Scientific Publications by FDA Staff

Clin Cancer Res 2020 May 11 [Epub ahead of print]

Differentiation syndrome with ivosidenib and enasidenib treatment in patients with relapsed or refractory IDH-mutated AML: a U.S. Food and Drug Administration systematic analysis.

Norsworthy KJ, Mulkey F, Scott EC, Ward AF, Przepiorka D, Charlab R, Dorff SE, Deisseroth A, Kazandjian D, Sridhara R, Beaver JA, Farrell AT, de Claro RA, Pazdur R

PURPOSE: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1 and IDH2-mutated acute myeloid leukemia (AML), respectively. EXPERIMENTAL DESIGN: During U.S. Food and Drug Administration review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria and narratives were reviewed to adjudicate DS cases. RESULTS: We identified 72/179 (40%) potential cases for ivosidenib and 86/214 (40%) for enasidenib; 34/179 (19%) and 41/214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1-78) and 19 (1-86) days. Grade >/= 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts >/= 48% and peripheral blood blasts >/= 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery (CRh) rates were lower in patients with vs without DS (ivosidenib 18% [95% CI 7-35%] vs 36% [28-45%]; enasidenib 18% [7-33%] vs 25% [18-32%]). CONCLUSIONS: DS is a common and potentially fatal adverse reaction of IDH inhibitors and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.