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.

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

“…12 These findings prompted evaluation of venetoclax in combination with an HMA (azacitidine or decitabine; NCT02203773) or LDAC (NCT02287233) in patients 65 years of age or older newly diagnosed with AML and not eligible for standard induction therapy. Results from these studies 13,14 demonstrated that the combination of venetoclax with an HMA or LDAC leads to higher overall response rates (ORRs) than those reported for either LDAC or HMA alone. Both combinations were granted breakthrough designations and were approved by the United States Food and Drug Administration (FDA) under accelerated approval pathway.…”

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

“…With regards to its cancer relevance, another interesting miR-16 target that has been established is the anti-apoptotic protein Bcl2 (40). Bcl2 inhibitors are currently being introduced as potential therapeutic tools in AML (41), and interestingly, a synergy between venetoclax and the FLT3-inihibitor quizartinib has been described (42). It would be interesting to establish whether miR-16-dependent regulation of Bcl2 is involved in this process.…”

New drugs creating new challenges in acute myeloid leukemia

“…In a study of 145 patients, venetoclax plus azacitidine or decitabine produced a CR/CRi in 67%, median OS lasting 17.5 months and 46% were alive at 2 years . Similarly, in study of 82 patients (prior HMA exposure allowed), venetoclax plus LDAC (20 mg/m 2 subcutaneous daily d1‐10) produced a CR/CRi in 54%, median OS lasting 10.1 months and 44% were alive at 1 year . Importantly, responses were achieved rapidly (median ~1 month), with virtually no clinical tumor lysis syndrome and low early (30‐day) mortality (3%‐6%).…”

“…64 In clinical studies, although the selective BCL-2 inhibitor venetoclax has modest activity as monotherapy in R/R AML, 65 were alive at 1 year. 67 Importantly, responses were achieved rapidly 82 This is a promising preliminary efficacy in elderly AML despite the lack of superiority of combination therapy over azacitidine alone in higher-risk MDS. 83 A phase 3 randomized study of pracinostat (or placebo) in combination with azacitidine is currently underway in patients unfit for standard induction chemotherapy (NCT03151408).…”