Differentiation syndrome

Differentiation syndrome (DS; originally called “retinoic acid syndrome”) is a potentially fatal complication of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide, treatment of acute myeloid leukemia (AML) with inhibitors of isocitrate dehydrogenase (IDH; eg, IDH2 inhibitor, enasidenib; IDH1 inhibitor, ivosidenib), and treatment of AML with mutant FLT3 (Fms-related tyrosine kinase 3) with gilteritinib.


The clinical presentation, diagnosis, and treatment of differentiation syndrome will be discussed here.



Clinical manifestations, diagnosis, and treatment of APL and an overview of AML are presented separately. (See “Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults” and “Initial treatment of acute promyelocytic leukemia in adults” and “Overview of acute myeloid leukemia in adults”.)






DS occurs in roughly one-quarter of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO), up to one-fifth of patients treated with ivosidenib or enasidenib for acute myeloid leukemia (AML), and a small fraction of those treated with gilteritinib. Factors that predict development of DS are not well defined.


Acute promyelocytic leukemia – DS is reported in approximately one-quarter of patients who are treated with ATRA for APL, but the incidence has ranged from 2 to 48 percent; the wide range in incidence reflects differences in induction regimens, preventive measures, and different diagnostic criteria . For patients treated with ATO for APL, the incidence of DS ranged from 7 to 31 percent . DS can also occur in patients with relapsed APL who were treated with ATRA and/or ATO . The incidence of DS was similar in both arms of a trial in which patients were randomly assigned to ATRA plus ATO versus ATRA plus chemotherapy . DS has not been reported with ATO treatment of non-APL malignancies or during consolidation or maintenance phase of APL, because the syndrome depends on the presence of leukemic blasts and/or promyelocytes .

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