Difference between revisions of "Acute myeloid leukemia, IDH-mutated"
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− | < | + | <span id="BackToTop"></span> |
− | + | <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"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
− | <big>'''Note: these are biomarker-specific | + | {{#lst:Editorial board transclusions|aml}} |
− | + | <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> | |
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
− | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div> | + | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div> |
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> | ||
|} | |} | ||
{{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= | ||
+ | ==Azacitidine monotherapy {{#subobject:791718|Regimen=1}}== | ||
+ | <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) | ||
+ | |- | ||
+ | |} | ||
+ | <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}}=== | ||
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
+ | |- | ||
+ | |} | ||
+ | {| 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/pmc7019193/ Roboz et al. 2019 (AG120-C-001 untreated)] | ||
+ | |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==== | ||
+ | *Gene: IDH1 | ||
+ | *Alteration: R132 | ||
+ | </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=== |
− | ==Enasidenib monotherapy {{#subobject: | + | #'''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] |
− | {| class="wikitable" style=" | + | #'''HOVON 150 AML:''' [https://clinicaltrials.gov/study/NCT03839771 NCT03839771] |
+ | =IDH1 relapsed or refractory= | ||
+ | ==Ivosidenib monotherapy {{#subobject:214f83|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:e548f6|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/10.1056/NEJMoa1716984 DiNardo et al. 2018 (AG120-C-001 r/r)] | ||
+ | |2014-03-12 to 2017-05-08 | ||
+ | | style="background-color:#91cf61" |Phase 1/2 (RT) | ||
+ | | style="background-color:#8c96c6" |ORR: 42% | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====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 | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Olutasidenib (Rezlidhia)]] 150 mg PO twice per day | ||
+ | '''Continued indefinitely''' | ||
+ | </div></div> | ||
+ | ===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] | ||
+ | |||
+ | =IDH2 first-line therapy, older or 'unfit' patients= | ||
+ | ==Enasidenib monotherapy {{#subobject:b11758|Regimen=1}}== | ||
+ | <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 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ====Biomarker eligibility criteria==== |
− | !Study | + | *Alteration: IDH2 gene variant |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | </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] | ||
+ | |||
+ | =IDH2 Relapsed or refractory= | ||
+ | ==Azacitidine monotherapy {{#subobject:531b70|Regimen=1}}== | ||
+ | <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:// | + | |[https://doi.org/10.1182/blood.2021014901 de Botton et al. 2023 (IDHENTIFY)] |
− | |style="background-color:# | + | |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 | ||
+ | </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 |
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===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] | ||
+ | ==Enasidenib monotherapy {{#subobject:226cb2|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:c110c9|Variant=1}}=== | ||
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
+ | |- | ||
+ | |} | ||
+ | {| 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/pmc/articles/PMC5572791/ Stein et al. 2017 (AG-221-C-001 relapsed)] | ||
+ | |2013-2016 | ||
+ | | style="background-color:#91cf61" |Phase 1/2 (RT) | ||
+ | | | ||
+ | | 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 2 expansion cohort; enrolled patients were required to have IDH2-mutated advanced myeloid malignancies.'' | ||
+ | <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''' | '''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. [https://doi.org/10.1182/blood-2017-04-779405 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 | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Cytarabine (Ara-C)]] 20 mg SC twice per day on days 1 to 10 | ||
+ | '''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] |
[[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 00:53, 27 June 2024
Section editor | |
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Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA |
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
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 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
- 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
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 PubMed 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
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 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
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 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
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 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
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 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
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 contains dosing details in manuscript link to PMC article PubMed 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 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
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 contains dosing details in manuscript PubMed NCT02577406