Risk-Adapted Study Enhances Response to IDH2-Targeted Therapy for AML


Sheng F. Cai, MD, PhD, discusses the results of the BEAT AML master trial in patients with acute myeloid leukemia.

Sheng F. Cai, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the results of the BEAT AML master trial (NCT03013998) in patients with acute myeloid leukemia (AML).

The phase 1b/2 trial included multiple sub-studies based on genomic screening of patients to receive investigational therapies. In this sub-study, patients with IDH2 mutations were assigned to receive enasidenib (Idhifa) monotherapy; those who did not have a completer remission (CR) or CR with incomplete count recovery (CRi) went on to receive azacitidine in combination with enasidenib.

Cai says that 17 out of 60 patients did not respond adequately to enasidenib and were enrolled in the phase 1b cohort with added azacitidine. Eight out of these 17 achieved a CR or CRi, and some were able to receive allogeneic stem cell transplant.

Patients experienced adverse events such as nausea and electrolyte abnormalities. Differentiation syndrome that was considered serious occurred in over 20% of patients who initially received enasidenib, and several patients also experienced it when receiving the combination. According to Cai, this is an on-target effect of the IDH2 inhibitor. Based on these outcomes, the trial demonstrated the viability of stratifying patients by biomarker into receiving additional targeted therapy.


0:08 | We found that we could, by proof of principle, that we could...do this risk-adaptive method. So those patients that received enasidenib monotherapy had an overall response rate of about 48%, inclusive of CR, CRi, and [CR with partial hematologic recovery]. If you add in those patients that also achieved the morphologic leukemia-free state, the overall response rate in the phase 2 monotherapy cohort, the overall response rate was 50%.

Seventeen out of those patients then had progression of disease and enrolled on the phase 1b cohort, where azacitidine was added, and 8 out of those 17 patients achieved the CR or CRi. And some of those patients were also able to go on to transplant. So overall, this demonstrated that...this trial was feasible to do in a risk-adapted fashion after having identified IDH2 mutation in a newly diagnosed patient cohort.

1:07 | Adverse events included some [gastrointestinal] toxicity, including nausea and electrolyte abnormalities. Interestingly, we also did note differentiation syndrome. So in the phase 2 monotherapy cohort, we saw differentiation syndrome at the rate of about 23%. And for those patients in the phase 1b cohort, we saw differentiation syndrome at the rate of about 17%. Again, consistent with prior report showing that there is an on-target effect...of IDH2 inhibition therapy.

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