Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed after or Were Refractory to Ibrutinib or Idelalisib

Background: Patients (pts) with CLL who relapse after or become refractory to B-cell receptor inhibitor (BCRi) therapy experience poor outcomes. VEN is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor with substantial activity in heavily pretreated pts with CLL. VEN monotherapy was evaluated in pts who relapsed after or were refractory to ibrutinib or idelalisib.

Methods: In this Phase 2, open label, two-arm study, pts with CLL who relapsed after or were refractory to ibrutinib (Arm A) or idelalisib (Arm B) received VEN starting at 20 mg with stepwise dose ramp up over 5 weeks to the final 400 mg daily dose. Pts started VEN after a 7-day washout from prior therapy. Disease assessments for efficacy were performed using 2008 iwCLL criteria at weeks 8, 24, and every 12 weeks thereafter for up to 1 year. Minimal residual disease (MRD) in blood was evaluated in a central laboratory by six-color flow cytometry from week 24 (sensitivity ≤10^-4).

Results: As of 10 June 2016, 64 pts were enrolled in the study. Forty-three pts enrolled in Arm A and were on prior ibrutinib for a median of 17 months (range: 1-56), with 39 (91%) refractory to ibrutinib (ie, disease progression on therapy); pts received VEN for a median of 13 months (.1-18). Twenty-one patients in Arm B were on prior idelalisib for a median of 8 months (1-27), with 14 (67%) refractory to idelalisib. These patients received VEN for a median time of 9 months (1.3-16). Twenty pts discontinued VEN (16 in Arm A; 4 in Arm B): 14 due to disease progression, 2 due to AEs (multi-organ failure, respiratory failure [1 each]), 2 underwent stem cell transplant (both had partial remission [PR] prior to discontinuation), 1 withdrew consent, and 1 had pre-existing ITP refractory to interventions. Six pts died during the study (5 in Arm A; 1 in Arm B): 4 due to disease progression, 1 due to respiratory failure, and 1 due to septic shock. All pts experienced at least one AE: the most common AEs in ≥25% of patients were diarrhea (42%), nausea (41%), neutropenia (36%), anemia (36%), fatigue (31%), and decreased platelet count (25%). Common Grade 3/4 AEs in ≥15% of pts were neutropenia (31%), anemia (22%), and thrombocytopenia (16%), Serious AEs in ≥2 pts were febrile neutropenia (6), pneumonia (5), multi-organ failure, septic shock, and increased blood potassium (2 each). One pt who could not receive uric acid reducers had laboratory TLS and another pt had 2 AEs of TLS per investigator, though neither event met Howard criteria for laboratory TLS; no clinical sequelae was reported for either pt.

Thirty-nine pts in Arm A and 21 in Arm B completed week 24 and subsequent assessments. For Arm A, the objective response rate (ORR) by independent review committee (IRC) was 30/43 (70%) and by investigator assessment was 29/43 (67%). For patients in Arm A considered refractory to ibrutinib, ORR was 26/39 (67%) by IRC and 27/39 (69%) by investigator assessment. For Arm B, ORR was 10/21 (48%) by IRC and 12/21 (57%) by investigator assessment; for pts considered in Arm B refractory to idelalisib, ORR was 8/14 (57%) by both IRC and investigator assessment.

At the time of this analysis, neither the median progression-free (13 events) nor overall survival (6 deaths) has been reached. For all patients, estimated 12-month progression-free survival was 72% (95% CI: 57%, 82%) and overall survival was 90% (79%, 96%).

Fourteen of 42 (33%) pts assessed demonstrated MRD-negative peripheral blood between weeks 24-48.

Conclusions: Venetoclax is the first agent to demonstrate robust activity, with good tolerability in pts with CLL progressing during or after treatment with ibrutinib or idelalisib, including a subset who were refractory to these therapies. Low rates of complete response have been thus far observed at an early time point; however, pts will be monitored to determine whether deeper responses are seen, as has been reported in prior VEN trials in CLL. Extended follow up will also be required to assess the durability of responses with venetoclax in this population.

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