Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration Systematic Analysis

Abstract

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1-and IDH2-mutated acute myeloid leukemia (AML), respectively.Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases.Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1-78) and 19 (1-86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) þ CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%-35%) vs. 36% (28%-45%); enasidenib 18% (7%-33%) vs. 25% (18%-32%)].Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.

Differentiation therapy of myeloid leukemia: four decades of development

“… 23 , 29 , 41 In contrast to a rapid occurrence of DS in APL (median of 12 days), 38 , 42 , 43 the onset of DS was delayed in patients treated with IDH inhibitors. 23 , 40 , 41 A recent comprehensive analysis concluded that the incidence of DS in IDH inhibitor-treated patients (19%) 40 is similar to the rate observed for ATRA-treated APL ( ∼ 25%). 39 , 42 , 43 This necessitates routine monitoring for DS in patients on IDH inhibitor therapy.…”

“…The most common clinical features of IDH-DS were dyspnea and pulmonary infiltrates or pleuropericardial effusion, while hypotension was the least common symptom. 40 IDH-DS was effectively managed by dose interruption and treatment with glucocorticoids and hydroxyurea. 23 , 29 , 41 In contrast to a rapid occurrence of DS in APL (median of 12 days), 38 , 42 , 43 the onset of DS was delayed in patients treated with IDH inhibitors.…”

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

“…What might further contribute to a lower DS incidence in IDH-inhibitors and retinoic acid derivatives is that three of the four clinical trials were phase 1 and using dose escalation, meaning that part of the patients received very low doses of the differentiating drugs. Since our estimates of the incidence of DS in the treatment with the IDH-inhibitors, ivosidenib and enasidenib, is based on the published phase 1/2 clinical trials, we may be underestimating the real-world incidence and mortality of DS associated with IDH-inhibitors [ 13 , 14 , 91 ].…”

“…Additionally, the delayed time to onset observed in the IDH-inhibitors indicates that either DS develops later in these patients, or there was a delay in clinical detection. A recent systematic analysis by the US FDA conducted an algorithmic analysis to improve the capture of DS cases in patients using IDH-inhibitors as many of the signs and symptoms of DS may not be initially recognized [ 14 ]. The authors concluded that DS was likely common with the IDH-inhibitors, and increased awareness of the early signs and symptoms is needed to decrease the potential for severe or fatal complications.…”

“…Although DS is rare within the overall population, it occurs in up to one-quarter of patients treated with the differentiating agents, ATRA and ATO, making it a highly significant adverse drug reaction in these patients [ 7 ]. More recently, two clinical trials of isocitrate dehydrogenase (IDH)-inhibitor drugs for the treatment of relapsed/refractory IDH2-mutated (non-M3) AML unexpectedly observed DS as an adverse event, thereby identifying the IDH-inhibitors as potential differentiating agents [ 12 , 13 , 14 , 15 ]. The IDH-inhibitors enasidenib (IDHIFA ® , Celgene) and ivosidenib (TIBSOVO ® , Agios Pharmaceuticals) were approved by the US Food and Drug Administration (FDA) in 2017 and 2019, respectively.…”