Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study

Abstract

Purpose: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.

Patients and methods: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m² per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).

Results: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).

Conclusion: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

Trial registration: ClinicalTrials.gov NCT02287233.

FIG 1.

Complete remission (CR)/CR with incomplete blood count recovery (CRi) rates by patient subgroups. The graph shows the rates of CR and CRi in all patients, as well as key patient subgroups sorted by baseline characteristics. The numbers in the bars represent the percentage of patients with a given response, and the black number at the top of each bar is the total CR/CRi percentage in a given subgroup. Partial remissions are not shown, because only one patient had a partial remission. AML, acute myeloid leukemia; HMA, hypomethylating agent; intrmed, intermediate.

FIG 2.

Overall survival and duration of response. Kaplan-Meier curves showing (A) duration of remission for patients who had complete remission (CR)/CR with incomplete blood count recovery (CRi); (B) overall survival of all patients; (C) overall survival broken down by the patients’ best response; (D) overall survival by prior hypomethylating agent (HMA) exposure. NOTE: Numbers in parentheses are 95% CIs. DS, discontinued prior to assessment; LDAC, low-dose cytarabine; MLFS, morphologic leukemia–free state; NA, not available; NR, not reached; PD, progressive disease; PR, partial remission; RD, resistant disease; Ven, venetoclax.