IDH1/2

Differentiation syndrome associated with enasidenib in AML patients

In June 2017, the AML Global Portal (AGP) reported results of a phase I/II dose escalation and expansion AG221-C-001 study (NCT01915498), which evaluated the safety, clinical activity, maximum tolerated dose and pharmacodynamic profile of enasidenib, a first-in-class, oral, selective Isocitrate Dehydrogenase 2 (IDH2) inhibitor, in patients with mutant IDH2 hematologic malignancies.1

Findings from this study demonstrated that enasidenib was well tolerated, induced hematologic responses and was associated with a median survival of over 9 months in patients with mutated IDH2 Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML). However, IDH-inhibitor associated Differentiation Syndrome (IDH-DS) was observed in some of the patients treated in this phase I/II study.1 Differentiation Syndrome is a potential serious condition that is associated with the proliferation of differentiated leukemic cells that can alter cytokine balance leading to tissue damage and inflammation.2

The prevalence, characteristics, and the course of IDH-DS in R/R AML in patients treated in the AG221-C-001 study were then evaluated retrospectively by an Independent Differentiation Syndrome Review Committee (DSRC). The results of the study were published in JAMA Oncology by Amir T. Fathi  from Massachusetts General Hospital Cancer Center, Boston, MA, and other investigators in the AG221-C-001 study.2

In total, 281 R/R AML patients who were enrolled in this phase I/II study were reviewed by the DSRC. The committee identified and agreed on signs and symptoms of IDH-DS and developed an algorithm for identification and treatment. The DSRC reviewed 72 suspected cases of IDH-DS and identified 33 R/R AML patients (median age = 70 years) with potential IDH-DS. The review panel compared the characteristics and outcomes of patients who experienced IDH-DS to patients who did not.

Key findings:
  • Characteristics of IDH-DS
    • Median time from beginning of enasidenib treatment to IDH-DS onset: 30 days (range, 7–129 days)
    • Patients with IDH-DS were significantly less likely to have less than 20% bone marrow blasts than patients without IDH-DS: 6% vs 22%, P = 0.04
    • Patients with IDH-DS had higher peripheral blood blast count than patients without IDH-DS
  • Clinical manifestation of IDH-DS
    • Most frequent signs and symptoms of IDH-DS includes dyspnea (85%), unexplained fever (79%), pulmonary infiltrates (73%), and hypoxia (58%)
    • Thirteen patients experienced leukocytosis
    • There were no deaths arising from IDH-DS
  • Clinical management of IDH-DS
    • Twenty-eight IDH-DS patients were administered symptomatic treatment with corticosteroids, median duration of treatment for 20 of the 28 patients was 12 days
    • Eleven of 13 patients with concomitant leukocytosis received hydroxyurea, median duration of treatment was 15 days
    • Enasidenib regimen was interrupted for 15 patients (45.5%) until IDH-DS symptoms improved
    • Discontinuation of therapy from IDH-DS did not occur
  • Efficacy
    • Overall Response Rate (ORR) in patients with or without IDH-DS were 45.5% (15/33) and 37.5% (93/248), respectively
    • Complete Remission (CR)/ CR with incomplete platelet or neutrophil recovery with or without IDH-DS were 36.4% and 26.2%, respectively, P = 0.22

Key limitations of the study includes its small size and the authors suggested that a larger study is required. Additionally, in this phase I/II study, IDH-DS was not initially anticipated and thus the protocol did not define proactive monitoring for it. The authors, however, noted that IDH-DS monitoring is now part of clinical protocols for enasidenib clinical studies.

In an interview with the AGP, Amir Fathi, noted that IDH-DS is a “recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML”. He further concluded that the potential IDH-DS observed with the use of mutant IDH inhibitors should be promptly recognized and managed properly so that patients are treated effectively.

References
  1. Stein E. M. et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10; 1306): 722–731. DOI: :10.1182/blood-2017-04-779405. Epub 2017 Jun 6.
  2. Fathi A. T. et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: Analysis of a phase 1/2 study. JAMA Oncol. 2018 Jan 18. DOI: 10.1001/jamaoncol.2017.4695. [Epub ahead of print].
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