Incidence of Differentiation Syndrome Associated with Treatment Regimens in Acute Myeloid Leukemia: A Systematic Review of the Literature

Abstract

Differentiation syndrome (DS) is a potentially fatal adverse drug reaction caused by the so-called differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), used for remission induction in the treatment of the M3 subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL). However, recent DS reports in trials of isocitrate dehydrogenase (IDH)-inhibitor drugs in patients with IDH-mutated AML have raised concerns. Given the limited knowledge of the incidence of DS with differentiating agents, we conducted a systematic literature review of clinical trials with reports of DS to provide a comprehensive overview of the medications associated with DS. In particular, we focused on the incidence of DS reported among the IDH-inhibitors, compared to existing ATRA and ATO therapies. We identified 44 published articles, encompassing 39 clinical trials, including 6949 patients. Overall, the cumulative incidence of DS across all treatment regimens was 17.7%. Incidence of DS was notably lower in trials with IDH-inhibitors (10.4%) compared to other regimens, including ATRA and/or ATO (15.4–20.6%). Compared to other therapies, the median time to onset was four times longer with IDH-inhibitors (48 vs. 11 days). Treating oncologists should be mindful of this potentially fatal adverse drug reaction, as we expect the current trials represent an underestimation of the actual incidence.

Differentiation therapy for myeloid malignancies: beyond cytotoxicity

“…Clinical DS has been a relatively commonly reported adverse event at 18% for ivosidenib [ 92 ] and 7% for enasidenib [ 55 ]. Compared to the DS seen with ATO-ATRA therapy in APL, the median time to onset is significantly longer (48 vs. 11 days), though the clinical presentation and management are similar [ 93 ]. The mechanism by which the IDH inhibitors are thought to act is by suppressing production of the oncometabolite 2-hydroxyglutarate (2-HG), which is produced by the mutant enzyme [ 94 ].…”

Case report: High-risk acute promyelocytic leukemia and COVID-19-related myocarditis one patient, two cytokine storms

“…described the first case series of 9 patients diagnosed with ATRA syndrome ( 16 ). Its pathophysiology is still incompletely understood and its clinical manifestations are highly polymorphic; they include unexplained fever, pulmonary infiltrates and respiratory distress, renal failure, rapid weight gain, cardiac failure, hypotension, pleural and pericardial effusions ( 17 ). The pathogenesis of DS is complex and is characterised by the release of pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor(TNF)-alpha) by differentiating blasts cell, resulting in a systemic inflammatory response syndrome (SIRS), capillary leak syndrome, and endothelial damage ( 18 , 19 ).…”

Molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and potential treatment strategies

“…Accumulating evidence suggests that tumors carrying IDH mutations may be sensitive to IDH inhibitors. Two IDH inhibitors, Idhifa and Tibsovo, have been approved by the US Food and Drug Administration (FDA) for the treatment of AML or Cholangiocarcinoma 45 . Currently, several clinical trials evaluating treatment therapies of IDH inhibitors against NSCLC are ongoing.…”

“…Two IDH inhibitors, Idhifa and Tibsovo, have been approved by the US Food and Drug Administration (FDA) for the treatment of AML or Cholangiocarcinoma. 45 Currently, several clinical trials evaluating treatment therapies of IDH inhibitors against NSCLC are ongoing. Specifically, various other approaches, including hypermethylated drugs, kinase inhibitors, immunotherapy, and combination therapy, are being evaluated.…”