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)

Chemo-immunotherapyChemo-immunotherapy Novel agentsNovel agents Who should be referred for allogeneic SCT?Who should be referred for allogeneic SCT? Agenda in CLL

DisclosuresDisclosures Member Medical Advisory Board – Genentech, Teva, Celgene, GSK, Sanofi Member Medical Advisory Board – Genentech, Teva, Celgene, GSK, Sanofi

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: , Blood 2008;112: FR - Byrd et al Blood 2003;101:6-14 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: , Blood 2008;112: FR - Byrd et al Blood 2003;101:6-14

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%. 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%.

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

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 Phase III International Randomized study N=817 Median Age = 61 years Median follow up 3.5 years FCR Arm FCR Arm ORR/CR - 90/44* ORR/CR - 90/44* OS 84 % OS 84 % FC Arm FC Arm ORR/CR - 80/22 # ORR/CR - 80/22 # OS 79 % # # OS 79 % # # * cf Keating CRs 72% # P<0.001 ## P = 0.01

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

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

AuthorNumber of patients CROR Hallek et al81744/22 (FCR/FC)90/80 (FCR/FC) Keating et al Tam et al Byrd et al (FR)10447/28 (FCR concurrent / FCR Sequential ) 90/77 Fischer et al (BR) FCR vs BR – an overview

FCR (German) BR (German) Anemia 22 (5%)23(19.7%) Thrombocytopenia30 (7%)26(22.2%) Infections103 (25%)9(7%) Age >65 (n/CR%)(54/43) (26/3) FCR vs BR – an overview FCR (MDACC) - 5(2.2%) 2.6% of courses (30/47)

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

Single agent Lenalidomide is active in elderly patients. Single agent Lenalidomide is active in elderly patients. Phase II study – n=59,RR CLL 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 continuously in 28 day cycles. Rituximab was administered for 12 cycles. 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 continuously in 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%. 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%) Grade 3/4 toxicity - neutropenia (73%). Grade 3/4 Infection or febrile episode (24%) Single agent Lenalidomide is active in elderly patients. Single agent Lenalidomide is active in elderly patients. Phase II study – n=59,RR CLL 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 continuously in 28 day cycles. Rituximab was administered for 12 cycles. 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 continuously in 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%. 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%) Grade 3/4 toxicity - neutropenia (73%). Grade 3/4 Infection or febrile episode (24%) Len-RituximabLen-Rituximab Badoux et al JCO; Dec26th 2012

BCR Signaling pathway Choi M et al Cancer J 2012;18:

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 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

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. Abstract – 189, Byrd J. et al IbrutinibIbrutinib

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. 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. Oral drug (420 mg qd), irreversible Btk inhibitor. N=116, Relapsed refractory CLL(n=61) vs frontline (n=31; all age >65 yrs). N=116, Relapsed refractory CLL(n=61) vs frontline (n=31; all age >65 yrs). ORR 67 % vs 71%, well tolerated. ORR 67 % vs 71%, well tolerated. 22 months PFS – 76% and 96%. 22 months PFS – 76% and 96%. Combination trials with Ofatumumab, FCR or BR are ongoing. Combination trials with Ofatumumab, FCR or BR are ongoing. 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. 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. Oral drug (420 mg qd), irreversible Btk inhibitor. N=116, Relapsed refractory CLL(n=61) vs frontline (n=31; all age >65 yrs). N=116, Relapsed refractory CLL(n=61) vs frontline (n=31; all age >65 yrs). ORR 67 % vs 71%, well tolerated. ORR 67 % vs 71%, well tolerated. 22 months PFS – 76% and 96%. 22 months PFS – 76% and 96%. Combination trials with Ofatumumab, FCR or BR are ongoing. Combination trials with Ofatumumab, FCR or BR are ongoing. Byrd J et al ASH 2012

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. 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 17/20 pts – ORR 85% in high risk patients 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. 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 17/20 pts – ORR 85% in high risk patients Burger JA et al ASH 2012 Shorter redistribution Lymphocytosis due to Rituximab

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

Idelalisib Combined With Ofatumumab Substantially Increased Overall Response Rate GS-1101 Mono (N=55) Overall Response b (OR) Lymph Node Response a (LNR) LNR (N=20 c ) OR (N=20) OR  6 cycles d (N=16) GS O Response a Rate +95% CI 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 84% n=46 CR 10% 24% n=13 85% n=17 80% n=16 94% n=15 CR 6% d Subjects having received  6 cycles of therapy Furman RR et al ASCO 2012

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 Idelalisib (GS-1101) with BR Abstract – 191, Coutre SE et al

GS-1101 with R or with B or with both BR. GS-1101 with R or with B or with both BR. GS ‑ 1101 dose of 150 mg/dose BID orally. 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%. 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. 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. Adverse effects were common with GS ‑ 1101/B arm. GS-1101 with R or with B or with both BR. GS-1101 with R or with B or with both BR. GS ‑ 1101 dose of 150 mg/dose BID orally. 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%. 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. 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. Adverse effects were common with GS ‑ 1101/B arm. Idelalisib (GS-1101) with BR Abstract – 191, Coutre SE et al

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 # Indications of allo SCT in CLL #These indications may change after the approval of BCR inhibitors for the therapy of CLL

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)