Deep and Durable Responses Following Venetoclax (ABT-199 / GDC-0199) Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from a Phase 1b Study

Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy.

Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200–600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous.  Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%).

Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200–600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50–88) years.  The median (range) number of prior regimens was 2 (1–5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease.  Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV.

As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR).  The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR.  4 had SD, 2 had PD, and 1 died before assessment (fatal TLS).  9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2–9) months.  BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall.  Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months.  The median PFS has not been reached.  At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03–32) months. 94% were alive at 12 months; the median OS has not been reached.  Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups.  8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time.  2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4–24) months off VEN.  The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate.

Treatment-emergent AEs in >25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in >10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD.  Key efficacy data are summarized in the table.

Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile.  41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity.  Remission off all therapy has been maintained in pts achieving MRD-negative CR.  The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%.  The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL.  VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471).