Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy

Abstract

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.

Figure 1.

Patients’ status in the study by treatment group. Swimmers plot depicts the duration of venetoclax therapy, where each bar represents a patient. The primary reasons for discontinuation of venetoclax were CLL progression (indicated as PD), Richter’s transformation (indicated as PD-RT), elective discontinuation to proceed to allogeneic stem cell transplantation in response, patient noncompliance, and 1 patient with well-controlled preexisting ITP whose ITP required treatment that did not allow for continuation on study (indicated as other).

Figure 2.

Progression-free survival for patients with CLL progressing after idelalisib who are treated with venetoclax. Shown is the Kaplan-Meier curve for investigator-assessed progression-free survival for all 36 patients from the main and expansion cohorts. Below the curve is the number of patients at risk for the event at each time. Tick marks represent patients censored for each outcome measure.

Figure 3.

Percentage of patients with MRD negativity in peripheral blood. Eight patients (all PR) assessed were MRD negative in the peripheral blood, with 2 of these patients demonstrating subsequent bone marrow MRD negativity (the 6 other patients have not yet had bone marrow assessments). Shown are the percentage of patients with MRD negativity in peripheral blood based on all 36 patients (intent-to-treat), as well as for 4 patients who achieved CR/CRi as best response and 16 patients who achieved PR as best response.