Difference between revisions of "Acute myeloid leukemia, IDH-mutated"

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m (Text replacement - "==[https://www.nccn.org/ NCCN]==" to "==NCCN==")
 
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''
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<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
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[[#top|Back to Top]]
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| style="background-color:#F0F0F0; width:15%" |[[File:MartinSchoen.jpg|frameless|upright=0.3|center]]
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</div>
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| style="width:35%" |<big>[[User:Marteens|Martin W. Schoen, MD, MPH]]<br>Saint Louis University<br>St. Louis, MO</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/mwschoen mwschoen]
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{{#lst:Editorial board transclusions|aml}}
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<big>'''Note: these are regimens tested in biomarker-specific populations for patients with IDH-mutated AML, please see the [[Acute myeloid leukemia|main AML page]] for other regimens.'''</big>
 
<big>'''Note: these are regimens tested in biomarker-specific populations for patients with IDH-mutated AML, please see the [[Acute myeloid leukemia|main AML page]] for other regimens.'''</big>
 
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 +
=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 [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411 NCCN Guidelines - Acute Myeloid Leukemia].''
 
=IDH1 first-line therapy, older or 'unfit' patients=
 
=IDH1 first-line therapy, older or 'unfit' patients=
−
==Ivosidenib monotherapy {{#subobject:b11758|Regimen=1}}==
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==Azacitidine monotherapy {{#subobject:791718|Regimen=1}}==
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{| class="wikitable" style="float:right; margin-left: 5px;"
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<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:7509ab|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2117344 Montesinos et al. 2022 (AGILE)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Azacitidine_.26_Ivosidenib|Azacitidine & Ivosidenib]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*IDH1 mutation
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 7
 +
'''28-day cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1056/nejmoa2117344 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35443108/ PubMed] [https://clinicaltrials.gov/study/NCT03173248 NCT03173248]
 +
==Azacitidine & Ivosidenib {{#subobject:79gjaa8|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:7y15ab|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2117344 Montesinos et al. 2022 (AGILE)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Azacitidine_monotherapy|Azacitidine]]
 +
| style="background-color:#1a9850" |Superior EFS (primary endpoint)<br>EFS12: 37% vs 12%<br>(HR 0.33, 95% CI 0.16-0.69)<br><br>Superior OS (secondary endpoint)<br>Median OS: 24 vs 7.9 mo<br>(HR 0.44, 95% CI 0.27-0.73)
 
|-
 
|-
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|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*IDH1 mutation
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> 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'''
 +
</div></div>
 +
===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. [https://doi.org/10.1056/nejmoa2117344 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35443108/ PubMed] [https://clinicaltrials.gov/study/NCT03173248 NCT03173248]
 +
==Ivosidenib monotherapy {{#subobject:b11758|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:40a68c|Variant=1}}===
 
===Regimen {{#subobject:40a68c|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
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|-
 
|-
 
|}
 
|}
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{| class="wikitable" style="width: 50%; text-align:center;"  
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{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
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!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
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!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/132/Suppl_1/561 AG120-C-001]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7019193/ Roboz et al. 2019 (AG120-C-001 untreated)]
−
| style="background-color:#91cf61" |Phase I/II
+
|2014-03-12 to 2017-05-08
 +
| style="background-color:#91cf61" |Phase 1/2 (RT)
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
−
 
+
*Gene: IDH1
−
*Alteration: IDH1 R132 gene variant
+
*Alteration: R132
−
 
+
</div>
−
====Chemotherapy====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
*[[Ivosidenib (Tibsovo)]] 500 mg PO once per day
+
*[[Ivosidenib (Tibsovo)]] 500 mg PO once per day on days 1 to 28
−
 
+
'''28-day cycles'''
−
'''Continued indefinitely'''
+
</div></div>
  
 
===References===
 
===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. [https://doi.org/10.1182/blood.2019002140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7019193/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31841594/ PubMed] [https://clinicaltrials.gov/study/NCT02074839 NCT02074839]
−
#'''AG120-C-001:''' 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. [https://ashpublications.org/blood/article-lookup/doi/10.1182/blood.2019002140 Blood. 2019 Dec 16. Epub ahead of print] [https://clinicaltrials.gov/ct2/show/NCT02074839 NCT02074839]
+
#'''HOVON 150 AML:''' [https://clinicaltrials.gov/study/NCT03839771 NCT03839771]
−
 
+
=IDH1 relapsed or refractory=
−
=IDH1 relapsed or refractory, salvage therapy=
 
 
==Ivosidenib monotherapy {{#subobject:214f83|Regimen=1}}==
 
==Ivosidenib monotherapy {{#subobject:214f83|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
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<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:e548f6|Variant=1}}===
 
===Regimen {{#subobject:e548f6|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
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|-
 
|-
 
|}
 
|}
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{| class="wikitable" style="width: 75%; text-align:center;"  
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{| class="wikitable sortable" style="width: 80%; text-align:center;"  
−
! style="width: 33%" |Study
+
!style="width: 25%"|Study
−
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 25%"|Dates of enrollment
−
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/10.1056/NEJMoa1716984 DiNardo et al. 2018 (AG120-C-001)]
+
|[https://doi.org/10.1056/NEJMoa1716984 DiNardo et al. 2018 (AG120-C-001 r/r)]
−
| style="background-color:#91cf61" |Phase I/II (RT)
+
|2014-03-12 to 2017-05-08
 +
| style="background-color:#91cf61" |Phase 1/2 (RT)
 
| style="background-color:#8c96c6" |ORR: 42%
 
| style="background-color:#8c96c6" |ORR: 42%
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
 +
*Alteration: IDH1 R132 gene variant
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Ivosidenib (Tibsovo)]] 500 mg PO once per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div>
  
 +
===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. [https://doi.org/10.1056/NEJMoa1716984 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29860938/ PubMed] [https://clinicaltrials.gov/study/NCT02074839 NCT02074839]
 +
==Olutasidenib monotherapy {{#subobject:21gj23|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:e5kgx6|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|Dates of enrollment
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s2352-3026(22)00292-7 Watts et al. 2022 (2102-HEM-101)]
 +
|2016-2018
 +
| style="background-color:#91cf61" |Phase 1/2 (RT)
 +
| style="background-color:#8c96c6" |CR+CRh rate: 35%
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 
*Alteration: IDH1 R132 gene variant
 
*Alteration: IDH1 R132 gene variant
−
 
+
</div>
−
====Chemotherapy====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
*[[Ivosidenib (Tibsovo)]] 500 mg PO once per day
+
*[[Olutasidenib (Rezlidhia)]] 150 mg PO twice per day
−
 
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
+
</div></div>
 
===References===
 
===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. [https://doi.org/10.1016/s2352-3026(22)00292-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370742/ PubMed] [https://clinicaltrials.gov/study/NCT02719574 NCT02719574]
−
#'''AG120-C-001:''' 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. [https://www.nejm.org/doi/10.1056/NEJMoa1716984 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29860938 PubMed]
 
  
 
=IDH2 first-line therapy, older or 'unfit' patients=
 
=IDH2 first-line therapy, older or 'unfit' patients=
 
==Enasidenib monotherapy {{#subobject:b11758|Regimen=1}}==
 
==Enasidenib monotherapy {{#subobject:b11758|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:40a68c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9724489/ Pollyea et al. 2019 (AG-221-C-001 untreated)]
 +
|2013-NR
 +
| style="background-color:#91cf61" |Phase 1/2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:40a68c|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*Alteration: IDH2 gene variant
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Enasidenib (Idhifa)]] 100 mg PO once per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1038/s41375-019-0472-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9724489/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30967620/ PubMed] [https://clinicaltrials.gov/study/NCT01915498 NCT01915498]
  
−
{| class="wikitable" style="width: 50%; text-align:center;"  
+
=IDH2 Relapsed or refractory=
−
! style="width: 25%" |Study
+
==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}==
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:39f96a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pubmed/30967620 AG120-C-001]
+
|[https://doi.org/10.1182/blood.2021014901 de Botton et al. 2023 (IDHENTIFY)]
−
| style="background-color:#91cf61" |Phase I/II
+
|2015-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enasidenib_monotherapy_2|Enasidenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
−
 
 
*Alteration: IDH2 gene variant
 
*Alteration: IDH2 gene variant
−
 
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
 
+
*[[Azacitidine (Vidaza)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 7
−
*[[Enasidenib (Idhifa)]] 100 mg PO once per day
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===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. [https://doi.org/10.1182/blood.2021014901 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35714312/ PubMed] [https://clinicaltrials.gov/study/NCT02577406 NCT02577406]
  
−
#'''AG-221-C-001:''' 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. [https://www.ncbi.nlm.nih.gov/pubmed/30967620 Pubmed] [https://clinicaltrials.gov/ct2/show/NCT01915498 NCT01915498]
 
−
 
−
=IDH2 Relapsed or refractory, salvage therapy=
 
 
==Enasidenib monotherapy {{#subobject:226cb2|Regimen=1}}==
 
==Enasidenib monotherapy {{#subobject:226cb2|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:c110c9|Variant=1}}===
 
===Regimen {{#subobject:c110c9|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 122: Line 231:
 
|-
 
|-
 
|}
 
|}
−
{| class="wikitable" style="width: 75%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 33%" |Study
+
!style="width: 20%"|Study
−
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Dates of enrollment
−
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/ Stein et al. 2017 (AG-221-C-001)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/ Stein et al. 2017 (AG-221-C-001 relapsed)]
−
| style="background-color:#91cf61" |Phase I/II (RT)
+
|2013-2016
 +
| style="background-color:#91cf61" |Phase 1/2 (RT)
 +
|
 
| style="background-color:#8c96c6" |ORR: 40%
 
| style="background-color:#8c96c6" |ORR: 40%
 +
|-
 +
|[https://doi.org/10.1182/blood.2021014901 de Botton et al. 2023 (IDHENTIFY)]
 +
|2015-NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|1a. [[#Azacitidine_monotherapy_2|Azacitidine]]<br>1b. [[#Low-dose_Cytarabine_monotherapy_.28LoDAC.29|LoDAC]]<br>1c. [[#Intermediate-dose_Cytarabine_monotherapy_.28IDAC.29_888|IDAC]]<br>1d. [[Acute_myeloid_leukemia_-_null_regimens#Best_supportive_care_888|Best supportive care]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 6.5 vs 6.2 mo<br>(HR 0.86, 95% CI 0.67-1.10)
 
|-
 
|-
 
|}
 
|}
−
''This is the dose used in the phase II expansion cohort; enrolled patients were required to have IDH2-mutated advanced myeloid malignancies.''
+
''This is the dose used in the phase 2 expansion cohort; enrolled patients were required to have IDH2-mutated advanced myeloid malignancies.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
 +
*Alteration: IDH2 gene variant
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Enasidenib (Idhifa)]] 100 mg PO once per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div>
 +
===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. [http://www.bloodjournal.org/content/130/6/722.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28588020/ PubMed] [https://clinicaltrials.gov/study/NCT01915498 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. [https://doi.org/10.1182/blood.2021014901 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35714312/ PubMed] [https://clinicaltrials.gov/study/NCT02577406 NCT02577406]
  
 +
==Low-dose Cytarabine monotherapy (LoDAC) {{#subobject:25e1c6|Regimen=1}}==
 +
LoDAC: '''<u>Lo</u>'''w '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
 +
<br>LDAC: '''<u>L</u>'''ow-dose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:a3d4fb|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1182/blood.2021014901 de Botton et al. 2023 (IDHENTIFY)]
 +
|2015-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enasidenib_monotherapy_2|Enasidenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 
*Alteration: IDH2 gene variant
 
*Alteration: IDH2 gene variant
−
 
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
 
+
*[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10
−
*[[Enasidenib (Idhifa)]] 100 mg PO once per day
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===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. [https://doi.org/10.1182/blood.2021014901 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35714312/ PubMed] [https://clinicaltrials.gov/study/NCT02577406 NCT02577406]
−
#'''AG-221-C-001:''' 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. [http://www.bloodjournal.org/content/130/6/722.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28588020 PubMed]
 
  
 
[[Category:Acute myeloid leukemia regimens]]
 
[[Category:Acute myeloid leukemia regimens]]
 
[[Category:Biomarker-specific pages]]
 
[[Category:Biomarker-specific pages]]
 
[[Category:Acute leukemias]]
 
[[Category:Acute leukemias]]

Latest revision as of 11:33, 13 May 2024

Back to Top

Section editor
AK.JPG
 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

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

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

Targeted therapy

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

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

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

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

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

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

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

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
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