Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2).

Abstract

7015 Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS), with manifestations akin to retinoic acid syndrome seen during acute promyelocytic leukemia Tx. Methods: A phase 1 dose-escalation/expansion study (N = 239) (NCT01915498) included 109 pts with relapsed/refractory AML who received enasidenib 100 mg /day. An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential IDH-DS cases. The DSRC identified and agreed on signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. Of the 109 pts, the DSRC identified and retrospectively reviewed 27 cases (8 investigator reported IDH-DS cases and 19 cases suggestive of IDH-DS) to determine consistency with IDH-DS. Results: The DSRC found 13 of the 27 cases to be consistent with IDH-DS (11.9% of 109 pts). Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in > 2 pts were dyspnea (n = 10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4 cases and hydroxyurea was used for cytoreduction. Enasidenib was interrupted for 9 pts (median 7 days) but dose reductions or discontinuation were not required. Six of 13 pts had clinical responses (2 complete remission [CR], 2 CR with incomplete hematologic recovery, 1 partial remission, 1 morphologic leukemia-free state), 6 had stable disease and 1 had progressive disease. Conclusions: Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective management strategies, should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in m IDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, differentiation. Clinical trial information: NCT01915498.

Important Considerations in the Intensive Care Management of Acute Leukemias

“…[45][46][47] This is explained by the blockade of cellular differentiation observed with overexpression of IDH-mutant enzymes, and as such, selective inhibition of IDH allows for blast cell maturation and therefore very similar conditions to ATRA/ATO in APL. 48 Notably, DS has been observed with other investigational differentiating leukemia agents such as menin-inhibitors with similar mechanistic pathology. 49 APL-associated DS is observed in a bimodal time distribution with 47% of cases observed in the first week and 25% observed in the third week of therapy.…”

New Food and Drug Administration–Approved and Emerging Novel Treatment Options for Acute Myeloid Leukemia

“…In a majority of the cases, corticosteroids were used to mitigate IDH‐DS. There were four cases in which leukocytosis was reported, and hydroxyurea was implemented for cytoreduction . The recommended dosage of hydroxyurea is 2–4 g/day orally, and the recommended corticosteroid regimen is dexamethasone 10 mg orally every 12 hours for 3 days or until improvement …”

“…23 Approximately 13 cases of IDH-DS have been reported, with the median time to onset being 30 days (range 7-116 days) and most patients presenting with dyspnea, pyrexia, lung infiltrates, and pleural effusions. 24,25 In a majority of the cases, corticosteroids were used to mitigate IDH-DS. There were four cases in which leukocytosis was reported, and hydroxyurea was implemented for cytoreduction.…”

“…There were four cases in which leukocytosis was reported, and hydroxyurea was implemented for cytoreduction. 25 The recommended dosage of hydroxyurea is 2-4 g/day orally, and the recommended corticosteroid regimen is dexamethasone 10 mg orally every 12 hours for 3 days or until improvement. 24 Additionally, although enasidenib is a minor substrate of the CYP system, there are currently no known major DDI.…”

The role of targeted therapy in the management of patients with AML

“…29 As well, ;12% of enasidenib-treated patients experienced a differentiation syndrome variably characterized by fever, dyspnea/lung infiltrates, pleural effusions, leukocytosis, and kidney injury. 30 Similar to the management of APL differentiation syndrome, systemic corticosteroids led to the resolution of these symptoms.…”