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

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)