Ivosidenib Safe, Efficactive in Early Myelodysplastic Syndrome Trial

By Andrew John, MD /alert Contributor
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Monotherapy with ivosidenib was efficacious and well-tolerated in patients with myelodysplastic syndrome, according to interim findings presented at the 63rd ASH Annual Meeting and Exposition.

“Ivosidenib is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation,” Marie Sebert, MD, PhD, of the Department of Clinical Hematology, at Hôpital Saint Louis, Paris, France, and colleagues wrote. “Little is known on its efficacy in patients with IDH1 mutated MDS.”

The researchers performed a phase 2 trial of the efficacy and tolerability of ivosidenib in 32 patients with IDH1-mutated myelodysplastic syndrome. Twenty-six patients were evaluable for the main outcome. These patients had been sorted into three cohorts: cohort A consisted of higher-risk patients who failed azacytidine treatment (n = 13), cohort B included higher-risk treatment-naive patients who did not have life-threatening cytopenias (n = 11) and cohort C consisted of patients with lower-risk disease who failed erythropoietin (n = 2).

Sebert and colleagues treated patients in all three cohorts with continuous 28-day cycles of ivosidenib at a dose of 500 mg daily. In cohort B, the researchers added azacytidine after three cycles if patients did not demonstrate IWG 2006 response. The main outcome was hematologic response rate at the 3- and 6-month marks.

Patients were a median of 76 years old, and half were female.

The overall response rate was 69% (n = 18), the researchers reported. Seventeen patients had a response after three cycles. Of those who responded, 12 patients had a complete response. Seven patients in cohort A (54%), 10 (91%) in cohort B and one (50%) in cohort C experienced responses. Three patients in cohort A achieved a complete response, compared with eight in cohort B and one in cohort C.

Median follow-up was 9.1 months, Sebert and colleagues wrote. Responders had a median duration of 7.4 months of response. Of these, nine patients lost their response, whereas two more died without losing their response -- one following HSCT and another from bleeding.

Researchers reported that 12 patients progressed by the time of data cutoff. Nine of these were in cohort A, two were in cohort B and one was in cohort C. Eleven patients (42%) had died by this time, 10 of whom were in cohort A and one of whom was in cohort C. Five died of relapse or disease progression, one died of suicide, one of infection, one of hemorrhage and three of other unrelated causes.

The overall median OS was 14 months: 7.7 months in cohort A and not reached in cohort B, the researchers wrote.

Differentiation syndrome was the most common adverse event, the researchers reported. One patient died of this event, and three more had their issues resolved without further complication. One patient experienced febrile neutropenia related to the study drug; however, this was also resolved without sequelae.

“Ivosidenib was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, Ivosidenib was particularly effective in treatment-naïve higher risk MDS patients with IDH1 mutations (cohort B),” Sebert and colleagues wrote. “These encouraging preliminary results have to be [confirmed] in more patients.”

Disclosure: Sebert reports consulting roles with Abbvie and BMS. See the abstract for all authors’ relevant financial disclosures.


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