A phase Ib/II study presented at the 2022 American Society of Hematology Annual Meeting found that the combination of decitabine/cedazuridine, venetoclax, and an IDH1 inhibitor was effective in treating IDH-mutated acute myeloid leukemia (AML).
ASTX727 is an oral, fixed-dose combination of decitabine and cedazuridine (35 mg/100 mg) approved for the treatment of myelodysplastic syndromes. This is the first study to assess an all-oral triplet regimen of ASTX727, venetoclax, and either ivosidenib or enasidenib for this patient population.
The study included adult patients with relapsed/refractory IDH1– or IDH2-mutated AML or newly diagnosed AML ineligible for intensive chemotherapy. For this interim report, 32 patients were enrolled in the trial, with three screen failures and two patients still in the first treatment cycle. After a median follow-up of 5.7 months, the results capture data from 27 evaluable patients: 10 patients receiving ivosidenib and 10 receiving enasidenib.
Median patient age at enrollment was 73 years (range, 50-81 years); 44% (n=12) had newly diagnosed disease, and 15 had relapsed/refractory disease. Patients were classified as intermediate (52%) or adverse (44%) risk, per the European LeukemiaNet classification. Patients received a median of four treatment cycles. In the relapsed/refractory cohort, 78% of patients (n=11) previously received a hypomethylating agent, BCL2 inhibitor, and/or IDH inhibitor, with a median of two prior treatment cycles.
The composite remission rate (CRc) was 72% overall, including 100% in the newly diagnosed cohort and 53% in the relapsed/refractory setting. Measurable residual disease-negative CRc by flow cytometry was 65% overall, including 83% in the newly diagnosed setting and 42% in the relapsed/refractory setting. Four patients went on to receive hematopoietic stem cell transplant (two in each cohort).
The researchers noted that there were high rates of MRD-negative CRc, “most notably in de novo patients and relapsed/refractory patients without prior venetoclax exposure.”
The most common non-hematologic grade 3/4 adverse event was hyperbilirubinemia (n=2; 7%). Two patients had possible/probable differentiation syndrome that resolved with treatment. Two episodes of reversible grade 1 tumor lysis syndrome also occurred. The 60-day mortality was 8% (n=1) in the newly diagnosed cohort and 0% in the relapsed/refractory group. One newly diagnosed patient withdrew from the study and went home on hospice after admission for febrile neutropenia.
Study enrollment is ongoing, the authors noted.
Atluri H, Maiti A, Sasaki K, et al. Phase Ib/2 study of oral decitabine/cedazuridine (ASTX727) and venetoclax in combination with targeted mutant IDH1 inhibitor ivosidenib or the targeted mutant IDH2 inhibitor enasidenib in IDH mutated acute myeloid leukemia. Abstract #2746. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.