apr-246 and Thrombocytopenia

TP53-mutated acute myeloid leukaemia is associated with poor outcomes. Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. We aimed to evaluate the combination of eprenetapopt and venetoclax with or without azacitidine in patients with TP53-mutated acute myeloid leukaemia.. This phase 1, multicentre, open-label, dose-finding and cohort expansion study was done at eight academic research hospitals in the USA. Inclusion criteria were age of at least 18 years; at least one pathogenic TP53 mutation; treatment-naive acute myeloid leukaemia according to the 2016 WHO classification; an ECOG performance status of 0-2; and a life expectancy of at least 12 weeks. In dose-finding cohort 1 patients received previous therapy with hypomethylating agents for myelodysplastic syndromes. In dose-finding cohort 2, previous use of hypomethylating agents was not permitted. Treatment cycles were 28 days. Patients in cohort 1 received intravenous eprenetapopt 4·5 g/day on days 1-4 and oral venetoclax 400 mg/day on days 1-28; those in cohort 2 also received subcutaneous or intravenous azacitidine 75 mg/m. Between Jan 3, 2020, and July 22, 2021, 49 patients were enrolled across all cohorts. Six patients were initially enrolled into each of dose-finding cohorts 1 and 2; after no dose-limiting toxicities were observed, cohort 2 was expanded to enrol an additional 37 patients. The median age was 67 years (IQR 59-73). 24 (49%) of 49 patients were female and 25 (51%) male, and 40 (82%) were White. At data cutoff (Oct 1, 2021), the median length of follow-up was 9·5 months (IQR 6·1-11·5). No dose-limiting toxicities were recorded and the recommended phase 2 dose for eprenetapopt combinations was 4·5 g/day on days 1-4. Across all patients, adverse events of grade 3 or worse occurring in at least 20% of patients were febrile neutropenia (23 [47%] of 49 patients), thrombocytopenia (18 [37%] patients), leukopenia (12 [25%] patients), and anaemia (11 [22%] patients). Treatment-related serious adverse events occurred in 13 (27%) of 49 patients and there was one (2%) treatment-related death (sepsis). 25 (64%, 95% CI 47-79) of 39 patients had an overall response with eprenetapopt and venetoclax with azacytidine; 15 (38%, 23-55) had a complete response.. Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia.. Aprea Therapeutics.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thrombocytopenia; Treatment Outcome; Tumor Suppressor Protein p53