Real-World Assessment of Isocitrate Dehydrogenase Inhibitor- Associated Differentiation Syndrome

Oxana Megherea, PharmD, BCOP
Hematology/Oncology Clinical Pharmacy Specialist
Hospital of the University of Pennsylvania Perelman Center for Advanced Medicine
Philadelphia, PA

Introduction
The treatment of acute myeloid leukemia (AML) has evolved with the introduction of new classes of agents that target mutated isocitrate dehydrogenase (IDH) 1 and IDH2, which are present in approximately 20% of patients with AML, to promote resumption of normal myeloid differentiation.1 Ivosidenib is approved by the U.S. Food and Drug Administration (FDA) for newly diagnosed IDH1-mutated AML in patients whose age or comorbidities pre- clude the use of intensive induction therapy. Ivosidenib and enas- idenib are approved in the setting of relapsed or refractory (R/R) IDH1- and IDH2-mutated AML, respectively.

IDH mutations block normal cellular differentiation by promot- ing the abnormal reduction of alpha-keto glutarate to the oncometabolite, R-2-hydroxyglutarate (2-HG), resulting in DNA and histone hypermethylation and inhibition of cellular differentiation.2 The inhibition of IDH1 and IDH2 by ivosidenib and enasidenib, respectively, reduces 2-HG levels and restores hemato- poietic differentiation.3 The restoration of this process can lead to differentiation syndrome (DS), a complication initially reported in patients with acute promyelo- cytic leukemia (APL), that is characterized by cytokine imbalance leading to tissue damage and inflammation.4,5 There are no pathognomonic signs and symptoms for DS and the presentation can be confounded by co-occurring conditions, such as infections or leukemic progression, thus potentially hindering diagnosis and leading to delays in management. The treatment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome (IDH-DS) includes administration of dexamethasone with hydroxyurea in patients with co-occurring leukocytosis.6

Given the variations in both the presentation and timing of IDH-DS, determining its true incidence is difficult. This study sought to evaluate real-world data on IDH-DS among several institutions in the U.S.

Methods
This was a multicenter, retrospective study of patients 18 years of age or older with myeloid malignancies and a confirmed IDH1 or IDH2 mutation by next generation sequencing, treated with ivos- idenib or enasidenib. The primary aim of this study was to determine the incidence of IDH-DS per the Montesinos criteria7 based on the presence of at least two of the following signs and symptoms occurring within 7 days of one another, in the absence of significant secondary causes: dyspnea and/or hypoxia, unexplained fever (body temperature of ≥38.0 ⁰C for at least 2 days), edema or weight gain >5 kg from therapy initiation, unexplained hypotension, acute kidney injury (≥ grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, pulmonary edema, pulmonary infiltrates, or pleural/pericardial effusions confirmed by imaging. Based on the number of symptoms at presentation, each episode of IDH-DS was classified as moderate (two to three symptoms) or severe (four or more of the symptoms listed above). Secondary ob- jectives included the frequency of IDH-DS clinical manifestations, the severity of IDH-DS, time to IDH-DS, treatment practices for IDH-DS (including the percentage of patients started on corticoste- roids and hydroxyurea), and time to initiation of these therapies. Additional secondary endpoints included: percentage of patients that had ivosidenib or enasidenib therapy held, reduced, or discontinued secondary to IDH-DS, and all-cause mortality while on IDH inhibitor therapy (defined as mor- tality during therapy or within 14 days of therapy discontinuation).

Results
Forty-nine patients treated with ivosid- enib or enasidenib for a myeloid malig- nancy from 1 August 2017 to 1 Septem- ber 2019 were included. Fifteen patients (31%) had a documented diagnosis of IDH-DS and eight of these patients (16%) met the criteria of IDH-DS per Montesi- nos et al.7 The median age of patients was 69 years (range 29 to 90). Of the patients with a documented diagnosis of IDH-DS, 27% received an IDH inhibitor for newly diagnosed AML, while 60% received treatment for R/R AML. In patients with R/R AML experiencing IDH-DS, 54% had 2 or more previous anti-cancer treatments.

Patients that experienced IDH-DS were more likely to have an el- evated WBC count at the onset of symptoms, with 27% of patients in the IDH-DS group meeting the definition of leukocytosis (WBC  >10 x 109/L) vs. 3% in the no-IDH-DS group (p=0.026). The most common symptoms of IDH-DS per Montesinos et al in this cohort were dyspnea/hypoxia (56%) and unexplained fever (56%), followed by edema or weight gain >5 kg from therapy initiation (39%), and pleural or pericardial effusions (33%). Other common findings, not included in the Montesinos criteria, were bone pain/arthralgia and leukocytosis, occurring in 44% and 39% of patients, respectively. Among patients that met the criteria of IDH-DS per Montesinos et al, an equal number of moderate and severe episodes were noted. Hospitalization occurred in 67% of episodes, 11% of which involved a critical care admission.

The median time to symptom onset from IDH inhibitor initiation was 10 days (range 0 to 164 days), with 67% of episodes occurring within 30 days of therapy initiation. Corticosteroids were started in 72% of episodes of documented IDH-DS at a median daily dose of 14.5 mg of dexamethasone equivalent, started within a median of 2 days of symptom onset and continued for a median of 10 days (range 2 to 71). All patients presenting with leukocytosis were started on hydroxyurea within a median of one day of symptom onset (range 0 to 3). The IDH inhibitor regimen was interrupted for 22% of episodes of IDH-DS and 44% of episodes resulted in therapy discontinuation. No patients had dose reductions secondary to IDH-DS. The all-cause mortality of patients on an IDH inhibitor was 14%.

Discussion and Conclusion
The incidence of IDH-DS in our population appears to be higher than previously reported, both when a clinically documented diagnosis of IDH-DS was present and the stricter Montesinos criteria were utilized at 31% and 16%, respectively; however, it is similar to the incidence of IDH-DS reported in a recent systemat- ic analysis conducted by the FDA.8-10 These findings suggest that the actual incidence of IDH-DS may be higher than previously reported.

The most common manifestations of IDH-DS in our population were consistent with those in patients with APL.7 Bone pain or arthralgia were present in 44% of all IDH-DS episodes, occurring in 13% of patients receiving ivosidenib and 16% of patients receiving enasidenib. Given the retrospective design of the study, it is pos- sible that bone pain and arthralgia may have occurred at a higher rates than documented, especially if lower-grade.

Patients in the current study who experienced IDH-DS were more likely to have leukocytosis at the onset of symptoms, which is consistent with previous reports.7 No other factors were identified to be significantly different when comparing patients with and without IDH-DS. The time to IDH-DS in our population was similar to other reports, with a median of 10 days and most episodes occurring within the first month.^6,10 Dexamethasone was initiated in 72% of documented IDH-DS episodes at a median daily dose of 14.5 mg started within a median of two days of symptom onset, and hydroxyurea was initiated within a median of one day of symptom onset in all patients presenting with co-occurring leukocytosis. As almost one-third of patients in our cohort did not receive dexamethasone, there may be room for improvement in the recognition and management of the syndrome with these agents, as delaying the initiation of steroid therapy could be life-threatening.

This study provided a unique opportunity for the evaluation of the real-life incidence, presentation, and management practices of IDH-DS at five institutions in the U.S. Our findings suggest that DS may occur in more patients treated with IDH inhibitors than initially reported and support arthralgia and bone pain as common manifestations of IDH-DS. As such, more frequent monitoring and inclusion of bone pain/arthralgia in the assessment of IDH-DS should be considered in patients initiated on these agents. These findings suggest that more vigilance for IDH-DS may be necessary, particularly within the first month of initiation of IDH inhibitor therapy, to allow for the prompt diagnosis and management of a potentially life-threatening complication.

Note: Dr. Oxana Megherea and colleagues have published their findings on “Real-World Assessment of Isocitrate Dehydrogenase Inhibitor-Associated Differentiation Syndrome” in Leukemia & Lymphoma. Reference: Megherea O, Janes C, Kowalski A, et al. Leuk Lymphoma. 2021; 62(13): 3219-3225.

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