Acute myeloid leukemia, IDH-mutated

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Note: these are regimens tested in biomarker-specific populations for patients with IDH-mutated AML, please see the main AML page for other regimens.
Last updated on 2024-07-23:9 regimens on this page
9 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Myeloid Leukemia.
=IDH1 first-line therapy, older or 'unfit' patients=
==Azacitidine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Montesinos et al. 2022 (AGILE)	2018-2021 	Phase 3 (C)	Azacitidine & Ivosidenib	Shorter OS
====Biomarker eligibility criteria====
*IDH1 mutation
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
28-day cycle for at least 6 cycles
===References===
#AGILE: Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, Heuser M, Calado RT, Schuh AC, Yeh SP, Daigle SR, Hui J, Pandya SS, Gianolio DA, de Botton S, Döhner H. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519-1531. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03173248
==Azacitidine & Ivosidenib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Montesinos et al. 2022 (AGILE)	2018-2021 	Phase 3 (E-RT-esc)	Azacitidine	Longer EFS (primary endpoint)EFS12: 37% vs 12%(HR 0.33, 95% CI 0.16-0.69)Longer OS (secondary endpoint)Median OS: 24 vs 7.9 mo(HR 0.44, 95% CI 0.27-0.73)
====Biomarker eligibility criteria====
*IDH1 mutation
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 IV or SC once per day on days 1 to 7
====Targeted therapy====
*Ivosidenib (Tibsovo) 500 mg PO once per day on days 1 to 28
28-day cycle for at least 6 cycles
===References===
#AGILE: Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, Heuser M, Calado RT, Schuh AC, Yeh SP, Daigle SR, Hui J, Pandya SS, Gianolio DA, de Botton S, Döhner H. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519-1531. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03173248
==Ivosidenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Roboz et al. 2019 (AG120-C-001 untreated)	2014-03-12 to 2017-05-08	Phase 1/2 (RT)
====Biomarker eligibility criteria====
*Gene: IDH1
*Alteration: R132
====Targeted therapy====
*Ivosidenib (Tibsovo) 500 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AG120-C-001 untreated: Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, Altman JK, Arellano ML, Donnellan WB, Erba HP, Mannis GN, Pollyea DA, Stein AS, Uy GL, Watts JM, Fathi AT, Kantarjian HM, Tallman MS, Choe S, Dai D, Fan B, Wang H, Zhang V, Yen KE, Kapsalis SM, Hickman D, Liu H, Agresta SV, Wu B, Attar EC, Stone RM. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020 Feb 13;135(7):463-471. Epub 2019 Dec 16. link to original article link to PMC article EuroPMC NCT02074839
#HOVON 150 AML: NCT03839771
=IDH1 relapsed or refractory=
==Ivosidenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Efficacy
DiNardo et al. 2018 (AG120-C-001 r/r)	2014-03-12 to 2017-05-08	Phase 1/2 (RT)	ORR: 42%
====Biomarker eligibility criteria====
*Alteration: IDH1 R132 gene variant
====Targeted therapy====
*Ivosidenib (Tibsovo) 500 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AG120-C-001 r/r: 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. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018 Jun 21;378(25):2386-2398. Epub 2018 Jun 2. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02074839
==Olutasidenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Watts et al. 2022 (2102-HEM-101)	2016-2018 	Phase 1/2 (RT)	CR+CRh rate: 35%
====Biomarker eligibility criteria====
*Alteration: IDH1 R132 gene variant
====Targeted therapy====
*Olutasidenib (Rezlidhia) 150 mg PO twice per day
Continued indefinitely
===References===
#2102-HEM-101: Watts JM, Baer MR, Yang J, Prebet T, Lee S, Schiller GJ, Dinner SN, Pigneux A, Montesinos P, Wang ES, Seiter KP, Wei AH, De Botton S, Arnan M, Donnellan W, Schwarer AP, Récher C, Jonas BA, Ferrell PB Jr, Marzac C, Kelly P, Sweeney J, Forsyth S, Guichard SM, Brevard J, Henrick P, Mohamed H, Cortes JE. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023 Jan;10(1):e46-e58. Epub 2022 Nov 9. link to original article EuroPMC NCT02719574
=IDH2 first-line therapy, older or 'unfit' patients=
==Enasidenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Pollyea et al. 2019 (AG-221-C-001 untreated)	2013 to not reported	Phase 1/2
====Biomarker eligibility criteria====
*Alteration: IDH2 gene variant
====Targeted therapy====
*Enasidenib (Idhifa) 100 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AG-221-C-001 untreated: Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, Frattini MG, Xu Q, Tosolini A, See WL, MacBeth KJ, Agresta SV, Attar EC, DiNardo CD, Stein EM. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019 Nov;33(11):2575-2584. Epub 2019 Apr 9. link to original article link to PMC article EuroPMC NCT01915498
=IDH2 Relapsed or refractory=
==Azacitidine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
de Botton et al. 2023 (IDHENTIFY)	2015 to not reported	Phase 3 (C)	Enasidenib	Did not meet primary endpoint of OSMedian OS: 6.2 vs 6.5 mo(HR 1.16, 95% CI 0.91-1.49)
====Biomarker eligibility criteria====
*Alteration: IDH2 gene variant
====Chemotherapy====
*Azacitidine (Vidaza) 75 mg/m2 SC once per day on days 1 to 7
28-day cycles
===References===
#IDHENTIFY: de Botton S, Montesinos P, Schuh AC, Papayannidis C, Vyas P, Wei AH, Ommen H, Semochkin S, Kim HJ, Larson RA, Koprivnikar J, Frankfurt O, Thol F, Chromik J, Byrne J, Pigneux A, Thomas X, Salamero O, Vidriales MB, Doronin V, Döhner H, Fathi AT, Laille E, Yu X, Hasan M, Martin-Regueira P, DiNardo CD. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023 Jan 12;141(2):156-167. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02577406
==Enasidenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Stein et al. 2017 (AG-221-C-001 relapsed)	2013-2016 	Phase 1/2 (RT) 	 	ORR: 40%
de Botton et al. 2023 (IDHENTIFY) 	2015 to not reported	Phase 3 (E-switch-ooc)	1a. Azacitidine1b. LoDAC1c. IDAC1d. Best supportive care	Did not meet primary endpoint of OSMedian OS: 6.5 vs 6.2 mo(HR 0.86, 95% CI 0.67-1.10)
This is the dose used in the phase 2 expansion cohort; enrolled patients were required to have IDH2-mutated advanced myeloid malignancies.
====Biomarker eligibility criteria====
*Alteration: IDH2 gene variant
====Targeted therapy====
*Enasidenib (Idhifa) 100 mg PO once per day on days 1 to 28
28-day cycles
===References===
#AG-221-C-001 relapsed: 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. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731. Epub 2017 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01915498
#IDHENTIFY: de Botton S, Montesinos P, Schuh AC, Papayannidis C, Vyas P, Wei AH, Ommen H, Semochkin S, Kim HJ, Larson RA, Koprivnikar J, Frankfurt O, Thol F, Chromik J, Byrne J, Pigneux A, Thomas X, Salamero O, Vidriales MB, Doronin V, Döhner H, Fathi AT, Laille E, Yu X, Hasan M, Martin-Regueira P, DiNardo CD. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023 Jan 12;141(2):156-167. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02577406
==Low-dose Cytarabine monotherapy (LoDAC)==
LoDAC: Low Dose Ara-C (Cytarabine)
LDAC: Low-dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
de Botton et al. 2023 (IDHENTIFY)	2015 to not reported	Phase 3 (C)	Enasidenib	Did not meet primary endpoint of OSMedian OS: 6.2 vs 6.5 mo(HR 1.16, 95% CI 0.91-1.49)
====Biomarker eligibility criteria====
*Alteration: IDH2 gene variant
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 10
28-day cycles
===References===
#IDHENTIFY: de Botton S, Montesinos P, Schuh AC, Papayannidis C, Vyas P, Wei AH, Ommen H, Semochkin S, Kim HJ, Larson RA, Koprivnikar J, Frankfurt O, Thol F, Chromik J, Byrne J, Pigneux A, Thomas X, Salamero O, Vidriales MB, Doronin V, Döhner H, Fathi AT, Laille E, Yu X, Hasan M, Martin-Regueira P, DiNardo CD. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023 Jan 12;141(2):156-167. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02577406
Category:Acute myeloid leukemia regimens
Category:Biomarker-specific pages
Category:Acute leukemias