ASCO: Nearly 80% Response to Ivosidenib + Azacitidine in IDH1 mutated-AML

By Annette M. Boyle, /alert Contributor
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The combination of ivosidenib and azacitidine received breakthrough therapy designation for treatment of newly diagnosed IDH1-mutated acute myeloid leukemia (AML) from the FDA in March based on preliminary results of a phase I/II trial that showed a 78% objective response rate. More details from the study were  presented at the American Society of Clinical Oncology 2019 Annual Meeting in Chicago.

Ivosidenib is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1). IDH1 produces a metabolite which appears to contribute to the development of AML by interfering with cellular metabolism and epigenetic regulation. Ivosidenib received approval as a monotherapy for treatment of patients with relapsed or refractory IDH1 mutated-AML last year.


Leukemia cell. Source: Getty

Azacitidine is an analog of cytidine, a nucleoside in DNA and RNA, which is commonly used to treat AML and myelodysplastic syndrome, particularly in patients ineligible for stem cell transplantation.

As of October 9, 2018, 23 patients with IDH1-mutated AML had received the ivosidenib/azacitidine combination therapy for an average of 11 months; 12 patients remained on therapy at data cutoff. The median age of participants was 76 and 11 participants were male.

Eighteen patients responded to the therapy, for an objective response rate of 78%. Complete response was achieved in 13 patients (57%) and three patients (13%) had complete response with partial hematologic recovery, for a combined rate of 70%.

Among the 13 complete responders, nine demonstrated mutated IDH1 clearance, as did one patient with complete response with partial hematologic recovery. Clearance was determined by a sensitive digital polymerase chain reaction (PCR) assessment of mutated IDH1 allele frequency in bone marrow or peripheral blood mononuclear cells.

Patients responded to therapy at a median of 1.8 months and achieved complete response in 3.5 months, on average. The median duration of response had not been reached at the time of data cutoff.

Grade 3 or 4 adverse events in more than 10% of participants included thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolongation (13%_. The researchers said that all-grade cytopenia-related adverse events were infrequent compared to other non-intensive therapies.

Based on these findings, a phase III double-blind, placebo-controlled study of ivosidenib and azacitidine is now enrolling patients.

 

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