Ivosidenib induces durable responses in relapsed, refractory acute myeloid leukemia

Ivosidenib induced durable remissions among patients with IDH1-mutated relapsed or refractory acute myeloid leukemia, according to study results published in The New England Journal of Medicine.

Somatic IDH1 and IDH2 mutations occur in multiple tumor types, including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma.

Courtney D. DiNardo, MD, MSCE, assistant professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues conducted a phase 1 dose escalation study to assess ivosidenib (Agios Pharmaceuticals) — an oral, targeted, small molecule inhibitor of mutant IDH1 — for patients with IDH1-mutated AML.

The primary efficacy population included 125 patients with relapsed or refractory disease, all of whom received 500 mg daily ivosidenib and had a minimum 6 months of follow-up.

Approximately one in five (21.6%; 95% CI, 14.7-29.8) patients achieved complete remission, and nearly one-third (30.4%; 95% CI, 22.5-39.3) achieved complete remission or complete remission with partial hematologic recovery. Researchers reported a 41.6% (95% CI, 32.9-50.8) overall response rate.

Median duration of complete remission or complete remission with partial hematologic recovery was 8.2 months (95% CI, 5.5-12), median duration of complete remission was 9.3 months (95% CI, 5.6-18.3), and median duration of overall response was 6.5 months (95% CI, 4.6 to 9.3).

Seven (21%) of the 34 patients who achieved complete remission or complete remission with partial hematologic recovery had no residual detectable IDH1 mutations on digital polymerase chain reaction assay. No pre-existing single gene mutation predicted response to treatment.

Eighty-four patients were dependent on red cell transfusion, platelet transfusion or both at baseline. Of these, 29 (35%) achieved transfusion independence.

Twenty-three (56%) of the 41 patients who were transfusion independent at baseline maintained that independence for 56 days or longer during treatment.

The most common grade 3 or higher adverse events included QT interval prolongation (7.8%), IDH differentiation syndrome (3.9%), anemia (2.2%), thrombocytopenia (3.4%) and leukocytosis (1.7%).

Patients who achieved response appeared less likely than those who did not respond to develop infections or febrile neutropenia.

“Among patients with high-risk, molecularly defined relapsed or refractory AML, ivosidenib monotherapy was associated with a low rate of grade 3 or higher treatment-related adverse events, ... induced deep and durable remissions, and led to favorable outcomes as compared with historical outcomes in patients with advanced relapsed or refractory AML,” DiNardo and colleagues concluded. – by Andy Polhamus

Disclosures: Agios supported this study. DiNardo reports grant support and personal fees from Agios and Celgene, as well as personal fees from Bayer and Novartis outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.