Richard R. Furman Weill Cornell Medical College

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Presentation transcript:

Richard R. Furman Weill Cornell Medical College What is the Optimal Therapy for CLL Patients Failing to Achieve PR with CIT? Richard R. Furman Weill Cornell Medical College

The Evolution of Treatment Options in CLL Alkylators CR: 5% ORR: 30-50% 1970s Purine Analogs CR: 20 - 30% ORR: 50 - 80% 1980s Purine + alkylators CR: 35% ORR: 75 - 90% 1990s Chemo-immunotherapy CR: 41 - 70% ORR: 90 - 95% 2000s TKIs / SMIs CR: ??? ORR: 70-100% 2010s

Fact #1: Upfront chemoimmunotherapy (FCR) generates high response rates and progression free survival. Response RR ORR 95% CR 72% nPR 10% PR-i 7% PR-d 5% Tam CS. Blood 2008; 112:975.

FCR generates excellent time to progression Fact #2: FCR generates excellent time to progression Keating, MJ. JCO 2005; 23:4079.

Fact #3: Patients do progress and additional therapy is necessary Response TTP (months) CR 85 nPR 71 PR-i 50 PR-d 19 Tam CS. Blood 2008; 112:975.

Response to Second Line BR Chemotherapy Is Poor Fischer K. JCO 2011; 29:3559.

AUSct Toxicity: MDS/AML Risk of MDS/AML postautograft = 12.4% at 5 years Incidence of non-MN = 11% Milligan DW. BJH 2006; 133:173.

Overall Survival Post-Auto and Allogeneic Stem Cell Transplant Gribben JG. Blood 2005; 106:4389.

BCR-associated Kinases: Proven Effective Therapeutic Targets Syk (spleen tyrosine kinase): fostamatinib PRT062070 GS-9973 Btk (Bruton’s tyrosine kinase): ibrutinib CC-292 ACP-196 PI3K (phosphatidyl 3-kinase: Idelalisib (GS-1101) IPI-145 AMG319 Nat Rev Immunol 2:945

Targeting the “BCR++” Antigen Pathway:

Bruton’s Tyrosine Kinase (Btk) B-cell antigen receptor (BCR) signaling required for B cell survival Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway Inhibitors of Btk block BCR signaling and induces apoptosis

Idelalisib: inhibitor of PI3 Kinase-d

Same Enzyme - Different Targets PI3 Kinase Same Enzyme - Different Targets PI3K Isoforms Expression Broad Leukocytes Gene KO effect Lethal Benign Physiological role Insulin signaling Angiogenesis unknown B-cell signaling, development & survival Neutrophil, T-cell development IC50 (nM) 2154 427 8 182

Overall Survival for Idelalisib and Ibrutinib in Relapsed / Refractory Disease

PCYC-1102: Overall Response Among those patients whose initial response was PR-L, the majority achieved classic response by IWCLL criteria: TN: 9/13 (69%) R/R: 38/49 (78%) Combined ORR + (PR-L): TN = (84%) R/R = (88%) Furman RR. IWCLL 2013.

PCYC-1102: Progression Free Survival at 26 months TN: 96.3% R/R: 73.6% No del17p/11q: 92.2% del11q: 72.9% del17p: 53.1%

PCYC-1102: Patient Disposition TN ≥ 65 Years n = 31 R/R n = 85 Median time on treatment, months 21.3 (0.3, 26.6) 16.3 (0.3, 28.7) Patients still on treatment, n (%) 26 (84) 53 (62) Patients discontinuing treatment, n (%) 5 (16) 32 (38) Reasons for treatment discontinuation, n (%) AE Treatment-related AE Death due to AE 2 (6) 1 (3) 10 (12) 1 (1) 1 (1)a Disease progression* SCT (while in response) Investigator decision (not SCT) Patient decision Lost to Follow-up 4 (5) 3 (4) *7 patients (1 TN, 6 R/R) had disease progression with Richter’s transformation Furman RR. iWCLL 2013

Ibrutinib Common AEs (> 20 %) Treatment Naïve ≥ 65 yrs Grade 1 Grade 2 Grade 3 Grade 4

Rate of > Grade 3 Infections / 100 patient months Rate of Severe Infections with Ibrutinib (PCYC-1102 Study – Rel/Ref Population) Rate of > Grade 3 Infections / 100 patient months First 6 months >7 months All Patients (N=85) 7.1 2.6 By duration of exposure: <12 months (N=22) 17.7 4.1 >12 months (N=63 4.8 Byrd J. NEJM 2013.

PCYC-1102: Changes in Median Serum Immunoglobulin Levels – TN + R/R Furman RR. IWCLL 2013.