Site Editor

Rebecca Olin, MD, MS


Differentiation Syndrome With IDH Inhibitors in Resistant AML: FDA Analysis

By: Sarah Campen, PharmD
Posted: Monday, August 24, 2020

In patients with relapsed or refractory acute myeloid leukemia (AML), the rates of differentiation syndrome—a potentially fatal clinical syndrome associated with the IDH inhibitors ivosidenib and enasidenib—appear to be higher than previously reported in pivotal trials, according to a study published in Clinical Cancer Research. A comprehensive systematic analysis by the U.S. Food and Drug Administration (FDA) retrospectively identified differentiation syndrome in 19% of patients receiving IDH inhibitors using an algorithmic approach, compared with 11% to 14% of patients originally identified.

“Increased recognition of the signs and symptoms of [differentiation syndrome] through the framework of the Montesinos criteria may lead to earlier diagnosis and treatment, which may decrease severe complications and mortality,” stated Richard Pazdur, MD, of the FDA’s Oncology Center of Excellence, and colleagues.

The FDA reviewed data from the pivotal trials to identify cases of differentiation syndrome in patients with relapsed or refractory IDH1- and IDH2-mutated AML treated with ivosidenib (n = 179) and enasidenib (n = 214), respectively. The researchers screened patient adverse events—dyspnea, fever, weight gain, unexplained hypotension, acute renal failure, and pulmonary infiltrates or pleuropericardial effusion on chest x-ray—as well as laboratory abnormalities and vital signs in the first 90 days of treatment to identify those who fulfilled the diagnostic criteria.

In total, cases were adjudicated as differentiation syndrome based on the diagnostic algorithm in 34 patients (19%) treated with ivosidenib and 41 patients (19%) treated with enasidenib. Leukocytosis was present in the majority of cases (79% and 61%), and the median time to onset was 20 and 19 days, respectively. Grade ≥ 3 adverse reactions occurred in 68% and 66% of cases; fatalities were reported in 6% and 5% of cases, respectively. Of note, the rates of complete remission and complete remission with partial hematologic recovery were lower in patients with differentiation syndrome than in those without.

 Disclosure: The authors reported no conflicts of interest.

By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.