïve CLL

  16. Ibrutinib for Untreated CLL: Toxicity Treatment Naive (n=31) SM O’Brien et al. Lancet Oncol 2014; 15:48-58 Grade 1 Grade 2 Grade 3 Grade 4

  17. Ibrutinib for Untreated CLL: Response PR w/ lymphs SM O’Brien et al. Lancet Oncol 2014; 15:48-58

  18. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

  19. Idelalisib + Rituximab in Frontline CLL Nodal Response at 8wks Best Nodal Response SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

  20. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)

  21. Implications for Practice? *BOLD indicates actively recruiting • Idelalisib and ibrutinib are both expected to be approved for relapsed disease this year • Use in the frontline setting remains investigational • Search for effective yet less-toxic alternatives to CIT continues, and several new agents are showing promise • OSU13031: A Phase II Study of MOR00208 in Combination with Lenalidomide for Patients with Relapsed or Refractory CLL/SLL/PLL(SLL) or Patients with Untreated CLL/SLL/PLL (untreated patients 2nd Qtr 2014) • OSU 12101: A phase Ib multicenter dose-finding and safety study of GDC-0199 and obinutuzumab in patients with relapsed or refratory or previously untreated CLL (3rd Qtr 2014) • Trials of novel agents v. conventional CIT open at OSU • A041202: A Randomized Phase III Study of Bendamustine Plus Rituximab versus Ibrutinib Plus Rituximab versus Ibrutinib Alone in Untreated Older Patients (≥ 65 Years Of Age) with Chronic Lymphocytic Leukemia (CLL) • Early intervention for high-risk disease needs revisited • OSU 10156: Phase II study of lenalidomide to repair immune synapse response and humoral immunity in early-stage, asymptomatic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with high-risk genomic features • GCLLSG CLL12: Phase III Trial to Compare the Efficacy and Safety of Ibrutinib vs. Placebo in Previously Untreated Binet Stage A CLL Patients with Risk of Early Disease Progression

  22. Relapse TherapyEmerging Agents

  23. Idelalisib and Rituximab for Relapsed CLL Disease progression,* death, or discontinuation due to AE Stratified by del(17p)/TP53 mutation, IGHV mutation status Primary Study 116 Extension Study 117 Idelalisib 150 mg BIDn = 110 Idelalisib300 mg BID Clinical Endpoints Primary: PFS as assessed by IRC Events: Disease progression or death Secondary: ORR, LNR, OS Rituximab†(6 mos) Patientswith heavily pretreated, relapsed CLL Placebo BIDn = 110 Idelalisib 150 mg BID Rituximab†(6 mos) Planned interim analyses at 50% and 75% of events *Patients with disease progression continued on idelalisib Extension Study 117.†Rituximab schedule: 375 mg/m2, then 500 mg/m2 every 2 wks x 4, then 500 mg/m2 every 4 wks x 3. Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]

  24. R-Idelalisib for Relapsed CLL: Response Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]

  25. R-Idelalisib for Relapsed CLL: Survival Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]

  26. Ph2 Ibrutinib+Rituximab for High-Risk CLL • Rituximab 375 mg/m2 • Cycle 1 (Mo 1), Days 1, 8, 15, 21 • Cycle 2 (Mos 2-6), on Day 1 of each mo • Ibrutinib given 420 mg orally once daily • Continually for duration of trial • If patients benefited after 12 cycles, they could continue ibrutinib alone • Eligibility criteria: • High-risk CLL/SLL previously treated with ≤ 3 courses or previous therapy • Presence of del(17p) or del(11q) or TP53 (treated or untreated) • Remission duration of < 3 yrs after previous frontline chemoimmunotherapy treatment indicated per 2008 IWCLL • ECOG PS 0/1 • Adequate renal and hepatic function Burger J, et al. ASH 2013. Abstract 675.

  27. Ph2 Ibrutinib+Rituximab for High-Risk CLL • Lymphocytosis peaked at 1 wk, decreased >50% from BL in ≤12 wks • Marrow lymphs decreased by approx 50% after 12 mo (P < .00001) • Majority showed > 50% decreases in both spleen and node size • PFS at 18 mos: All patients: 78%; Del(17p): 72%; Others: 84% • OS at 18 mos: All patients: 84%; Del(17p): 78%; Others: 89% *At 12 mos or best response before study discontinuation. † 1/4 Minimum residual disease negative Burger J, et al. ASH 2013. Abstract 675.

  28. Ibrutinib + Rituximab in High-Risk CLL Burger et al. ASH Annual Meeting 2012, Abstract 187

  29. PI3K-ɣ/δ Inhibitor IPI-145 in Relapsed CLL Dose escalation:8 mg BID increased to 100 mg BIDMTD = 75 mg BID Phase I: total relapsed/refractory CLL (n = 52) were enrolled in dose-escalation and expansion cohorts (25 mg and 75 mg BID) • CLL patients with cytopenias were allowed in the expansion cohorts • 40% grade ≥ 3 cytopenias at baseline in relapsed/refractory CLL • Expansion cohort also ongoing at 25 mg BID for high-risk, treatment-naive patients Cohort 1 (n = 28)Relapsed/refractory CLL≤ 25 mg BID Cohort 2 (n = 24)Relapsed/refractory CLL75 mg BID Flinn I, et al. ASH 2013. Abstract 677.

  30. IPI-145 in Relapsed CLL: Safety Flinn I, et al. ASH 2013. Abstract 677.

  31. IPI-145 in Relapsed CLL: Nodal Response • CT assessment: 98% (42/43) patients had a reduction in adenopathy • 89% (24/27) in ≤ 25 mg BID arm had nodal response or ≥ 50% reduction in adenopathy Relapsed/refractoryn = 43; < 25 mg BID n = 27; 75 mg BID n = 16 PD 0 -20 -40 Best Percent Change -60 -80 -100 17p(del)/p53 mutPrior BTK-inhibitor failureCRPR ≤ 25 mg BID75 mg BID Flinn I, et al. ASH 2013. Abstract 677.

  32. IPI-145 in Relapsed CLL: Response *Includes patients with 17p(del) or p53 mutation. Median time to response was < 2 mos Flinn I, et al. ASH 2013. Abstract 677.

  33. ABT-199:Bcl-2 Inhibitor in Relapsed CLL/SLL Seymour JF, et al. ASH 2013. Abstract 872.

  34. ABT-199 in Relapsed CLL/SLL: Safety • 100% of evaluable patients (n = 38) showed a ≥ 50% reduction of lymphocyte count; median time to 50% reduction: 15 days (range: 1-170) • 88% of evaluable patients (n = 57) had a ≥ 50% reduction in sum of product of diameters of nodal masses; median time to 50% reduction 6 wks • MRD assessed in 9 pts with CR: no detectable MRD in 5 pts Seymour JF, et al. ASH 2013. Abstract 872.

  35. ABT-199 in Relapsed CLL/SLL: Safety Seymour JF, et al. ASH 2013. Abstract 872.

  36. 2nd Gen CDKI dinaciclib for relapsed CLL • Broad inhibitor of CDK1, CDK2, CDK5, CDK9 with broader therapeutic index versus flavopiridol • Phase 1 study treated 52 relapsed/refractory CLL/SLL patients with escalating doses of dinaciclib in a 3 + 3 design • Primary endpoints: safety, tolerability, phase 2 dose • 2-hour IV infusion on Days 1, 8 and 15 of a 28-day cycle • First dose of treatment administered inpatient • Aggressive TLS management • Rasburicase prophylaxis • Neulasta day 16 of therapy Dinaciclib (SCH 727965) Flynn JM, et al. ASH 2013. Abstract 871.

  37. Dinaciclib for relapsed CLL: Response Responses seen at all dose levels N= 52 ORR = 54% RR similar in all risk groups Flynn JM, et al. ASH 2013. Abstract 871.

  38. Dinaciclib for relapsed CLL: Safety Flynn JM, et al. ASH 2013. Abstract 871.

  39. Trial Options for Relapsed CLL/SLL at OSU/James* *BOLD indicates actively recruiting • OSU 13031: MOR00208 (anti-CD19 moAb) + lenalidomide • OSU 12101: ABT-199 (anti BCL2) + GA-101 (obinutuzumab) • OSU 12095: TRU-016 (anti CD37 moAb) + rituximab • OSU 12142: TG02 (oral CDKI) • OSU 11120: dinaciclib (iv CDKI) + ofatumumab • OSU 13018: ibrutinib + lenalidomide • OSU 12062: KPT-330 (oral signaling inhibitor) • OSU 13187: GDC-0853 (2nd generation BTK inhibitor) • OSU 13225: ACP-196 (2nd generation BTK inhibitor) • OSU 13226: ofatumumab +/- IPI-145 (PI3K inihibitor) • OSU 13255: ocratuzumab (3rd generation anti-CD20 moAb) – consolidation therapy

  40. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

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