1. New Data for Old Drugs in CLL Kanti R. Rai MD Joel Finkelstein Cancer Foundation Professor of Medicine Hofstra North Shore-LIJ School of Medicine Hempstead, NY Hempstead, NY Lymphoma and Myeloma Meeting – NYC 24 th October 2014

2. “Older” drugs in CLL Goals of ongoing clinical trials Focus of current clinical research in CLL is to combine older therapies with newer biological agents to improve safety, efficacy and developing treatments suitable for elderly CLL patients with multiple comorbidities who are unfit for FCR

3. “Older” drugs in CLL Most commonly used “Older” drugs in routine clinical practice  Chlorambucil  Fludarabine  Rituximab  FCR - Chemoimmunotherapy  Bendamustine

4. Treatment of CLL: Small Improvements in Survival Brenner H, et al. Blood. 2008;111:4916-4921,

5. Chemo-immunotherapy FCR, FR, PCR,BR + Newer Biological Agents 41 - 70% CR 90 - 95% ORR Wait and watch or Alkylating Agents Chlorambucil Cyclophosphamide 5% CR 30-50% ORR Purine Analogs Fludarabine Pentostatin Cladribine 20 - 30% CR 50 - 80% ORR Treatment options in CLL Slide Adopted from Dr R Furman Purine Analogs + alkylators FC, PC 35% CR 75 - 90% ORR 2000s1970s1960s1980s1990s2012-14 TKI Ibrutinib mAb Obinutuzumab

6. Combination - Chlorambucil (Clb) with Rituximab Rituximab (R) with Clb (n=100) in phase II trial Median follow-up - 30 months. Median age was 70 years (range,43-86 years), with median of seven comorbidities. Neutropenia and lymphopenia 41% and 23%. ORR - 84% and CR - 10% of patients. Median PFS - 23.5 months and Median OS was not reached Hillmen P. et al JCO 2014; 32:1236-1241 In another trial, Rituximab maintenance improved PFS vs observation in elderly patients who received induction with R-Clb Foa. R. et al AJH 2014

7. Combination - Chlorambucil (Clb) with Ofatumumab Ofatumumab (Ofa) with Clb (n=221) is compared with Clb alone (n=226) in a phase III randomized study for pts ineligible for fludarabine based therapies – COMPLEMENT-1 trial ORR was 82% vs 69% (P <0.001) and CR 14% vs 1% in Ofa-Clb vs Clb alone Median PFS after 29 month follow up was superior in Ofa+Clb (22.4 months vs 13.1 months in Clb alone) Hillmen P. et al Blood 2013;122: Abstract 528.

8. “Older” drugs in CLL – New Data Combination of older drugs with newer agents ─ Newer anti-CD20 mAb’s – obinutuzumab ─ BCR signaling kinase inhibitors – ibrutinib or with idelalisib Long term follow up studies of previously published pivotal clinical trials Impact of novel mutations in CLL, on responses achieved by FCR

9. NEJM 2014; Goede et al NEJM 2014; 2014;370:1101-1110 Clb Alone (n = 118) O-Clb (n = 238) RClb (n = 233) ORR32%78%65% CR021%7% Median PFS11 months27 months16 months Gr 3-5 AE50%73%55% Neutropenia163527 Obinutuzumab + chlorambucil (OClb), rituximab + Clb (RClb) versus Clb alone in elderly patients with CLL and comorbidities: CLL11 trial O-Clb improved OS compared with Clb alone HR- 0.41; 95% CI, 0.23 to 0.74; p=0.002

10. Bendamustine (B) was compared with chlorambucil (Clb) in a phase III trial Knauf W.U. et al BJH 2014 Median follow up – 54 monthsMedian follow up – 54 months CR – 21 vs 11%CR – 21 vs 11% Time to next treatment - 32 vs 10 months OS not significantly differentOS not significantly different

11. Fludarabine vs. Chlorambucil: Long term overall Survival Rai K. Clin Lymp Myeloma June 2011 % OS 8 years: Flu = 31% Chl = 19% P=0.04 Rai K. et al N Engl J Med 2000;343:1750-1757

12. 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

13. FCR – Post progression survival by duration of first remission Tam CS et al Blood 2014 Median follow up – 142 monthsMedian follow up – 142 months 156/300 pts progressed156/300 pts progressed Pts with short initial remission <3 yrs progressed irrespective of salvage therapyPts with short initial remission <3 yrs progressed irrespective of salvage therapy Very few pts received TKI based RxVery few pts received TKI based Rx

14. FCR (n=284) BR (n=280) ORR98% CR47%38% MRD72%67% 2 year PFS85%78% Grade 3-5 AE91%78% FCR vs. BR – CLL10 Trial Eichhorst B et al ASH 2013;Abstract 526

15. FCR vs. FC Phase III Trial GCLLSG 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) Overall Survival Hallek et al Lancet 2010

16. Presence of TP53 and SF3B1 mutations were independently predictive of poor PFS Presence of NOTCH1 mutations predicted for poor PFS and OS in patients with FCR Prognostic impact of new mutations in patients in CLL8 trial (FCR vs. FC) Stilgenbauer et al Blood 2014

17. Rituximab combined with ibrutinib Combination of ibrutinib with rituximab is studied in 40 patients with high risk CLL 87% achieved PR and 8% CR. The ORR in patients with del17p or TP53 mutation was 95%. The combination was well tolerated Burger J et al Lancet Oncology Aug 2014 Shorter redistribution Lymphocytosis likely due to Rituximab

18. Idelalisib is a targeted, highly selective, oral inhibitor of p110PI3Kδ IR (n=110) vs R alone (n=110) in a phase 3 study Median Age 71 years with severe co-morbidities Idelalisib 150 mg bid continuously with standard dose R ORR - 81% in IR vs 13% in R alone. All PR. Nodal response 93% in IR vs 4% in R alone Median PFS at 6 months was 93% vs 46% in R alone Median OS at 12 months was 92% vs 80% in R alone Most frequent Gr ≥3 AEs were Neutropenia (34% vs 22%), Thrombocytopenia (10% vs 16%), Diarrhea and/or colitis in 4% vs 0%. Overall – 56% vs 48% in IR vs R alone respectively Rituximab with idelalisib in relapsed CLL Furman R et al NEJM Jan 2014

19. Where Do We Go From Here? Participation in clinical trials should be prioritized: ─ NAIG trial for young: FCR vs. ibrutinib- rituximab ─ NAIG trial for elderly: BR vs. ibrutinib vs. Ibrutinib-rituximab ─ LRF trial: FCR vs. ibrutinib-rituximab Slide Courtesy by Kay N. et al

20. Future Perspectives Randomized clinical trials comparing ibrutinib with/without anti-CD20 mAb with FCR Ibrutinib/other novel TKI with obinutuzumab in elderly patients BTK selective TKI such as CGI-1746 Other molecules such as ABT-199 (Bcl2 antagonists)

21. In Conclusion, we have exciting times in CLL Advent of TKI’s like ibrutinib are very promising agents with/without combinations. Modifications of CART and ROR1 may prove curative in “difficult” CLL cases.

22. THANKS