Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2

Fathi, Amir T.; DiNardo, Courtney D.; Kline, Irina; Kenvin, Laurie; Gupta, Ira; Attar, Eyal C.; Stein, Eytan M.; Botton, Stéphane de; Investigators, Ag C Study

doi:10.1001/jamaoncol.2017.4695

Cited by 163 publications

(179 citation statements)

References 17 publications

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“…They were tumor lysis syndrome (n = 2), and (n = 1 each): anemia, leukocytosis, cardiac tamponade, diastolic dysfunction, pericardial effusion, gastrointestinal hemorrhage, infection, decreased appetite, acute kidney injury, and IDH differentiation syndrome (IDH-DS). An independent Differentiation Syndrome Review Committee (DSRC; including the authors SdB, CDD, and EMS) conducted a retrospective review of TEAEs consistent with IDH-DS (e.g., dyspnea, fever, peripheral edema, weight gain, pulmonary infiltrates, hypoxia), in the absence of secondary causes, for all patients in the study [21]. The DSRC identified five patients (13%) with previously untreated AML as likely having experienced IDH-DS.…”

Section: Safetymentioning

confidence: 99%

Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

et al. 2019

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Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12-15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58-87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1-35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3-4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3-4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.

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Section: Safetymentioning

confidence: 99%

Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

et al. 2019

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“…Blood samples (approximately 5 mL each) for measurement of Enasidenib and its metabolite AGI-16903 concentrations were collected at the following time points: prior to the dose (0 hour) and 1,2,3,4,6,9,12,18,24,48,96,168,240,336,504, and 672 hours postdose. PK blood draws were performed at the nominal time(s) specified in this clinical protocol.…”

Section: Blood Collection For Pharmacokinetic Analysismentioning

confidence: 99%

“…Enasidenib was approved in the United States (US) for the treatment of adult patients with relapsed or refractory (R/R) AML with an IDH2 mutation (as detected by a Food and Drug Administration [FDA] approved test) at a dose of 100 mg daily until disease progression or unacceptable toxicity . Patients treated with Enasidenib may experience symptoms of differentiation syndrome and the most common adverse reactions (≥20%) included nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite …”

Section: Introductionmentioning

confidence: 99%

“…17 Patients treated with Enasidenib may experience symptoms of differentiation syndrome and the most common adverse reactions (≥20%) included nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. [17][18][19] Enasidenib PK has been well characterized both in healthy subjects and in subjects with relapsed and refractory AML. 14,17,20 The absolute bioavailability of Enasidenib after 100 mg oral dose was approximately 57%.…”

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confidence: 99%

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Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects

Li¹,

Liu

Gomez³

et al. 2018

Pharmacology Res & Perspec

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The aim of this study was to assess and compare the pharmacokinetics (PK) and safety of Enasidenib in healthy adult male Japanese subjects to healthy adult male Caucasian subjects. This was a phase 1, single dose study to evaluate the PK and safety of Enasidenib in healthy adult male Japanese subjects relative to healthy adult male Caucasian subjects. A total of 62 subjects (31 Japanese and 31 Caucasian) were enrolled into three dose cohorts (single doses of 50 mg, 100 mg, or 300 mg Enasidenib). Blood samples for PK assessment were collected up to 672 hours postdose. Safety was evaluated throughout the study. In the present study, we found that PK exposures of Enasidenib and its metabolite AGI‐16903 for Caucasian and Japanese subjects were comparable at the 50, 100, and 300 mg dose levels, demonstrated by that the 90% confidence intervals (CIs) of geometric mean ratios for AUCs and C max between these two populations generally contained 100% from all three treatment cohorts. In conclusion, PK exposures of Enasidenib and its metabolite AGI‐16903 for Caucasians and Japanese subjects were comparable and Enasidenib was safe and well tolerated with no apparent differences between Japanese and Caucasian subjects when administered as single oral doses of 50 mg, 100 mg, and 300 mg.

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“…Although ATRA is highly efficient for leukemia harboring PML-RAR α gene fusions, ATRA does not show differentiation responses in non-APL leukemia. Recent development of epigenetic differentiation therapy for IDH1 mutated and IDH2 mutated AML with ivosidenib and enasidenib, respectively, has reinvigorated such approaches for other molecular subtypes of AML 11,12 . Large-scale drug response data repositories of cancer cells have been made available together with the associated gene expression profiles 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index

Thomas

Deutzmann

et al. 2019

Preprint

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Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an antihelminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model.These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

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Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2

Abstract: clinicaltrials.gov Identifier: NCT01915498.

Cited by 163 publications

References 17 publications

Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects

Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index

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