Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

by Selleckchem | Jun 13 2023

Background: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.

Methods: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.

Results: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.

Conclusions: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Comments:

The study is a phase 2 substudy conducted as part of the Beat AML Master Trial. The aim of the substudy was to evaluate the effectiveness of entospletinib, an oral inhibitor of spleen tyrosine kinase, in combination with decitabine in older patients with newly diagnosed acute myeloid leukemia (AML) who had specific genetic mutations or karyotype abnormalities associated with poor prognosis.

The trial enrolled two cohorts of patients. Cohort A included patients with AML who had tumor protein p53 (TP53) mutations with or without a complex karyotype, while cohort B consisted of patients with AML who had a complex karyotype without TP53 mutation. The treatment regimen for both cohorts involved entospletinib administered at a dose of 400 mg twice daily and decitabine given at a dose of 20 mg/m2 on days 1-10, repeated every 28 days for up to three induction cycles. This was followed by up to 11 consolidation cycles, during which decitabine was reduced to days 1-5. Entospletinib maintenance therapy was administered for up to 2 years.

The primary endpoint of the study was the achievement of complete remission (CR) or CR with hematologic improvement after up to six cycles of therapy. The results showed that the composite CR rates for cohorts A and B were 13.3% and 30.8%, respectively, with corresponding confidence intervals. The median duration of response was 7.6 months for cohort A and 8.2 months for cohort B. Median overall survival was 6.5 months for cohort A and 11.5 months for cohort B. However, due to the crossing of futility boundaries in both cohorts, the study was halted.

In conclusion, the combination of entospletinib and decitabine showed some activity and was tolerable in older AML patients with TP53 mutations and complex karyotype. However, the rates of complete remission were low, and overall survival was relatively short. The study highlights the ongoing need for novel treatment strategies to improve outcomes for older patients with these particular genetic mutations and karyotype abnormalities in AML.