Chronic Lymphocytic Leukemia: State of the Art

Transcription

1 14th Annual INDY Hematology Review March 2017 Chronic Lymphocytic Leukemia: State of the Art Adrian Wiestner, MD/PhD Bethesda, MD

2 Disclosures Grant/research support: Pharmacyclics Acerta Pharma Off-label/investigative use(s): Ibrutinib with chemotherapy or antibody therapy Idelalisib in combination with chemotherapy

3 CLL8 study (FCR vs FC): improved outcome with chemoimmunotherapy Progression free survival Overall survival FC & Rituximab: 52 months del 17p Cyclophosphamide plus Fludarabine (FC): 33 months Hallek et al. Lancet, 2010

4 P e r c e n t p r o g r e s s io n -fr e e Long term disease free survival in patients with IGHV mutated CLL treated with FCR FCR: MD Anderson experience Reduced FCR for IGHV mutated CLL N P ro g -fre e IG H V m u ta te d IG H V u n m u ta te d p < T im e (Y e a rs ) Thompson et al, Blood 2015 Thompson, ASH 2016, abstract #232 courtesy Ph. Thompson

5 LENALIDOMIDE MAINTENANCE FOLLOWING FIRSTLINE IMMUNOCHEMOTHERAPY Physically fit, active disease (n=468) Firstline FCR, BR, FR, FC PFS with maintenance lenalidomide Median f/u: 17.5 months Lenalidomide High risk (n=89) Lenalidomide (n=60) Placebo (n=29) HR:0.15; P< risk reduction of 80% Median dose 9.1mg C1 5mg, C2-6 10mg, C mg Placebo: 13.3 months Stop 43% AE 32% PD 7% Stop 72% AE 21% PD 45% Fink, ASH abstract # 229; courtesy B. Eichhorst

6 ALL AE/SAE ANY GRADE AS OF MARCH 2016 Blood and Lymphatic disorders Cardiac Disorders Ear and Labyrinth disorders Eye disorders Gastrointestinal Disorders General Disorders Hepatobiliar Dosorders Immune System Disorders Infections and Infestations Injury, Poisoning and Procedural Complications Investigations Metabolism and Nutrition Disorders Musculosceletal and Connective Tissue Disorders Neoplasm benign, malignant and unspecified Nervous System Disorders Psychiatric Disorders Renal and Urinary Disorders Reproductive and Breast Disorders Respiratory, Thoracis and Mediastinal Disorders Skin and Subcutaneous Disorders Surgical and Medical Procedures Vascular Disorders not coded so far Placebo, 29 pts Lenalidomide, 60 pts Fink, ASH abstract # 229; slide courtesy B. Eichhorst

7 CLL10 STUDY: FCR VS BR IN FRONT-LINE Progression-free survival, Median follow-up 37 months All patients Patients >65 years: FCR (31%), BR (39%) Median PFS FCR 55.2 months BR 41.7 months P < Median PFS FCR not reached BR 48.5 months P = 0.17 BR has inferior PFS (HR = 1.6) than FCR, less AEs, no difference in OS Eichhorst, ASH 2014 Courtesy B. Eichhorst Eichhorst, et al, Lancet Oncology 2016

8 Kinase inhibitors to target B-cell receptor signaling Wiestner, Haematologica 2015

9 Progression free survival (%) Randomized phase 3 studies in rel/ref CLL Ibrutinib vs ofatumumab Rituximab with idelalisib vs Rituximab with placebo ORR: 43% vs 4.1% ORR: 81% vs 13% ibrutinib Idelalisib + ritux Median 8.1 months ofatumumab Median 5.5 months Placebo + ritux Months Byrd et al, NEJM 2014 Months Furman et al, NEJM 2014

10 Five-Year Experience With Single-Agent Ibrutinib Survival Outcomes Progression-Free Survival Overall Survival NR, not reached. Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57% O Brien, ASH abstract # 233; courtesy S. O Brien ASH 2016, year Update; O Brien et al.

11 Survival Outcomes by Number of Lines of Prior Therapies and Chromosomal Abnormalities (R/R Patients only) PFS by treatment status PFS by FISH category Median 5-year Prior therapies PFS PFS 0 (n=31) NR 92% 1-2 (n=27) 63 mo 60% 3 (n=14) 59 mo 41% 4 (n=60) 39 mo 38% O Brien, ASH abstract # 233; courtesy S. O Brien FISH category Median 5-year PFS PFS Del17p (n=34) 26 mo 19% Del11q (n=28) 55 mo 33% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 66% ASH 2016, year Update; O Brien et al.

12 Cumulative Frequency of Grade 3 Adverse Events Over 5-Year Follow-Up Non-hematologic 5% Hematologic Infectious R/R TN R/R TN R/R TN Grade 3 Grade 4 Grade 5 O Brien, ASH abstract # 233; courtesy S. O Brien ASH 2016, year Update; O Brien et al.

13 RESONATE-2 (PCYC-1115/1116) Study Design Patients (N=269) Treatment-naïve CLL/SLL with active disease Age 65 years For patients years, comorbidity that may preclude FCR del17p excluded R A N D O M I Z E 1:1 ibrutinib 420 mg once daily until progression chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles CLL progression or 1115 study closure PCYC-1116 Extension Study* In clb arm, n=55 crossed over to ibrutinib following PD Stratification factors ECOG status (0-1 vs. 2) Rai stage (III-IV vs. II) Efficacy (PFS, OS, ORR) determined by investigator-assessment. Barr, ASH abstract # 233; courtesy P. Barr ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

14 Ibrutinib Improved PFS Regardless of IGHV Status and Overall Survival Compared to Chlorambucil Progression-Free Survival and IGHV Overall Survival Ibrutinib Chlorambucil (n=40) (n=58) (n=42) (n=60) 24-months OS Ibrutinib: 95% Chlorambucil: 84% P< M-CLL U-CLL 83% and 92% reduction in the risk of progression or death in IGHV M-CLL & U-CLL, respectively, compared to chemotherapy Barr, ASH abstract # 233; courtesy P. Barr ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

15 Most Patients Remain on Ibrutinib Treatment Median duration of ibrutinib treatment, mo (range) Treatment duration, n (%) 12 months >12-24 months >24-36 months First-line ibrutinib (n=135) 29 (1-36) 14 (10) 9 (7) 112 (83) Continuing ibrutinib on study, n (%) 107 (79) Discontinued ibrutinib, n (%) Disease Progression AEs Death Withdrawal of consent Investigator decision 28 (21) 4 (3) 16 (12) 6 (4) 2 (1) 0 Barr, ASH abstract # 233; courtesy P. Barr ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

16 Most Frequent AEs in Ibrutinib Arm Adverse Event, % Grade 1 Ibrutinib Arm (n=135) Grade 2 Grade 3 Grade 4 Grade 5 Any Grade Diarrhea Fatigue Cough Anemia Nausea Peripheral edema Arthralgia Pyrexia Major hemorrhage occurred in 9 (7%) of ibrutinib-treated patients (7 Grade 3, 1 Grade 4) Atrial fibrillation occurred in 14 (10%) of ibrutinib-treated patients (8 Grade 1-2, 6 Grade 3) No PJP occurred Barr, ASH abstract # 233; courtesy P. Barr ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

17 Treatment-Emergent AEs ( Grade 3) Over Time in First-Line Ibrutinib Patients ( 4% Over 29 Months Median Follow-Up) 0-12 months (n=135), % Ibrutinib Arm >12-24 months (n=123), % Grade 3 AEs in 4% of patients over the 29 mo follow-up: neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%) Most Grade 3 AEs in ibrutinib-treated patients decreased over time >24-36 months (n=112), % Neutropenia Pneumonia* Anemia Hypertension Hyponatremia Atrial fibrillation Barr, ASH abstract # 233; courtesy P. Barr ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

18 Acalabrutinib (ACP-196) in relapsed/refractory CLL/SLL Kinase profile of BTK inhibitors ORR 100% Kinase Acalabrutinib Ibrutinib BTK 5.1 ± ± 0.2 BMX 46 ± ± 0.1 ITK > ± 1.2 TEC 93 ± ± 2.5 TXK 368 ± ± 0.3 EGFR > ± 1.3 ERBB2 ~ ± 1.8 ERBB4 16 ± ± 1.3 JAK3 > ± 15 BLK > ± 0.0 PFS (at median follow-up 14 months) Byrd et al, NEJM 2015

19 Acalabrutinib in Patients with Ibrutinib Intolerance (ACE-CL-001): Recurrence of Prior Ibrutinib-Related AEs 12 of 33 (36%) patients with recurrent AE: 14 of 16 events decreased/unchanged in severity. No patients discontinued acalabrutinib because of a prior ibrutinib-related AE. Acalabrutinib in ibrutinib-intolerant patients(nct ); Acalabrutinib vs ibrutinib in R/R high risk CLL (NCT ) Grade Change in Severity on Acalabrutinib vs on Ibrutinib Adverse Event Increased Decreased Unchanged Arthralgia (n = 1) 2 1 Atrial fibrillation (n = 1) 2 2 Contusion (n = 1) 1 2 a Diarrhea (n = 2) Ecchymosis (n = 1) 2 1 a Fatigue (n = 3) 1 2 a Muscle spasms (n = 1) 1 1 Myalgia (n = 1) 1 1 Peripheral edema (n = 1) 1 1 Panniculitis (n = 1) 3 2 a Rash (n = 3) 3 1* a Determined by investigator as related to acalabrutinib a Awan, ASH abstract #638. Courtesy of F. Awan

20 Mutations in BTK and PLCγ2 confer ibrutinib resistance 20 of 246 CLL patients (8%) had secondary resistance (>6months on therapy); eight with transformation. Acquired mutations in six patients: C481S mutation in five, activating mutations in PLCg2 in two Woyach, NEJM 2014; Furman, NEJM 2014; Liu, Blood 2015 Wiestner, Haematologica 2015

21 Discontinuation of ibrutinib and survival (OSU experience) Survival Probability Patient disposition Overall survival after discontinuation Other Event: Infection (n = 31) Other Event: Not Infection (n = 44) CLL Progression (n = 55) Transformation (n = 28) On study PD TF Months from Ibrutinib Discontinuation Months from Ibrutinib Discontinuation Woyach, ASH abstract # 55; courtesy J. Woyach

22 BTK and PLCG2 mutations arise many months before clinical relapse Transformation Months from Start of Ibrutinib Ahn, AACR 2016 Ahn, Underbayev et al, Blood 2017 Woyach, ASH abstract # 55; courtesy J. Woyach

23 CD19+ CAR T-cell Therapy (JCAR014) for High-Risk CLL Turtle, ASH abstract # 56; courtesy C. Turtle

24 Turtle, ASH abstract # 56; courtesy C. Turtle

25 PFS by MRD status in responding patents Turtle, ASH abstract # 56; courtesy C. Turtle

26 Turtle, ASH abstract # 56; courtesy C. Turtle

27 Venetoclax (ABT-199) Venetoclax is an orally bioavailable, selective BCL2 inhibitor, directly inducing apoptosis in CLL cells independent of p53 1 Increased BCL-2 Expression Venetoclax Binds to and Apoptosis is Initiated Allows Cancer Cell to Survive Inhibits Overexpressed Apoptosome BCL-2 Venetoclax Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) 2 BH3-only BAX BAK BCL-2 BCL-2 3 APAF-1 Cytochrome c Active Caspase Procaspase Mitochondria Mitochondria Mitochondria First-in-human study of venetoclax showed a 79% ORR in relapsed/refractory CLL (Roberts AW et al., NEJM 2015) 27

28 n = 107; median follow-up 12.1 months ORR 79%, CR 8% Treatment-emergent adverse events Overall and Progressionfree Survival OS PFS months 22 (24%) of 107 patients had PD 11 Transformation (median 4.7mo) 13 progressive CLL (median 6.3 mo) Stilgenbauer, ASH 2015

29 A r m B A rm A Venetoclax for CLL Patients R/R to Ibrutinib or Idelalisib Median time on study (range): Arm A, 13 months (0.1 18); Arm B, 9 months (1.3 16) # # P D R/R Ibrutinib # # * # # # # # # # P D P D P D P D -R T P D P D P D P D P D P D -R T P D # R/R Idelalisib # P D A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) D is c o n tin u e d # P D P D C R i a s b e s t re s p o n s e * # M R D n e g a tiv e in b lo o d Data as of 10June PD, progressive disease. PD-RT, progressive disease due to Richter's transformation. Early discontinuations were due to AEs (n=3) and withdrawn consent (n=1). T im e o n v e n e to c la x, m o n th s Jones, ASH abstract # 637; courtesy J. Jones

30 P r o g re s s io n -fre e s u rv iv a l (% ) Efficacy and Safety 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%) No clinical TLS was observed; 1 patient with criteria for laboratory TLS Progression-free survival P ro g re s s io n -F re e S u rv iv a l A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) A ll p a tie n ts M o n th s s in c e firs t d o s e Jones, ASH abstract # 637; courtesy J. Jones Grade 3/4 and serious adverse events Event, n (%) All Patients N=64 Grade 3/4 AEs 53 (83) Common grade 3/4 AEs ( 10% patients) Neutropenia Thrombocytopenia Anemia Decreased WBC Febrile neutropenia Pneumonia 29 (45) 18 (28) 14 (22) 8 (13) 7 (11) 7 (11) Serious AEs 34 (53) Febrile neutropenia Pneumonia Multi-organ failure Septic shock Increased potassium 6 (9) 5 (8) 2 (3) 2 (3) 2 (3)

31 Progression-free survival Progression-free survival 79% not reached 21 months 13 months 24% 11 months Chanan-Khan et al, Lancet Oncol 2015 Zelenetz et al, Lancet Oncol 2017

32 Obinutuzmab, Ibrutinib, & Venetoclax in R/R CLL: Phase 1b results of phase 1b/2 study: C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 Cycle = 28 days Obinutuzumab 1000 mg IV Ibrutinib 420 mg daily PO Venetoclax (cohort dose) mg daily PO Response assessed (CT + BMBx) After Cycle 8 2 months beyond end Cycle 14 Drugs initiated sequentially to limit risk for tumor lysis syndrome (TLS) All patients discontinue treatment after Cycle 14 Sequential cohorts of 3 underwent dose escalation to target venetoclax dose in Cycle 3 to establish MTD of venetoclax in combination Jones, ASH abstract # 639; courtesy J. Jones

33 Adverse Events Grade 3 Response (before cycle 9) Adverse Event No (%) Patient Response MRD (%) in PB Hypertension 3 (25) Hypophosphatemia 3 (25) Fatigue 2 (16.7) Thrombocytopenia 2 (16.7) Headache 1 (8.3) Infusion Related Reaction 1 (8.3) AST Increased 1 (8.3) Flu-like Symptoms 1 (8.3) Hypokalemia 1 (8.3) Abdominal Pain 1 (8.3) Blood Bilirubin Increased 1 (8.3) Hypocalcemia 1 (8.3) aptt Prolonged 1 (8.3) Stomach Pain 1 (8.3) No DLT at any venetoclax dose level No TLS observed Ven 100 Ven 200 Ven 400 PR 0.00 PR 0.00 PR 1.70 PR 1.00 PR 0.00 CR 0.00 PR 0.00 PR 0.00 CR 0.10 PR 0.00 ne ne Jones, ASH abstract # 639; courtesy J. Jones

34 CLL2-BIG: BENDAMUSTINE FOLLOWED BY GA101 & IBRUTINIB FOLLOWED BY IBRUTINIB & GA101 MAINTENANCE Bendamustine cycles 1-2: day 1 & 2: 70mg/m² i.v. (if absolute lymphocyte count /µl and/or lymph nodes 5cm) GA101 cycle 1: day 1, 8, 15: 1000mg i.v. cycles 2-6: day 1: 1000mg i.v. Ibrutinib cycles 2-6: days 1-28: 420mg p.o. GA101 cycles 1-8: day 1: 1000mg i.v. Ibrutinib: cycles 1-8: 420mg p.o. Median age: 66 years (range 36-83) First-line (FL): N = 30; Relapse/refractory (RR): N = 31 ECOG: 0-1 v Treschkow, ASH abstract # 640; slide courtesy B. Eichhorst

35 Adverse Events Adverse Events Neutropenia 14.8% Thrombocytopenia 13.1% Infusion related reaction (IRR) 4.8% Pneumonia 3.3% Acute vestibular syndrome 1.6% Anemia 1.6% Bursitis 1.6% Cholestasis 1.6% Cluster headache 1.6% Febrile infection 1.6% Headache 1.6% Inguinal hernia 1.6% Lymph node abscess 1.6% Nodule 1.6% Pancreas infection 1.6% Seroma 1.6% Tumor lysis syndrome 1.6% Induction response ORR = 100% (n=61) FL (%) RR (%) N (%) CRu 13 (43) 15 (48) 28 (46) PR 17 (57) 16 (52) 33 (54) MRD FL (%) RR (%) N (%) Negative (< 10-4 ) 16 (53) 13 (42) 29 (48) v Treschkow, ASH abstract # 640; slide courtesy B. Eichhorst

36