Differentiation Syndrome Associated with Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2 Analysis of a Phase 1/2 Study

Research

JAMA Oncology | Brief Report Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2 Analysis of a Phase 1/2 Study

Amir T. Fathi, MD; Courtney D. DiNardo, MD; Irina Kline, MD; Laurie Kenvin, BSN; Ira Gupta, MD; Eyal C. Attar, MD; Eytan M. Stein, MD; Stephane de Botton, MD, PhD; for the AG221-C-001 Study Investigators

Invited Commentary IMPORTANCE Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein page 1110 inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by Supplemental content the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity.

OBJECTIVE To characterize IDH-inhibitor–associated DS (IDH-DS) and its effective management.

DESIGN, SETTING, AND PARTICIPANTS Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS.

INTERVENTIONS Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles.

MAIN OUTCOMES AND MEASURES Unexpected adverse events of IDH-DS during the phase 1/2 study.

RESULTS Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Author Affiliations: Author CONCLUSIONS AND RELEVANCE Isocitrate dehydrogenase differentiation syndrome is a affiliations are listed at the end of this recognizable and potentially lethal clinical entity, occurring in approximately 12% of article. enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition Group Information: The members of the AG221-C-001 Study Investigators and management. As use of mutant IDH inhibitors increases, these findings and appear at the end of the article. recommendations are increasingly germane to care of patients with mutant-IDH neoplasms. Corresponding Author: Amir T. Fathi, MD, Massachusetts General TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01915498 Hospital, Assistant Professor, Harvard Medical School, JAMA Oncol. 2018;4(8):1106-1110. doi:10.1001/jamaoncol.2017.4695 55 Fruit St, Boston, MA 02114 Published online January 18, 2018. ([email protected]).

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enetic and epigenetic alterations that block cellular differentiation underlie the development of myeloid Key Points neoplasms.1 Agents that induce resumption of differen- G Question What are the signs, symptoms, and appropriate tiation may be clinically beneficial; however, drug-induced dif- approaches to management of isocitrate dehydrogenase ferentiation of leukemic cells can be accompanied by a poten- differentiation syndrome, an unexpected event observed in the tially serious condition, differentiation syndrome (DS), as seen first clinical study of enasidenib mesylate, recently approved for during treatment of acute promyelocytic leukemia.2-5 Prolifera- relapsed/refractory mutant IDH2 acute myeloid leukemia? tion of differentiated leukemic cells can alter cytokine balance, Findings In a phase 1/2 clinical trial of 281 patients with relapsed/ leading to tissue damage and inflammation.4 Signs and symp- refractory acute myeloid leukemia treated with enasidenib, possible toms of DS include unexplained fever, weight gain, respiratory or probable isocitrate dehydrogenase differentiation syndrome was symptoms, and pleural or pericardial effusions.4 identified in 33 patients and had recognizable signs and symptoms, Enasidenib mesylate (AG-221; IDHIFA; Celgene Corpora- including dyspnea, unexplained fever, pulmonary infiltrates, and hypoxia. These signs and symptoms could occur months after tion) is a first-in-class, oral inhibitor of mutant isocitrate dehy- initiation of enasidenib treatment and could mimic symptoms seen drogenase 2 (mIDH2) proteins. Enasidenib was approved by the during treatment and progression of myeloid neoplasms; prompt US Food and Drug Administration (FDA) in August 2017 for treat- intervention with systemic corticosteroid therapy was an effective ment of adult patients with mutant IDH2 (OMIM 147650) management approach. (mIDH2) relapsed/refractory acute myeloid leukemia (R/R AML). Meaning As use of mutant isocitrate dehydrogenase inhibitors Mutant IDH2 proteins neomorphically catalyze the onco- increases, awareness of the potential for isocitrate dehydrogenase 6 metabolite, (R)-2-hydroxyglutarate ([R]-2HG). High (R)-2HG differentiation syndrome is imperative so that patients can be concentrations promote hypermethylation, altered gene ex- promptly and effectively treated. pression, and blocked differentiation of hematopoietic cells.7 Enasidenib suppresses 2HG and induces differentiation of mIDH2 leukemic cells, producing fully functioning neutro- Table 1. Frequency of Signs and Symptoms Consistent With IDH-DSa 8,9 phils that retain the IDH2 mutation. Patients who respond to Patients With treatment with enasidenib exhibit evidence of hematopoietic IDH-DS, No. (%) Sign or Symptom (n = 33)b 3,8 recovery, typically without intervening bone marrow aplasia. Dyspnea 28 (85) In the first human, phase 1/2 study of enasidenib in patients Unexplained fever (body temperature 26 (79) with mIDH2 malignant hematologic neoplasms, investigators re- of 38.0°C for 2 d) ported adverse events reminiscent of those seen in DS. Similar Pulmonary infiltrates 24 (73) events have been reported for ivosidenib (AG-120), a mutant IDH1 Hypoxia 19 (58) protein inhibitor.10 These signs and symptoms of mutant-IDH Acute kidney injury (CTCAE grade ≥2) 14 (42) Pleural effusion 14 (42) inhibitor–associated DS (termed IDH differentiation syndrome Bone pain or arthralgia 9 (27) [IDH-DS])11 are nonspecific and can resemble other clinical con- Lymphadenopathy 8 (24) ditions common in AML. To characterize IDH-DS and establish Rash 8 (24) practicable diagnostic and therapeutic recommendations, an in- Disseminated intravascular coagulopathy 7 (21) dependent differentiation syndrome review committee (DSRC) Edema or weight gain of >5 kg from screening 7 (21) retrospectively evaluated potential cases of IDH-DS among pa- Pericardial effusion 5 (15) tients with R/R AML enrolled in the aforementioned study. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events14; IDH-DS, isocitrate dehydrogenase differentiation syndrome. a Signs and symptoms included in this table are based on retrospective Methods differentiation syndrome review committee review of clinical records. b Patients may have had multiple symptoms. This was a multicenter, open-label, pivotal phase 1/2 study. Study design, conduct, eligibility criteria, and clinical re- proliferation in the blood or bone marrow, and with subsequent sponse and safety assessments in the phase 1 dose-escalation clinical response to corticosteroid therapy.Hematologic response and expansion study portions are reported elsewhere.3 Phase was assessed per International Working Group 2003 AML 2 enrollment was limited to adult patients with R/R AML, all criteria.13 Baseline characteristics of patients who did or did not of whom received 100 mg of enasidenib once daily. This study experience IDH-DS were summarized and compared using the was conducted in accordance with the Declaration of Helsinki.12 Wilcoxon Mann-Whitney test (continuous variables) or Fisher ex- All patients provided written informed consent. The institu- act test (categorical variables). Pvalues are 2-sided, with a signifi- tional review boards that approved the study can be found in cance level of .05. Statistics were performed using SAS 9.2 sta- the eAppendix in the Supplement. tistical software (SAS Institute Inc). The DSRC independently reviewed cases of investigator- reported DS and those with adverse events suggestive of IDH-DS (eTable 1 in the Supplement). Isocitrate dehydrogenase differen- Results tiation syndrome was considered when characteristic signs and symptoms occurred in the absence of significant secondary Two hundred eighty-one patients with R/R AML participated causes, with concurrent evidence of cellular differentiation and between August 27, 2013, and data cutoff (October 14, 2016).

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Figure. Differentiation Syndrome Review Committee Amended Protocol for Isocitrate Dehydrogenase Differentiation Syndrome (IDH-DS) Diagnosis and Management

Suspicion of IDH-DS Initiate treatment with dexa- Hospitalization indicated in setting of rapidly DIC indicates disseminated New onset or worsening of methasone, 10 mg twice progressing symptoms (especially respiratory intravascular coagulation; characteristic symptoms of daily, as indicated symptoms), development of hypoxia, renal failure, WBC, white blood cells. unexplained etiology, • Empiric therapy for other rising WBC count, or DIC including fever, rapid weight possible causes (eg, anti- • Stop/interrupt enasidenib treatmentb a Typical onset is between 7 to 10 gain or edema, repiratory infective agents) days and 5 months from start of • Hydroxyurea for manage- symptoms with or without enasidenib treatment or reinitiation infiltrates, pleural or peri- ment of co-occurring cardial effusions, hypo- leukocytosis Improvement of Continue dexamethasone of enasidenib after prolonged tension, and acute renal • Hyperuricemia agents for IDH-DS signs/ until significant improve- treatment interruption. a co-occurring tumor lysis symptoms ment or resolution of failure b syndrome signs/symptoms, then Owing to the long half-life of taper per institutional enasidenib, treatment may not guidelines immediately reverse symptoms of IDH-DS.

The DSRC reviewed 72 suspected cases of IDH-DS and, of them, receiving greater than 100 mg/d. Frequency of IDH-DS was not identified 33 patients (11.7% of all patients with R/R AML) as statistically different among these groups. having experienced possible or probable IDH-DS. The median age of patients with possible or probable IDH-DS was 70 IDH-DS Management years (range, 38-80 years). Twenty of the 33 (60.6%) were male. Twenty-eight of the 33 patients with IDH-DS (84.8%) re- Twenty-five patients had 1 IDH-DS episode, 6 had 2 episodes, ceived symptomatic treatment with corticosteroids. For 20 pa- and 2 experienced 3 episodes. Reasons for rejecting an IDH-DS tients with available data, median duration of corticosteroid diagnosis included alternative causes for symptoms, lack of therapy for IDH-DS was 12 days (range, 4-43 days). Eleven of clinical evidence of cellular differentiation, lack of response 13 patients with concomitant leukocytosis received hydroxy- to corticosteroid therapy, and clear evidence of disease pro- urea (median, 15 days [range, 4-71 days]). The enasidenib regi- gression as a more likely explanation for the constellation of men was interrupted for 15 patients (45.5%) until IDH-DS symp- clinical signs and/or symptoms. toms improved. Two patients (6.1%) had dosage reduced, but Baseline characteristics were generally comparable be- none discontinued enasidenib therapy permanently because tween patients who experienced IDH-DS and those who did of IDH-DS. not (eTable 2 in the Supplement). Patients with IDH-DS were Isocitrate dehydrogenase differentiation syndrome man- significantly less likely to have had less than 20% bone mar- agement guidelines have been incorporated into an amended row blasts (6% vs 22%, P = .04) and more likely to have protocol. At first suspicion of IDH-DS, dexamethasone, 10 mg undergone a lower median number of previous antileukemic twice daily, is recommended until signs and symptoms are sig- regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05). nificantly improved (Figure). Higher peripheral blast counts (median 31% [range, 0%-88%] vs 13% [range, 0%-98%], P = .05) and greater proportion of Efficacy those with lactate dehydrogenase levels above 1 × upper limit Overall response rate for patients with IDH-DS was 45.5% (15 of normal (51% vs 36%, P = .09) were noted for patients with of 33 patients) and for patients without IDH-DS, 37.5% (93 of IDH-DS, but these variables did not reach statistical signifi- 248) (Table 2). Complete remission or complete remission with cance. In multivariate analysis, only a lesser median number incomplete platelet or neutrophil count recovery was experi- of previous antileukemic therapies was significantly associ- enced by 36.4% of patients (12 of 33) in the IDH-DS group and ated with IDH-DS (odds ratio, 0.66; 95% CI, 0.44-1.00; P = .05). 26.2% (65 of 248) in the non–IDH-DS group (P = .22). Disease Median time from beginning of enasidenib treatment to remained stable in approximately half of the patients in each IDH-DS onset was 30 days (range, 7-129 days); onset at day 129 group. occurred for 1 patient after a treatment interruption of approximately 1 month. The most frequent clinical manifestations of IDH-DS were dyspnea, culture-negative fever, pulmo- Discussion nary infiltrates, and hypoxia (Table 1). Ten patients required intensive care unit admission for related symptoms. Leuko- Isocitrate dehydrogenase differentiation syndrome is a newly cytosis occurred concurrently in 13 patients. No death was at- defined clinical entity in patients with mIDH2 AML receiving tributed to IDH-DS. Clinical and laboratory profiles for 2 illus- enasidenib, likely owing to the drug’s mechanism of action, trative cases in patients who experienced IDH-DS are described promoting differentiation of myeloblasts into mature cells.8 in eFigures 1 and 2 in the Supplement. No single pathognomonic clinical sign or laboratory result is Dosages greater and less than 100 mg/d were evaluated in diagnostic of IDH-DS. A constellation of findings supports the small patient cohorts during dose escalation. Events related diagnosis, which can be challenging because signs and symp- to IDH-DS occurred in none of 19 patients with R/R AML re- toms can mimic those of leukemic progression or other acute ceiving enasidenib dosages less than 100 mg/d, 26 of 214 pa- comorbidities. Diagnosis should be suspected on exclusion of tients (12.1%) receiving 100 mg/d, and 7 of 48 patients (14.6%) other potential causes of characteristic symptoms.

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initiation),4 IDH-DS onset can occur from 7 days to 5 months Table 2. Response Among Patients With and Without IDH-DS after initiation of enasidenib treatment. In addition, IDH-DS IDH-DS, No. (%) No IDH-DS, No. (%) can occur after enasidenib therapy interruption or dose esca- Patient Response (n = 33)a (n = 248) Overall responseb 15 (45.5) 93 (37.5) lation. Onset appears to correspond to enasidenib-induced my- CR 6 (18.2) 49 (19.8) eloid cell differentiation and maturation, similar to the “neutrophil surge” associated with DS in patients treated with FLT3 CRi/CRp 6 (18.2) 16 (6.5) (FMS-like tyrosine kinase 3) inhibitors, such as quizartinib.2 PR 2 (6.1) 14 (5.7) Although potentially life-threatening, IDH-DS can be effec- MLFS 1 (3.0) 14 (5.7) tively managed. When alternative secondary causes for charac- Stable diseasec 16 (48.5) 121 (48.8) teristic symptoms are excluded or do not respond to treatment, Disease progression 1 (3.0) 14 (5.7) or if symptoms worsen within 48 hours of initiating treatment Abbreviations: CR, complete remission; CRi, CR with incomplete hematologic for a different suspected cause, the event should be managed as recovery; CRp, CR with incomplete platelet recovery; IDH-DS, isocitrate potential IDH-DS (Figure). For concomitant leukocytosis, cyto- dehydrogenase differentiation syndrome; MLFS, morphologic leukemia-free state; PR, partial remission; R/R AML, relapsed/refractory acute myeloid reduction per local standard practice is recommended. leukemia. Approximately half of patients with IDH-DS received ena- a One patient was not evaluable for response; the patient developed IDH-DS on sidenib therapy without interruption. If associated with se- the ninth study day and discontinued treatment before a response vere pulmonary symptoms and/or renal dysfunction lasting assessment. more than 48 hours after corticosteroid treatment initiation, ena- b Investigator-reported overall response rate included CR, CRi/CRp, PR, or MLFS. sidenib therapy should be withheld until symptoms improve. c No international working group–defined response with no evidence of disease Symptoms may not resolve immediately. Given the prolonged 16 progression, sustained for 56 consecutive days. half-life of enasidenib (approximately 137 hours), drug treatment interruption is not an alternative to corticosteroid use. Our results showed that IDH-DS was significantly associated with fewer previous anticancer therapies and nonsignifi- Limitations cantly associated with higher baseline peripheral blast counts The studied population was relatively small, and larger stud- (P = .05) and lactate dehydrogenase levels (P = .09), both labo- ies are needed. In addition, because IDH-DS was not initially ratory markers suggestive of cellular turnover. Why fewer pre- anticipated, the protocol did not define proactive monitoring ceding therapies might increase risk is unclear. This IDH-DS for it; however, IDH-DS monitoring is now part of clinical pro- study population is small; further study is needed to deter- tocols for enasidenib studies. mine whether reliable biomarkers of the potential to develop IDH-DS exist. The rate of IDH-DS with enasidenib (11.7%) was lower than Conclusions DS rates reported with all-trans retinoic acid or arsenic trioxide in acute promyelocytic leukemia .5,15 Unlike all-trans reti- As use of mutant-IDH inhibitors increases, these recommen- noic acid– or arsenic trioxide–induced DS, which have a typi- dations are increasingly germane to care of patients with cal onset of approximately 7 to 12 days from treatment mutant-IDH hematologic neoplasms.

ARTICLE INFORMATION equally to this work and are co–senior authors. Drs Takeda and Exelixis. Dr DiNardo reported receiving Accepted for Publication: October 17, 2017. Fathi and DiNardo had full access to all the data in compensation for serving on advisory boards for the manuscript and take responsibility for the Agios, Daiichi Sankyo, Celgene, and Novartis, Published Online: January 18, 2018. integrity of the data and the accuracy of the data speakers fees from AbbVie, and receiving clinical doi:10.1001/jamaoncol.2017.4695 analysis. research support from Agios Pharmaceuticals, Inc, Open Access: This article is published under Study concept and design: Fathi, DiNardo, Kline, AbbVie, Daiichi Sankyo, Novartis, and Celgene the JN-OA license and is free to read on the day Gupta, Attar, Stein, de Botton. Corporation. Drs Kline, Kenvin, and Gupta are of publication. Acquisition, analysis, or interpretation of data: All employees and hold stock in Celgene Corporation. Author Affiliations: Department of Medicine, authors. Dr Attar is an employee of Agios Pharmaceuticals, Division of Hematology and Medical Oncology, Drafting of the manuscript: Fathi, DiNardo, Kline, Inc. Dr Stein reported receiving grants and personal Massachusetts General Hospital Cancer Center Gupta, de Botton. fees from Celgene Corporation and Agios (Fathi); Massachusetts General Hospital, Harvard Critical revision of the manuscript for important Pharmaceuticals. Dr de Botton reported receiving Medical School, Boston (Fathi); Department of intellectual content: All authors. personal fees from Agios Pharmaceuticals, Inc, Leukemia, The University of Texas MD Anderson Statistical analysis: Kline, Kenvin. Celgene Corporation, Novartis, Pfizer, and Servier. Cancer Center, Houston (DiNardo); Celgene Obtained funding: Kline. No other disclosures were reported. Corporation, Summit, New Jersey (Kline, Kenvin, Administrative, technical, or material support: Funding/Support: This study was funded by Gupta); Agios Pharmaceuticals, Inc, Cambridge, DiNardo, Gupta, Stein. Celgene Corporation and Agios Pharmaceuticals, Massachusetts (Attar); Leukemia Service, Study supervision: Fathi, Kline, Kenvin, Stein, Inc. de Botton. Department of Medicine, Memorial Sloan Kettering Role of the Funder/Sponsor: The funding Cancer Center, New York, New York (Stein); Conflict of Interest Disclosures: Dr Fathi reported organizations participated in study design and Department of Clinical Hematology, Gustave serving as a consultant for and receiving clinical trial conduct, managed the data, collected and analyzed Roussy, Villejuif, France (de Botton). support from Celgene Corporation and Seattle data in conjunction with the authors, reviewed the Author Contributions: Drs Fathi and DiNardo Genetics; serving on advisory boards for Agios manuscript for accuracy, and agreed to the decision contributed equally to this work and are co–lead Pharmaceuticals, Inc, Merck, Juno, Torero, and to submit the manuscript for publication. authors. Drs Stein and de Botton contributed Bexalata; and receiving clinical trial support from

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Group Information: The AG221-C-001 Study Company, Inc), provided editorial assistance that inhibitor, AG-120. Clin Lymphoma Myeloma Leuk. Investigators are Florida Cancer Specialists, was funded by Celgene Corporation. 2016;16(8):460-465. Sarasota: Manish Patel (principal investigator [PI]); 11. Medical Dictionary for Regulatory Activities. Sarah Cannon Research Institute, Nashville, REFERENCES https://www.meddra.org/. Accessed November 8, Tennessee: Ian Flinn (PI); Massachusetts General 1. Korn C, Méndez-Ferrer S. Myeloid malignancies 2017. Hospital Cancer Center, Boston: Amir Fathi (PI); and microenvironment. Blood. 2017;129(7):811-822. Memorial Sloan-Kettering Cancer Center, New York, 12. World Medical Association. World Medical New York: Eytan Stein (PI), Martin Tallman (sub-PI); 2. Sexauer A, Perl A, Yang X, et al. 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Evidence for clinical 100(suppl 1):379. develop procedures to diagnose and manage differentiation and differentiation syndrome in IDH-DS in current clinical trials. Sheila Truten, BS, patients with acute myeloid leukemia and IDH1 and Kelly Dittmore, MS (Medical Communication mutations treated with the targeted mutant IDH1

Invited Commentary Enasidenib-Induced Differentiation Syndrome in IDH2-Mutant Acute Myeloid Leukemia Shyam A. Patel, MD, PhD

For the past 40 years, the standard of care for acute myeloid The identification of IDH mutations in the AML genome leukemia (AML) has been cytotoxic chemotherapy of cytara- dates back to 2009.1 Massively parallel DNA sequencing per- bine and an anthracycline. The year 2017 has seen mile- formed on a de novo AML genome alongside a matched skin ge- stones in AML treatment nome showed a mutation in IDH1 (OMIM 147700), and 15 of 187 with the US Food and Drug additional AML genomes tested were found to harbor delete- Related article page 1106 Administration (FDA) rious IDH1 mutations.1 The functional significance of IDH1 and approval of novel therapies, IDH2 (OMIM 147650) mutations was demonstrated in 2010 with including the anti–CD33-calicheamicin conjugate the discovery that neomorphic enzyme activity arising from the gemtuzumab ozogamicin, a liposome-encapsulated formu- mutation leads to the production of 2-hydroxyglutarate.2 This lation of daunorubicin-cytarabine, the FLT3 inhibitor metabolite leads to epigenetic alterations, including DNA and midostaurin, and the mutant isocitrate dehydrogenase 2 histone methylation, ultimately resulting in a differentiation (mIDH2) inhibitor enasidenib mesylate. The FDA approval of block in myeloid cells.2 In contrast, wild-type IDH catalyzes the enasidenib in August 2017 represents a critical breakthrough conversion of isocitrate to α-ketoglutarate and permits normal for targeted therapy and precision medicine for AML. cellular metabolism. In 2014, it was shown that preleukemic

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