Differentiation syndrome (DS), also termed retinoic acid syndrome or all-trans retinoic acid (ATRA) syndrome, is a recognized complication in patients undergoing treatment with newer targeted therapies for acute myeloid leukemia (AML), such as FLT3 and IDH inhibitors.1 Evidence suggests the syndrome results from a severe systemic inflammatory response induced by a variety of inflammatory mediators.2 Prompt detection and management of DS is essential, as early intervention is often effective and rarely requires cessation of AML targeted therapy.1
In a review article published in the American Journal of Hematology, Amir T. Fathi, MD, of the division of hematology/oncology at Massachusetts General Hospital Cancer Center in Boston, MA, and colleagues, summarized current literature surrounding the diagnosis and management of DS in patients with AML treated with lower-intensity therapies.1
Differentiation Syndrome in AML
The clinical presentation of DS is similar to that of acute promyelocytic leukemia (APL). Signs and symptoms can include respiratory complications, such as hypoxia, dyspnea, pulmonary infiltrates, or pleuropericardial effusion; extrapulmonary manifestations can include hypotension, fever or leukocytosis in the absence of infection, acute renal failure, rash, or edema-related weight gain. DS has not been observed with conventional cytotoxic treatment regimens, but has been identified in smaller groups of patients undergoing treatment with newer, lower-intensity targeted therapies. At present, the mechanisms underlying DS remain poorly understood.1
DS has been reported in approximately 10% to 20% of patients with AML treated with IDH inhibitors, and less frequently with FLT3 inhibitors. There have also been some reports of DS with hypomethylating agents.1
While the onset of DS in patients with APL treated with ATRA or arsenic trioxide is typically rapid, DS symptoms observed among AML patients treated with lower-intensity therapies is often delayed, ensuing weeks to months post-treatment initiation. DS may occur concomitantly with evidence of clinical response (eg, blood blast counts declining and maturing myeloid cells increasing in the peripheral blood), resulting in inflammation, effusions, and edema manifesting as a DS event.1
Diagnosis and Management
Currently, there are no formally established guidelines for DS diagnosis in AML.1 In addition, grading of DS has not been standardized, but is needed as greater severity of DS has been associated with increased mortality.1,2 Given the heterogeneous nature of DS, the presenting signs and symptoms are similar to those observed with cardiac complications, infections, or AML disease progression, posing challenges in the accurate diagnosis of DS.1
With respect to treatment, rapid administration of corticosteroids (eg, dexamethasone, 10 mg twice daily until resolution of symptoms) is typically effective and carries limited risk in the event an alternate diagnosis is established. Hydroxyurea (2-4 g/day orally, with titration as needed) may also be given if concomitant leukocytosis is present. If symptoms do not improve following treatment with corticosteroids, other differential diagnoses should be considered, including thromboembolism, heart failure, pulmonary hemorrhage, or infection. Hospitalization may be necessary for patients with severe renal or pulmonary complications.1
Discontinuation of FLT3 or IDH inhibitors is unlikely to be effective in the short term due to their extended half-lives, although may be considered in those requiring hospitalization for severe DS. Recent evidence suggests that DS does not necessitate permanent cessation of treatment, but rather, dose or schedule alterations may be more appropriate, particularly in those that do not initially respond to corticosteroids.1
For more details on the management of DS, readers should refer to the full publication in the American Journal of Hematology.1
Expert Perspective: Novel Therapies for AML
“I’m hopeful there will be a series of regulatory approvals of novel, effective agents for AML in the next several years,” commented lead author Amir T. Fathi, MD.
“Any additional effective options for our patients would be very welcome,” Dr Fathi further explained.
Disclosure: Some guideline authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
- Fathi AT, Stein EM, DiNardo CD, Levis MJ, Montesinos P, de Botton S. Differentiation syndrome with lower-intensity treatments for acute myeloid leukemia. Am J Hematol. 2021;96(6):735-746. doi:10.1002/ajh.26142
- Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059. doi:10.4084/MJHID.2011.059