Acute myeloid leukemia, IDH-mutated

Section editor
	Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA LinkedIn

Note: these are regimens tested in biomarker-specific populations for patients with IDH-mutated AML, please see the main AML page for other regimens.

8 regimens on this page 8 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	Inferior 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 cycles

References

1. 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 contains dosing details in abstract PubMed 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	Superior EFS (primary endpoint) EFS12: 37% vs 12% (HR 0.33, 95% CI 0.16-0.69) Superior 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 cycles

References

1. 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 contains dosing details in abstract PubMed 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

1. 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 PubMed NCT02074839
2. 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

1. 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 contains dosing details in abstract PubMed 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

1. 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 PubMed 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-NR	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

1. 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 PubMed NCT01915498

IDH2 Relapsed or refractory

Azacitidine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
de Botton et al. 2023 (IDHENTIFY)	2015-NR	Phase 3 (C)	Enasidenib	Did not meet primary endpoint of OS

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

1. 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 contains dosing details in manuscript PubMed 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-NR	Phase 3 (E-switch-ooc)	1a. Azacitidine 1b. LoDAC 1c. IDAC 1d. Best supportive care	Did not meet primary endpoint of OS Median 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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT01915498
2. 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 contains dosing details in manuscript PubMed 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-NR	Phase 3 (C)	Enasidenib	Did not meet primary endpoint of OS

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

1. 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 contains dosing details in manuscript PubMed NCT02577406