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Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center

Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center New Hyde Park, NY. Hematology Highlights 2013 Expert Reviews of the Annual Hematology Meeting Chronic Lymphocytic Leukemia (CLL). Agenda in CLL. Chemo-immunotherapy Novel agents

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Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center

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  1. Kanti R. Rai, MD NSLIJ-Hofstra School of Medicine Long Island Jewish Medical Center New Hyde Park, NY Hematology Highlights 2013 Expert Reviews of the Annual Hematology MeetingChronic Lymphocytic Leukemia (CLL)

  2. Agenda in CLL • Chemo-immunotherapy • Novel agents • Who should be referred for allogeneic SCT?

  3. Disclosures • Member Medical Advisory Board – Genentech, Teva, Celgene, GSK, Sanofi

  4. Evolution of FCR in CLL • Keating et al introduced FCR and its dramatic results in front line CLL • Byrd et al (CALGB) introduced - FR. FCR - Keating et al JCO 2005;23:4079-4088, Blood 2008;112:975-980 FR - Byrd et al Blood 2003;101:6-14

  5. FCR – Keating et al, Tam et al • Single center Phase II Trial. • N = 300 • Median Age – 57 years • Over 70 year of age were 14%. • ORR 95% , CR 72 %. • MRD Negative CR – 78% • At 6 years OS 77% , FFS 51 % • 6 year survival : MRD Negative vs Positive : 84% vs 65%.

  6. FCR-300 Survival and Time to Fail OS Proportion Slide courtesy Dr Michael Keating

  7. FCR vs FC (CLL8 Trial) Hallek et al Lancet 2010;376:1164 • Phase III International Randomized study • N=817 • Median Age = 61 years • Median follow up 3.5 years • FCR Arm • ORR/CR - 90/44* • OS 84 % • FC Arm • ORR/CR - 80/22 # • OS 79 % # # * cf Keating CRs 72% # P<0.001 ## P = 0.01

  8. FCR vs FC Phase III Trial GCLLSG Overall Survival At 3 years, 87 % of patients in the FCR group were alive vs. 83% in the FC group (HR- 0·67 [95% CI 0·48–0·92], p<0·01) Hallek et al Lancet 2010

  9. Bendamustine with Rituximab (BR) by GCLLSG Fischer et al : Multicenter Phase II (JCO 2012) • N=117 • Median age 64 years • OR/CR – 88/23.1 % • CLL 10 trial comparing FCR and BR is closed now.

  10. FCR vs BR – an overview

  11. FCR vs BR – an overview

  12. Other variants of FCR • FCR lite -Foon et al JCO 2009, Blood March 2012. • Sequential F-C-R - Lamanna et al JCO 2009 • FCR with Alemtuzumab (CFAR) –Wierda et al Blood 2011 • FCR with mitoxantrone (R-FCM) –Bosch et al JCO-2009

  13. Len-Rituximab • Single agent Lenalidomide is active in elderly patients. • Phase II study – n=59 ,RR CLL • Rituximab (375 mg/m2) weekly C1 and on day 1 of C3-C12. Lenalidomide was started on day 9 of C1 at 10 mg daily continuouslyin 28 day cycles. Rituximab was administered for 12 cycles. • ORR - 66% (12%-CR). TTF (17.4 months). Median OS (NR) estimated survival at 36 months is 71%. • Grade 3/4 toxicity - neutropenia (73%). Grade 3/4 Infection or febrile episode (24%) Badoux et al JCO; Dec26th 2012

  14. BCR Signaling pathway Choi M et al Cancer J 2012;18: 404-410

  15. BCR signaling inhibitors • Btk (Bruton tyrosine kinase) Inhibitor – Ibrutinib and AVL-292 • PI3Kδ-p110 isoform inhibitor- GS-1101 and IPI-145 • Syk (spleen tyrosine kinase inhibitor) – Fostamatinib, Portola compounds • Lyn – Kinase inhibitor –Dasatinib, Bafetinib

  16. Abstract – 189, Byrd J. et al Ibrutinib Ibrutinib Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve and Refractory CLL/SLL Including Patients with High-Risk (HR) Disease: Updated Results of 116 Patients in a Phase Ib/II Study.

  17. Btk Inhibitor (Ibrutinib) • Bruton like tyrosine kinase (Btk) is a downstream mediator of B-cell receptor (BCR) signaling and is not expressed in T-cells or NK-cells. • Oral drug (420 mg qd), irreversible Btk inhibitor. • N=116, Relapsed refractory CLL(n=61) vs frontline (n=31; all age >65 yrs). • ORR 67 % vs 71%, well tolerated. • 22 months PFS – 76% and 96%. • Combination trials with Ofatumumab, FCR or BR are ongoing. Byrd J et al ASH 2012

  18. Btk Inhibitor (Ibrutinib) with Rituximab • Ibrutinib 420 mg PO daily, in combination with weekly rituximab (375 mg/m2) for weeks 1-4 (cycle 1), then daily ibrutinib plus monthly rituximab until cycle 6, followed by daily single-agent ibrutinib. • 17/20 pts – ORR 85% in high risk patients Shorter redistribution Lymphocytosis due to Rituximab Burger JA et al ASH 2012

  19. Idelalisib (GS-1101) • PI3K p110 δ isoform inhibitor. • Oral drug (150 mg po bid). • N=54, relapsed refractory CLL. • ORR 33% (all PR) and LN response in 100% cases. • Pneumonia and colitis 24% • Significant effect on lymphocyte trafficking and redistribution. • Combination trials with lenalidomide, Rituximab and Bendamustine are ongoing. Furman RR et al ASCO 2012

  20. Idelalisib Combined With Ofatumumab Substantially Increased Overall Response Rate GS-1101 Mono (N=55) GS-1101 + O 94%n=15 Responsea Rate+95% CI 85%n=17 84%n=46 80%n=16 24%n=13 CR 10% CR 6% Lymph Node Responsea(LNR) OverallResponseb(OR) OR 6 cyclesd(N=16) OR (N=20) LNR (N=20c) a Decrease by 50% in the nodal SPD b Response as assessed by investigators based on IWCLL criteria (Hallek 2008) C 1 Subject without follow-up assessment was excluded from analysis d Subjects having received 6 cycles of therapy Furman RR et al ASCO 2012

  21. Idelalisib (GS-1101) with BR Combinations of PI3Kδ inhibitor GS–1101 with Rituximab (R) and/or Bendamustine (B) Are Tolerable and Highly Active in Patients with RR CLL: Results From a Phase I Study Abstract – 191, Coutre SEet al

  22. Idelalisib (GS-1101) with BR • GS-1101 with R or with B or with both BR. • GS‑1101 dose of 150 mg/dose BID orally. • ORR for the GS‑1101/R, GS‑1101/B, and GS‑1101/BR regimens were 78%, 82% and 87%. • With a minimum follow-up of 40 weeks, 1-year PFS rates were 74%, 88% and 87% in the GS‑1101/R, GS‑1101/B, and GS‑1101/BR  respectively. • Adverse effects were common with GS‑1101/B arm. Abstract – 191, Coutre SEet al

  23. # Indications of allo SCT in CLL • Young and physically fit patients with Richter’s transformation • Refractory patients with del17p or TP53 mutations • Relapsed patients with fludarabine refractory disease • Ultra High risk patients with CLL #These indications may change after the approval of BCR inhibitors for the therapy of CLL

  24. CLL Collaborations • CLL Research Consortium (CRC) • NCI- Working Group on CLL • International Workshop on CLL (iwCLL) • German CLL Study Group • CLL Global Research Foundation • Alliance for Clinical Trials in Oncology (CALGB)