Serious side effect of AML treatment going unnoticed, FDA warns


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Enasidenib (Idhifa®)

The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).

Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.

The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.

However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.

The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).

However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.

Recognizing differentiation syndrome

The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.

The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.

Symptoms of differentiation syndrome include:

  • Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
  • Pulmonary infiltrates and pleural effusion
  • Fever
  • Lymphadenopathy
  • Bone pain
  • Peripheral edema with rapid weight gain
  • Pericardial effusion
  • Hepatic, renal, and multiorgan dysfunction.

The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.


If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.

Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.

If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.

Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.

Cases of differentiation syndrome

The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.

The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.

Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.

One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.

The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).

With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.

Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).

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