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.

Venetoclax for chronic lymphocytic leukaemia patients who progress after more than one B‐cell receptor pathway inhibitor

“…All 28 patients experienced at least one AE, and safety profile was consistent with prior reports of venetoclax monotherapy in R/R CLL (Coutre et al , ; Jones et al , ). Common AEs included grade 1/2 gastrointestinal toxicities and grade 3/4 cytopenias.…”

“…B‐cell receptor signalling pathway inhibitors (BCRi) have changed the treatment paradigm for chronic lymphocytic leukaemia (CLL), with durable responses achieved with ibrutinib monotherapy (Bruton tyrosine kinase inhibitor [BTKi]) (https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf, Burger et al , ) and idelalisib (phosphatidylinositol‐3‐kinase inhibitor [PI3Ki]) with rituximab or ofatumumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf, Byrd et al , ; Furman et al , ). For patients with progressive disease (PD) who have exhausted all available BCRi, treatments have only recently been characterized in prospective studies (Coutre et al , ; Jones et al , ).…”

“…The oral BCL2 inhibitor venetoclax has shown promising efficacy across clinical studies in relapsed/refractory (R/R) CLL and, based on the critical need for therapies following BCRi discontinuation, we report on a post‐hoc subgroup analysis of high‐risk patients who previously received BTKi and PI3Ki (>1 prior BCRi) from a phase 2 study of venetoclax in patients with CLL R/R to ibrutinib and/or idelalisib (Coutre et al , ; Jones et al , ).…”

“…This phase 2, open‐label trial (NCT02141282) enrolled patients with R/R CLL to ibrutinib and/or idelalisib, although prior investigational BTKi or PI3Ki were also allowed (Coutre et al , ; Jones et al , ). Patients in this post‐hoc analysis received >1 prior BCRi, including 16 who received BTKi then PI3Ki, nine who received PI3Ki then BTKi, two who received two BTKi, and one who received PI3Ki, then BTKi, then another PI3Ki (Table ).…”

“…Of 127 patients enrolled (Coutre et al , ; Jones et al , ), 28 received >1 prior BCRi (Table ), with a median follow‐up on venetoclax of 11·8 months (range: 0·1–30·6) for 28 patients who received >1 prior BCRi; this was 13·9 months (0·2–30·5) for 99 patients who received 1 prior BCRi. Investigator‐assessed objective response rate (ORR) for patients who received >1 vs. 1 prior BCRi was 43% (12/28: 1 CR, 11 partial remission [PR]) vs. 75% (74/99: 10 CR/CRi, 64 PR; Fig A).…”