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IDH Inhibitor Associated Differentiation Syndrome

MedGen UID:
1719763
•Concept ID:
C5238955
•
Disease or Syndrome
Synonym: IDH-DS

Definition

A constellation of signs and symptoms occurring in the context of administration of isocitrate dehydrogenase (IDH) inhibitors in hematologic malignancies. It is characterized by dyspnea, unexplained fever, pulmonary infiltrates, hypoxia, pleural effusion, acute kidney injury, pericardial effusion, arthralgia, lymphadenopathy, edema and weight gain. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVIDH Inhibitor Associated Differentiation Syndrome

Professional guidelines

PubMed

Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.
Parisi R, Cowen EA, Stoll JR, Zhu H, Dusza S, Pulitzer MP, Stein EM, Markova A
Leuk Res 2022 Dec;123:106970. Epub 2022 Oct 22 doi: 10.1016/j.leukres.2022.106970. PMID: 36308802Free PMC Article
Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration Systematic Analysis.
Norsworthy KJ, Mulkey F, Scott EC, Ward AF, Przepiorka D, Charlab R, Dorff SE, Deisseroth A, Kazandjian D, Sridhara R, Beaver JA, Farrell AT, de Claro RA, Pazdur R
Clin Cancer Res 2020 Aug 15;26(16):4280-4288. Epub 2020 May 11 doi: 10.1158/1078-0432.CCR-20-0834. PMID: 32393603Free PMC Article

Recent clinical studies

Etiology

Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome.
DiNardo CD, Venugopal S, Lachowiez C, Takahashi K, Loghavi S, Montalban-Bravo G, Wang X, Carraway H, Sekeres M, Sukkur A, Hammond D, Chien K, Maiti A, Masarova L, Sasaki K, Alvarado Y, Kadia T, Short NJ, Daver N, Borthakur G, Ravandi F, Kantarjian HM, Patel B, Dezern A, Roboz G, Garcia-Manero G
Blood Adv 2023 Jun 13;7(11):2378-2387. doi: 10.1182/bloodadvances.2022008378. PMID: 35973199Free PMC Article
Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.
Parisi R, Cowen EA, Stoll JR, Zhu H, Dusza S, Pulitzer MP, Stein EM, Markova A
Leuk Res 2022 Dec;123:106970. Epub 2022 Oct 22 doi: 10.1016/j.leukres.2022.106970. PMID: 36308802Free PMC Article
Real-world assessment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome.
Megherea O, Janes C, Kowalski A, Baron J, Ahn E, Soule A, Newman M
Leuk Lymphoma 2021 Dec;62(13):3219-3225. Epub 2021 Jul 27 doi: 10.1080/10428194.2021.1957868. PMID: 34313176
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM
N Engl J Med 2018 Jun 21;378(25):2386-2398. Epub 2018 Jun 2 doi: 10.1056/NEJMoa1716984. PMID: 29860938
Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.
Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S; AG221-C-001 Study Investigators
JAMA Oncol 2018 Aug 1;4(8):1106-1110. doi: 10.1001/jamaoncol.2017.4695. PMID: 29346478Free PMC Article

Diagnosis

Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome.
DiNardo CD, Venugopal S, Lachowiez C, Takahashi K, Loghavi S, Montalban-Bravo G, Wang X, Carraway H, Sekeres M, Sukkur A, Hammond D, Chien K, Maiti A, Masarova L, Sasaki K, Alvarado Y, Kadia T, Short NJ, Daver N, Borthakur G, Ravandi F, Kantarjian HM, Patel B, Dezern A, Roboz G, Garcia-Manero G
Blood Adv 2023 Jun 13;7(11):2378-2387. doi: 10.1182/bloodadvances.2022008378. PMID: 35973199Free PMC Article
Real-world assessment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome.
Megherea O, Janes C, Kowalski A, Baron J, Ahn E, Soule A, Newman M
Leuk Lymphoma 2021 Dec;62(13):3219-3225. Epub 2021 Jul 27 doi: 10.1080/10428194.2021.1957868. PMID: 34313176
Isocitrate dehydrogenase mutations in myeloid malignancies.
Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R
Leukemia 2017 Feb;31(2):272-281. Epub 2016 Oct 10 doi: 10.1038/leu.2016.275. PMID: 27721426Free PMC Article

Therapy

Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome.
DiNardo CD, Venugopal S, Lachowiez C, Takahashi K, Loghavi S, Montalban-Bravo G, Wang X, Carraway H, Sekeres M, Sukkur A, Hammond D, Chien K, Maiti A, Masarova L, Sasaki K, Alvarado Y, Kadia T, Short NJ, Daver N, Borthakur G, Ravandi F, Kantarjian HM, Patel B, Dezern A, Roboz G, Garcia-Manero G
Blood Adv 2023 Jun 13;7(11):2378-2387. doi: 10.1182/bloodadvances.2022008378. PMID: 35973199Free PMC Article
Real-world assessment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome.
Megherea O, Janes C, Kowalski A, Baron J, Ahn E, Soule A, Newman M
Leuk Lymphoma 2021 Dec;62(13):3219-3225. Epub 2021 Jul 27 doi: 10.1080/10428194.2021.1957868. PMID: 34313176
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM
N Engl J Med 2018 Jun 21;378(25):2386-2398. Epub 2018 Jun 2 doi: 10.1056/NEJMoa1716984. PMID: 29860938
Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.
Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S; AG221-C-001 Study Investigators
JAMA Oncol 2018 Aug 1;4(8):1106-1110. doi: 10.1001/jamaoncol.2017.4695. PMID: 29346478Free PMC Article
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, Tallman MS
Blood 2017 Aug 10;130(6):722-731. Epub 2017 Jun 6 doi: 10.1182/blood-2017-04-779405. PMID: 28588020Free PMC Article

Prognosis

Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib.
Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S
Blood 2019 Feb 14;133(7):676-687. Epub 2018 Dec 3 doi: 10.1182/blood-2018-08-869008. PMID: 30510081Free PMC Article
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM
N Engl J Med 2018 Jun 21;378(25):2386-2398. Epub 2018 Jun 2 doi: 10.1056/NEJMoa1716984. PMID: 29860938
Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.
Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S; AG221-C-001 Study Investigators
JAMA Oncol 2018 Aug 1;4(8):1106-1110. doi: 10.1001/jamaoncol.2017.4695. PMID: 29346478Free PMC Article
Isocitrate dehydrogenase mutations in myeloid malignancies.
Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R
Leukemia 2017 Feb;31(2):272-281. Epub 2016 Oct 10 doi: 10.1038/leu.2016.275. PMID: 27721426Free PMC Article

Clinical prediction guides

Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.
Parisi R, Cowen EA, Stoll JR, Zhu H, Dusza S, Pulitzer MP, Stein EM, Markova A
Leuk Res 2022 Dec;123:106970. Epub 2022 Oct 22 doi: 10.1016/j.leukres.2022.106970. PMID: 36308802Free PMC Article
Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin.
Förster A, Brand F, Banan R, Hüneburg R, Weber CAM, Ewert W, Kronenberg J, Previti C, Elyan N, Beyer U, Martens H, Hong B, Bräsen JH, Erbersdobler A, Krauss JK, Stangel M, Samii A, Wolf S, Preller M, Aretz S, Wiese B, Hartmann C, Weber RG
Acta Neuropathol 2021 Jul;142(1):191-210. Epub 2021 Apr 30 doi: 10.1007/s00401-021-02307-1. PMID: 33929593Free PMC Article
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM
N Engl J Med 2018 Jun 21;378(25):2386-2398. Epub 2018 Jun 2 doi: 10.1056/NEJMoa1716984. PMID: 29860938

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