"How I treat” differentiation syndrome associated with differentiating-agent therapy in AML

Many novel AML therapies exert their antileukemic effects by restoring aberrant leukemogenic differentiation.¹ Differentiating agents such as ATRA/ATO, IDH-1, FLT3, and menin inhibitors generally cause less myelosuppression and fewer typical chemotherapeutic side effects, such as mucositis and alopecia. However, they are associated with differentiation syndrome (DS; initially termed as retinoic acid syndrome).¹

A “how I treat” case series published by Issa et al.¹ in Blood discusses management approaches of DS associated with differentiating agents in the treatment of patients with AML. 

Key learnings

Early recognition of DS is crucial. The most common manifestations of DS include pulmonary issues (dyspnea, hypoxia, pulmonary infiltrates, and pleural ± pericardial effusions), weight gain, fever, hypotension, and renal insufficiency.

The treatment of DS involves prompt initiation of systemic corticosteroids, with tapering as symptoms resolve. Concurrent cytoreduction with HU, Ara-C, and GO is used to prevent leukostasis, including DIC. In severe DS, targeted therapies should be discontinued until symptoms resolve.

Prophylactic administration of corticosteroids is recommended to prevent/minimize DS in APL, but not outside of APL. Patients with relapsed AML should undergo cytoreduction before initiating targeted therapies to minimize the incidence and severity of DS and leukostasis, including DIC.

Further studies are needed to gain a deeper understanding of the underlying mechanisms of DS, establish diagnostic criteria specific to novel differentiating agents, and determine optimal therapeutic strategies to further reduce DS-related morbidity and mortality.