Clinical experience with the <scp>BCL</scp>2‐inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies

Abstract

Abstract Introduction Venetoclax (VEN), a selective BCL2 inhibitor, has single‐agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment‐naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported. Methods All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed. Results Forty‐three patients with median age 68 (range, 25–83) were treated for AML (91%), MDS (5%), or BPDCN (5%). Most ( n = 36, 84%) were ≥ salvage‐2 treatment status, including prior hypomethylating agent (HMA) in 77%. In combination with VEN, most patients received HMA therapy ( n = 31, 72%); eight (19%) received low‐dose cytarabine (LDAC). Patients received a median of 2 treatment cycles (range, 1–4). Objective response was observed in 9 (21%) patients, including 2 complete responses (CR), 3 CRi, and 4 morphologic leukemia‐free state (MLFS). Median survival was 3.0 months (range, 0.5–8.0), and estimated 6‐month survival was 24%. Responses were observed in five (24%) of 21 patients with intermediate‐risk cytogenetics, 3 (27%) of 11 IDH1/2 ‐mutant, and 4 (50%) of 8 RUNX1 ‐mutated patients. Two (20%) of 10 TP53 ‐mutated patients responded; both had concurrent RUNX1 mutations. Of the 3 (15%) responding patients with adverse cytogenetics, all had concurrent RUNX1 mutations. Conclusion Low‐intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1 , and/or IDH1/2 mutations.