New Treatments and Combinations for Relapsed Chronic Lymphocytic Leukemia (CLL) Susan O’Brien UC Irvine Health
Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia Susan O’Brien, MD 1,2 , Richard R. Furman, MD 3 , Steven Coutre, MD 4 , Ian W. Flinn, MD, PhD 5 , Jan Burger, MD, PhD 1 , Kristie Blum, MD 6 , Jeff Sharman, MD 7 , William Wierda MD, PhD 1 , Jeffrey Jones MD, MPH 6 , Weiqiang Zhao, MD, PhD 6 , Nyla A. Heerema, PhD 6 , Amy J. Johnson, PhD 6 , Ying Luan, PhD 8 , Danelle F. James, MD, MAS 8 , Alvina D. Chu, MD 8 , John C. Byrd, MD 6
Best Response TN (n=31) R/R (n=101) Total (N=132) 89% 89% 87% CR PR PR-L Median DOR, NR (0.0+ to 65.5+) 56.8 (0.0+ to 65.5+) NR (0.0+ to 65.5+) months (range) Median follow-up, 62 (1 – 67) 49 (1+ – 67) 56 (1+ – 67) months (range) NR, not reached. O’Brien SM, et al. Blood. 2016;128: Abstract 233.
Survival Outcomes: Overall Population Progression-Free Survival Overall Survival Median PFS 5-year PFS Median OS 5-year OS TN (n=31) NR 92% TN (n=31) NR 92% R/R (n=101) 52 mo 43% R/R (n=101) NR 57% NR, not reached. O’Brien SM, et al. Blood. 2016;128: Abstract 233.
Survival Outcomes by Chromosomal Abnormalities Detected by FISH in R/R Patients * Progression-Free Survival Overall Survival Median PFS 5-year PFS Median OS 5-year OS Del17p (n=34) 26 mo 19% Del17p (n=34) 57 mo 32% Del11q (n=28) 55 mo 33% Del11q (n=28) NR 61% Trisomy 12 (n=5) NR 80% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% Del13q (n=13) NR 91% No abnormality** (n=16) NR 66% No abnormality** (n=16) NR 83% *Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population. **No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q NR, not reached. O’Brien SM, et al. Blood. 2016;128: Abstract 233.
Venetoclax Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) who Relapsed After or Were Refractory to Ibrutinib or Idelalisib Jeffrey Jones, 1 Michael Y. Choi, 2 Anthony R. Mato, 3 Richard R. Furman, 4 Matthew S. Davids, 5 Leonard Heffner, 6 Bruce D. Cheson, 7 Nicole Lamanna, 8 Paul M. Barr, 9 Herbert Eradat, 10 Ahmad Halwani, 11 Brenda Chyla, 12 Maria Verdugo, 12 Rod A. Humerickhouse, 12 Jalaja Potluri, 12 William G. Wierda, 13 Steven Coutre 14 American Society of Hematology ● San Diego, California ● 5 December 2016
Venetoclax Dosing Schedule and TLS Mitigation • To mitigate TLS risk, patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before first venetoclax dose • Patients with high tumor burden were hospitalized for first dose at 20 and 50 mg and received IV hydration and rasburicase • Laboratory values were monitored at first dose and each subsequent dose increase High tumor burden: any lymph node ≥10 cm; or both lymph node ≥5 cm and ALC ≥25x10 9 /L Jones J, et al. Blood. 2016;128: Abstract 637. 7
Patient Characteristics Arm A Arm B n=43 n=21 Age, median (range), years 66 (48 – 80) 68 (56 – 85) Unmutated IGVH ,* n/N (%) 25/29 (86) 11/13 (85) del(17)(p13.1),* n/N (%) 21/43 (49) 2/21 (10) Baseline laboratory values, median (range) CrCl, mL/min 83 (54 – 119) 75 (44 – 140) Hemoglobin, g/dL 11.2 (5.8 – 14.6) 12.2 (7.1 – 14.4) Platelet count, x10 9 /L 117 (20 – 446) 115 (30 – 439) Neutrophil count, x10 9 /L 3.5 (0 – 24) 2.4 (0 – 49) Lymphocyte count, x10 9 /L 19 (.2 – 263) 14 (.3 – 407) Bulky nodal disease, n (%) ≥5 cm 15 (35) 11 (52) ≥10 cm 7 (16) 5 (24) 4 (1 – 12) † 3 (1 – 11) † Prior therapies, median (range) Prior ibrutinib, n (%) 43 (100) 5 (24) Months on ibrutinib, median (range) 17 (1 – 56) 6 (2 – 11) Refractory, n (%) 39 (91) 2 (10) Prior idelalisib, n (%) 4 (9) 21 (100) Months on idelalisib, median (range) 10 (2 – 31) 8 (1 – 27) Refractory, n (%) 2 (5) 14 (67) *Site reported data. † 2 received only frontline ibrutinib; 2 received only frontline idelalisib. Jones J, et al. Blood. 2016;128: Abstract 637.
Efficacy Arm A Arm B n=43 n=21 Assessed by Assessed by Best response, n (%) IRC Investigator IRC Investigator ORR 30 (70) 29 (67) 13 (62) 12 (57) CR/CRi 0/1 (2) 2 (5)/1 (2) 0/0 2 (10)/1 (5) 0 2 (5) 0 0 nPR PR 29 (67) 24 (56) 13 (62) 9 (43) Non-responder* 13 (30) 14 (23) 8 (38) 9 (43) SD – 9 (21) – 8 (38) 1 † (2) 1 † (5) PD – – D/C ‡ – 4 (9) – 0 *Non-responder category for IRC includes both SD or PD, which were not identified as separate categories per IRC. † CLL progression and discontinued due to progression. ‡ D/C, patient discontinued the study prior to assessment. Jones J, et al. Blood. 2016;128: Abstract 637.
Efficacy Per Independent Review • Median DoR, PFS, and OS had not been reached after 11.8 months of follow up • Estimated 12 month PFS for all patients: 80% (95% CI: 67%, 89%) P ro g re s s io n -F re e S u rv iv a l D u ra tio n o f R e s p o n s e P ro g re s s io n -fre e s u rv iv a l (% ) P a tie n ts w ith R e s p o n s e (% ) 1 0 0 1 0 0 7 5 7 5 5 0 5 0 2 5 2 5 A rm A (R /R ib ru tin ib ) A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) A rm B (R /R id e la lis ib ) A ll p a tie n ts A ll p a tie n ts 0 0 0 2 4 6 8 1 0 1 2 1 4 0 2 4 6 8 1 0 1 2 1 4 M o n th s s in c e firs t d o s e M o n th s s in c e firs t d o s e N o . a t r is k 3 0 2 9 2 3 1 8 1 0 1 4 3 3 7 3 6 2 8 2 7 1 5 3 1 0 8 6 5 2 2 1 1 7 1 5 6 5 2 4 0 3 7 2 9 2 3 1 2 1 6 4 5 4 5 1 3 4 3 2 1 7 3 Data as of 10June2016 Jones J, et al. Blood. 2016;128: Abstract 637.
Minimal Residual Disease in Peripheral Blood MRD-positive MRD-negative CRi PR Non-responder by IRC A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) 5 3 0 4 3 2 0 2 1 0 1 % C L L C e lls % C L L C e lls 0 .7 5 0 .7 5 0 .5 0 0 .5 0 0 .2 5 0 .2 5 0 .0 1 0 .0 1 * # P a tie n ts P a tie n ts *Patient had persistent splenomegaly and thrombocytopenia; categorized as stable disease by investigator. # Also had confirmed bone marrow MRD-negative assessment. • 14/31 (45%) patient samples have demonstrated MRD-negative peripheral blood between Weeks 24 – 48 • 5 patients demonstrating sustained MRD negative status in blood had subsequent marrow evaluations; 1 patient was MRD negative in bone marrow Jones J, et al. Blood. 2016;128: Abstract 637. Data as of 10June2016 11
Outcomes of CLL Patients Treated With Sequential Kinase Inhibitor Therapy: A Real World Experience Mato AR, Nabhan C, Barr PM, Ujjani CS, Hill BT, Lamanna N, Skarbnik AP, Howlett C, Pu JJ, Sehgal AR, Strelec LE, Vandegrift A, Fitzpatrick DM, Zent CS, Feldman T, Goy A, Claxton DF, Bachow SH, Kaur G, Svoboda J, Nasta SD, Porter D, Landsburg DJ, Schuster SJ1, Cheson BD, Kiselev P, Evens AM Mato et al. Blood. 2016 Nov 3;128(18):2199-2205. Epub 2016 Sep 6;
Outcomes with Second Kinase Inhibitor Therapy in CLL PFS for alternate KI. (A) PFS from start of alternate KI (ibrutinib → idelalisib, idelalisib → ibrutinib). (B) PFS from start of alternate KI stratified by reason for discontinuation (CLL progression vs KI intolerance). Mato AR, et al. Blood. 2016;128(18):2199-2205.
Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Jeffrey A. Jones, MD, MPH 1 ; Jennifer Woyach, MD 1 ; Farrukh T. Awan, MD 1 ; Kami J. Maddocks, MD 1 ; Thomas Whitlow, BA 2 ; Amy S Ruppert, MAS 1 ; and John C. Byrd, ASH 2016
Treatment Schema Jones JA, et al. Blood. 2016;128: Abstract 639.
Cycle 9 Treatment Response Jones JA, et al. Blood. 2016;128: Abstract 639.
Safety All Patients All Patients N=64 N=64 Event, n (%) Event, n (%) Grade 3/4 AEs 53 (83) Any grade AE 64 (100) Common grade 3/4 AEs Common all-grade AEs (≥10% patients) (≥20% patients) Neutropenia 29 (45) Neutropenia 37 (58) Thrombocytopenia 18 (28) Anemia 14 (22) Thrombocytopenia 28 (44) Decreased WBC 8 (13) Diarrhea 27 (42) Febrile neutropenia 7 (11) Pneumonia 7 (11) Nausea 26 (41) Serious AEs 34 (53) Anemia 23 (36) Febrile neutropenia 6 (9) 20 (31) Fatigue Pneumonia 5 (8) Decreased WBC 14 (22) Multi-organ failure 2 (3) Septic shock Hyperphosphatemia 14 (22) 2 (3) Increased potassium 2 (3) • No clinical TLS was observed; 1 patient with high tumor burden met Howard criteria for laboratory TLS Jones JA, et al. Blood. 2016;128: Abstract 639. Data as of 10June2016 17
Conclusions • Obinutuzumab, ibrutinib, and venetoclax can be safely administered at each single agent dose • Dose-limiting toxicity was not observed • Adverse events were manageable and largely consistent with those reported in studies of the single-agents – Hematologic toxicity was common but manageable – Grade 3/4 non-hematologic toxicity was uncommonly observed • Responses were recorded at Cycle 9 in all patients assessed – MRD negativity at cycle 9 was achieved in PB for 7 of 10 and in BM for 4 of 10 patients assessed • Accrual is nearly completed to parallel phase 2 cohorts of relapsed/refractory (n=25) and treatment-naive (n=25) patients. Jones JA, et al. Blood. 2016;128: Abstract 639.
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