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.
Highlights
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) drugs, which control cellular differentiation and proliferation
In the 39 clinical trials included in the systematic review, we identified a total of 6949 patients
We examined the incidence of DS with all differentiating agents, enabling an assessment of the incidence with the isocitrate dehydrogenase (IDH)-inhibitors compared to older existing therapies traditionally used in acute promyelocytic leukemia (APL) treatment
Summary
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) drugs, which control cellular differentiation and proliferation. The primary use of ATRA and ATO is for remission induction in treating the M3 subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) [1,2]. If treated early with the recommended induction therapy, consisting of ATRA and an anthracycline (idarubicin or daunorubicin) or ATRA and ATO, APL is a highly curable disease [5]. Despite the dramatic impact of ATRA and ATO in the treatment of APL, the causes of treatment failures during induction therapy include fatalities resulting from hemorrhage and infection as general complications of chemotherapeutic therapy. The adverse drug reaction DS is a serious and specific complication that can result from ATRA treatment of APL. While approximately half of early APL deaths are attributable to hemorrhage due to coagulopathy, DS remains one of the most frequently cited causes of death [6]. Up to a quarter of APL patients will experience DS during their treatment, yet evidence on the pathophysiology, epidemiology, predictive factors, and prevention is still scarce [1,7,8]
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