Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)

Background: BCRi have transformed treatment for CLL, although patients (pts) who are refractory or relapse (R/R) after these therapies experience poor outcomes. New therapies for pts who have already received available BCRi are urgently needed. VEN is a selective, orally bioavailable BCL-2 inhibitor with activity in heavily pretreated pts with CLL. In this report, we describe outcomes with VEN monotherapy for a subset of pts who received more than one prior BCRi.

Methods: In this Phase 2, open label study, pts with R/R CLL following ibrutinib or idelalisib were enrolled. Pts received VEN starting at 20 mg with stepwise dose ramp up over 5 weeks to the final 400 mg daily dose. Efficacy evaluations were based on 2008 iwCLL criteria.

Results: Of the total 127 pts enrolled in the study, 28 had received more than one prior BCRi (including ibrutinib, idelalisib, and investigational agents). These 28 pts had received a median of 6.5 prior CLL therapies (range: 2-15). Of pts assessed, 36% (10/26) had 17p deletion, 22% (6/27) had TP53 mutation, with two patients who had both 17p deletion and TP53 mutation. 30% (7/23) of patients had unmutated IGHV .

Sixteen pts had received a BTK inhibitor (BTKi) followed by PI3K inhibitor (PI3Ki), 9 received a PI3Ki followed by BTKi, 1 pt received 2 PI3Ki and a BTKi, and 2 pts received two BTKi. Pts received prior ibrutinib for a median of 17 months (range: 2-53) and of 22 pts with available data, best response to ibrutinib of complete remission (CR) was reported for 1 pt, partial remission (PR) in 11 pts, with 10 pts who did not respond to ibrutinib. Of 16 pts with available data for ibrutinib as their last prior BCRi, 1 discontinued prior ibrutinib due to adverse events (AEs) and 15 due to disease progression (PD). Pts received prior idelalisib for a median of 4 months (range: 1-33) and of 20 pts with available data, 8 had a best response to idelalisib of PR and 12 did not respond to idelalisib. Of 12 pts with available data for idelalisib as their last prior BCRi, 5 discontinued prior idelalisib due to AEs, 6 due to PD, and 1 refractory disease. Six pts received the investigational agent acalabrutinib (ACP-196) for a median of 9.4 months (range: 1-23); 2 had a best response of PR, and the 4 others did not respond. Four pts discontinued prior acalabrutinib due to PD, 1 for toxicity, and 1stopped the clinical trial due to BTK resistance.

As of 31 Jan 2017, these 28 pts have been on VEN for a median of 8.5 months (range: 0.1-26). The Investigator-assessed best objective response rate (ORR) was 39% (11/28; 1 CR, 10 PR) for all pts and 50% (11/22) among the 22 pts who had reached the 36-week response assessment. There was no apparent difference in response to VEN for those pts who discontinued prior BCRi for AE or PD. The estimated median progression-free survival was 16.4 months (95% CI: 8, -) and median overall survival was 21.6 months (95% CI: 17.1, -).

Seventeen pts discontinued VEN: 10 due to CLL progression, 2 had Richter's transformation, 2 due to adverse events (AEs), 1 due to investigator request, 1 due to non-compliance, 1 pt proceeded to stem cell transplant in remission. The median time to discontinuation for CLL progression was 7.8 months (range: 0.1 - 22.5) and for two pts with Richter's transformation was 4.4 and 16. 3 months. Thirteen pts went on to receive another CLL therapy after discontinuation of VEN, with a median time to next therapy from the last dose of VEN of 10 days (range: 0 - 188).

The most common AEs in ≥25% of pts receiving VEN were neutropenia (57%), diarrhea (54%), anemia (50%), hypomagnesemia (39%), nausea (36%), hyperkalemia (36%), fatigue (32%), thrombocytopenia (29%), peripheral edema (29%), hypocalcemia (29%), dyspnea (29%), hypophosphatemia (25%), and hyperuricemia (25%). Common Grade 3/4 AEs in ≥15% of pts were neutropenia (43%), anemia (39%), thrombocytopenia (25%), hypokalemia (21%), and hypophosphatemia (21%). Serious AEs were reported for 19 (68%) pts, no specific SAE was observed in more than one pt. None of the pts had TLS per Howard criteria.

Conclusions: VEN is active, with similar safety profile as previously reported, in pts R/R to more than one BCRi. Response rates appear to be lower than those we previously reported in pts who had only one prior BCRi.

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