Presentation on theme: "Supported by The Leukemia and Lymphoma Foundation Targeting Bcl-2 in CLL Asher Chanan-Khan, MDJennifer R Brown, MD PhD Professor of Medicine Director,"— Presentation transcript:
Supported by The Leukemia and Lymphoma Foundation Targeting Bcl-2 in CLL Asher Chanan-Khan, MDJennifer R Brown, MD PhD Professor of Medicine Director, CLL Center, DFCI Mayo Clinic FloridaAssociate Professor, Harvard
Bcl-2 (B-cell lymphoma 2) First detected in Follicular NHL having t(14;18) Translocation results in overproduction of Bcl-2 anti-apoptotic protein t(14;18) rarely seen in CLL, though Bcl-2 is overexpressed in ~80% of cases Bcl-2 prevents Bax/Bak pro-apoptotic executioner molecules Dysregulated expression counters physiologic apoptosis Bcl-2 protein bound to portion of Bax
Bcl-2 family proteins govern the decision to undergo mitochondrial apoptosis 3 J Clin Oncol. 2012, 30: 3127
4 Displacement of Bim from Bcl-2 induces rapid, irreversible cell death J Clin Oncol. 2012, 30: 3127
Bcl-2 Is Expressed in Most Types of Cancer Solid TumorsHematologic Cancers BreastMelanomaSCLCCLL Myeloma LymphomaAMLProstate (HR)Colorectal 1. Lanzafame S et al. Pathol Res Pract Yang H-B et al. Anticancer Res Jiang S-X et al. J Pathol Cerroni L et al. Am J Dermatopathol Sullivan GF et al. Clin Cancer Res Karakas T et al. Ann Oncol Lazaridou A et al. Leukemia Lymphoma Chen X et al. Chin J Oncol Puthier D et al. Leukemia
Bcl-2 expression is increased in and on CLL cells McCarthy et al Mol Med Sep-Oct;14(9-10): mRNA A. B. C.
High Bcl-2 Expression in CLL Is Associated with Lower Survival Cumulative Proportion Surviving Months Faderl et al., Leukemia. 16: , Bcl-2 <3.2 >3.2 Pats P= Died 23 36
Interaction with stromal cells increases anti-apoptotic Bcl-2 proteins in CLL cells Patel et al Leuk Lymph 2014 Apr;55(4): Bcl-2 Bcl-w Mcl-1 Bcl-x L
ABT-263 in Relapsed CLL: Thrombocytopenia is Dose-Limiting Intermittent - 250mgContinuous - 250mg 25 Lead-in dose of 100 mg x 7 days followed by continuous dosing minimizes platelet nadir
Navitoclax induces CLL cell apoptosis in vivo and reduces disease burden Roberts A W et al. JCO 2012;30:
ABT-263 in Relapsed CLL: Efficacy Best Response (N = 29 evaluable) –9 Partial Responses (PR) (1996 NCI-WG or CT of nodes) –ORR:31% (9/29) –19 of 21 pts with elevated ALC had >50% sustained reduction (90%) 11 of 29 pts with nodal disease had PR by CT (38%) Median time on study = 7 months
ABT-263 Phase 1 Study Progression-Free Survival Median PFS = 25 months
Response Correlates with Low MCL-1 and High BIM:MCL-1 or BIM:BCL-2 Ratios MCL-1BIM:MCL1 Ratio BIM:BCL2 Ratio
ABT-263 Slightly Less Potent than ABT-737: Likely Insignificant S Khaw D Huang AW Roberts
Apoptosis In Vitro Is Inhibited in Whole Blood, by Albumin Binding CCR 2010; 16: M ABT263 1M1M
Co-Culture with CD154 + Fibroblasts Leads to ABT-737 Resistance M Davids, J Brown, A Letai, unpublished data
ABT-199: Selective Bcl-2 small molecule inhibitor Developed by structure-based NMR- guided design using ABT-263 as a scaffold Potently binds Bcl-2 with a K i of 0.010nM Causes less thrombocytopenia than ABT-263 (due to less selectivity for Bcl- xL) Oral availability (daily dose schedule) Currently being investigated in phase III trials in CLL, Non-Hodgkin's lymphoma and multiple myeloma ABT-199 ABT-263 Bcl-2 Souers AJ et al. Nat. Med. (Vol.19) 2013; Seymour JF et al. ASCO 2013, Abstract #7018
ABT-199 Dosing Schema Daily ABT-199 doses increased weekly to the designated cohort dose (DCD) Initial Ramp-Up Schema: Dose Escalation Ramp-Up Schema: Expanded Safety Cohort * 3 patients (1 each in cohorts 2, 3, & 5) received ABT mg as initial dose ** Step-up doses range from 100 to 400 mg # DCD ranges from 150 to 1200 mg
Patient Characteristics (n=105) CharacteristicsAll CLL/SLL Age, yMedian66 [36 – 86] Bulky nodes, n (%)≥5 cm58 (55) ≥10 cm17 (16) Number of prior therapies Median4 [1 - 11] IGHV mutation statusUnmutated36/48 (75) 17p StatusDeleted23 (22) Not Deleted49 (47) Missing9/24 (31) Fludarabine, n (%)Prior Treatment 87 (83) Refractory62 (59)
Best Percent Change from Baseline in Blood Lymphocyte Count and Nodal Mass by CT Scan Nodal Mass by CT Scan (n= 93) The median time to 50% reduction 1.4 months, range [0.65 – 13.7]* 78 (84%) evaluable patients had at least a 50% reduction in sum of the product of diameters (SPD) of nodal masses *coincides with first protocol specified CT scan at 6 weeks. 30 Blood Lymphocytes (n=60) Median Time to 50% reduction: 14 days, range [1 – 49] Data represents patients with lymphocyte count >5 x 10 9 /L at baseline Cohort Dose (mg)
Best Percent Change from Baseline in Bone Marrow Infiltrate (n=51) Median time to 50% reduction: 5.5 months, range [1.9 – 17.4]* 46/51 (90%) evaluable patients have had at least a 50% reduction. Anti-tumor activity of ABT-199 was observed in all tumor compartments. # ^ # Patient had 70% infiltrate at baseline and at Week 24 ^Patient did not have CLL infiltrate at baseline.
Objective Responses of ABT-199 Treated Patients Responses All n (%), n = 78 del (17p) n (%), n = 19 F-Refractory n (%), n =41 IGHV Unmutated n (%), n =24 Overall response60 (77)15 (79)31 (76)18 (75) Complete response (CR/CRi) # 18 (23)5 (26)9 (22)7 (29) Stable disease10 (13)2 (11)7 (17)2 (8) Disease progression2 (3)1 (5)1 (3)2 (8) The median duration of response has not yet been reached based on current patient enrollment numbers.
Current Status of Enrolled Patients (n=105; April 9, 2014) Median Time on Study Dose Escalation Patients (all dose levels): 17.1 months, range [0.06 – 29.7] Safety Expansion Patients: 4.7 months, range [0.52 – 9.3] Discontinuations As of April 9, 2014, 105 patients are enrolled and 37 have discontinued for the following reasons: 22 Progressive Disease (of which 15 were from Richter’s) 12 Adverse Events 3 other (1 need for Coumadin, 2 proceeded to alloSCT) Based on the preliminary safety and efficacy profile of ABT-199, 400 mg is currently being explored as the safety expansion dose.
Progression Free Survival (PFS) at 400 mg or Higher Median PFS for patients treated at or above 400 mg has not yet been reached (median follow-up of 5.3 months, range [0.03 – 22]) As of April 9, 2014, the median PFS for all patients is approximately 18 months
BH3 Profiling provides functional confirmation of on target Bcl-2 antagonism and may predict depth of clinical response to ABT-199 Davids, Deng, Letai (unpublished data) p= % cyto C release ABT uM %cyto C release BAD 80 uM BAD vs. ABT-199 Mitochondrial Depolarization R square=0.7465
Dosing Schedule of ABT-199 and Rituximab – Cohorts OR: if one or more electrolytes meet Cairo-Bishop criteria and/or if there is ≥ 30% decrease in ALC with first dose 400mg, 500mg, 600mg and safety expansion cohorts dosed with this schedule
37 Current Status of Evaluable Patients (April 16, 2014 cut-off) Median time on study = 7.5 months, range [ ] Original Dosing Regimen = 13.3 months, range (1.5 – 19.6) Amended Dosing Regimen = 5.1 months, range (0.03 – 9.2) Active patients, SE = Safety Expansion Discontinuations 7 out of 45 patients Progressive Disease (n = 5) Richter’s transformation (4) Progressive CLL (1) Adverse Event (n = 1) Fatal tumor lysis Withdrew Consent (n = 1)
Responses of Patients treated with ABT- 199 and Rituximab Response Evaluable Patients n=25 (%) Overall Response21 (84) CR (n=4)/ CRi (n=5)*9 (36) Disease progression1 (4) Discontinued prior to M7 assessment # 2 (8 ) Of the 20 patients on study < 7 months (still receiving combination): 5 have a PR, 6 have a PR at first CT; 9 have not yet been evaluated
Complete Remission: Discontinuation of ABT patients have discontinued ABT-199 after achieving CR/CRi (2 with MRD negativity) Patients had 1, 3, and 4 prior therapies; one had fludarabine refractory disease –Patients are continuing follow-up on study –Patients remain in CR at the time of this analysis (8.6, 8.8, and 11.6 months after cessation)
Ongoing Clinical Trial 1. Phase III, randomized study in relapsed/refractory CLL to evaluate the benefit of ABT rituximab vs. BR. 2. Phase 2 study of ABT-199 in patients with relapsed or refractory CLL harboring 17p deletion.
Not just Bcl-2… Zeitlin B D et al. JCO 2008;26:
Potential mechanisms of resistance to ABT-199 Mcl-1 upregulation Stromal mediated resistance Mutations in BCL2 or BAX ABT199 alone (Low BCL2/MCL1 ratio) Touzeau et al Leukemia (2014) 28, 210–212; Soderquist et al J. Biol. Chem. 2014, 289: ; Fresquet et al Blood 2014 Jun 26;123(26):
Summary BCL-2 is a critical survival pathway in CLL BCL-2 family interactions are complex – influenced by multiple family members and the microenvironment –Targeting BCL-XL is problematic in CLL patients ABT199 has profound clinical activity, including in bone marrow clearance –Clinical care required due to TLS Resistance likely to emerge –? Early signal of excess Richter’s transformation