{"entity":{"id":"aml-older-unfit","kind":"cancer","name":"Acute myeloid leukaemia in older or unfit patients","aka":["Unfit AML","AML in the elderly","AML ineligible for intensive chemotherapy","Low-intensity AML therapy"],"tldr":"Most people with acute myeloid leukaemia are over 65, and many cannot take intensive chemotherapy. Venetoclax with azacitidine, two gentler drugs, doubled remission rates and lengthened life in this group, replacing the old choice between supportive care and low-dose chemotherapy.","summary":"Fitness for intensive induction is judged on age, performance status, organ function and comorbidity (the Ferrara criteria and geriatric assessment) rather than on a birthday. Older patients also carry worse biology: more adverse karyotypes, TP53 mutations and secondary disease, and fewer favourable NPM1 or core-binding-factor leukaemias. Until 2018 the options were azacitidine or decitabine alone, low-dose cytarabine or supportive care, with median survival under a year.\n\nVIALE-A, reported in 2020, randomised 431 newly diagnosed patients unfit for intensive therapy to venetoclax or placebo with azacitidine: composite complete remission 66.4 percent versus 28.3 percent, median overall survival 14.7 versus 9.6 months (hazard ratio 0.66), and 37.5 percent versus 16.7 percent alive at two years on longer follow-up. The benefit was largest in IDH-mutated and NPM1-mutated disease and smallest in TP53-mutated and FLT3-ITD disease. Venetoclax-azacitidine received full approval in 2020 and is the global standard; glasdegib with low-dose cytarabine is a lesser alternative, and ivosidenib-azacitidine competes in IDH1-mutated disease.\n\nThe regimen brings its own problems: prolonged neutropenia and infections, cycles that must be shortened or delayed, tumour lysis at the start, and azole antifungals that raise venetoclax levels. Current trials shorten the venetoclax course, add FLT3, IDH or menin inhibitors as triplets, take responders to reduced-intensity transplant, and test whether some fit older patients do better with venetoclax-azacitidine than with 7+3.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-flt3","aml-idh","aml-npm1-kmt2a","aml-secondary"],"cancers":[],"sections":[],"technologies":["bcl2-inhibitors","geriatric-assessment","g8-geriatric-screening"],"targets":["bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2"],"terms":["hma","tumor-lysis-syndrome","eln-risk"],"trials":["viale-a"],"people":[],"bottlenecks":[],"keyPapers":["paper-viale-a-venetoclax-azacitidine-nejm-2020","paper-agile-ivosidenib-azacitidine-nejm-2022","paper-aza-aml-001-dombret-blood-2015","paper-eln-2022-aml-dohner-blood-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The median age at diagnosis of acute myeloid leukaemia is about 68, and roughly half of patients are judged unable to withstand intensive chemotherapy because of age, frailty or other illnesses.","subtypes":["Newly diagnosed AML unfit for intensive chemotherapy (age 75 or over, or comorbidity)","AML in fit older patients (60 to 75) eligible for intensive therapy or CPX-351","IDH- or NPM1-mutated AML in unfit patients (best responders to venetoclax-azacitidine)","TP53-mutated AML in unfit patients","Relapsed AML after venetoclax-azacitidine"],"biomarkers":["Performance status and geriatric assessment","Comorbidity index and organ function","ELN 2022 risk group","IDH1/2, NPM1, FLT3 and TP53 mutations","Measurable residual disease by flow cytometry","Azole co-medication (venetoclax dose)"],"standardOfCare":[{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine (VIALE-A) or venetoclax plus decitabine; ivosidenib plus azacitidine for IDH1-mutated disease; targeted triplets in trials.","refs":["venetoclax","azacitidine","decitabine","viale-a","ivosidenib","agile","venetoclax-plus-hma"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Fit older patients, 60 to 75","approach":"7+3 or CPX-351 for secondary disease, with a FLT3 inhibitor where indicated, and reduced-intensity allogeneic transplant in remission.","refs":["cytarabine-7-3","cpx-351","midostaurin","quizartinib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Not a candidate for any leukaemia-directed therapy","approach":"Hydroxyurea for count control, transfusion support and palliative care; low-dose cytarabine or glasdegib combinations where tolerated.","refs":["hydroxyurea","transfusion-support","glasdegib","cytarabine"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapse after venetoclax-azacitidine","approach":"Genotype-directed drugs (gilteritinib, IDH inhibitors, menin inhibitors) or trials; transplant for the few who respond.","refs":["gilteritinib","ivosidenib","revumenib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["Venetoclax with azacitidine is the worldwide standard for unfit newly diagnosed patients, giving remission to two in three.","Geriatric assessment, not age alone, decides fitness for intensive treatment.","Reduced-intensity transplant after low-intensity remission is extending cure to patients in their seventies."],"history":[{"year":2004,"title":"Azacitidine approved for myelodysplastic syndromes, then adopted for low-blast AML","refs":["azacitidine"]},{"year":2018,"title":"Venetoclax and glasdegib combinations gain accelerated approval for unfit AML","refs":["venetoclax","glasdegib"]},{"year":2020,"title":"VIALE-A: venetoclax plus azacitidine lengthens life; full approval","refs":["viale-a","venetoclax","azacitidine"]},{"year":2022,"title":"AGILE: ivosidenib plus azacitidine for unfit IDH1-mutated patients","refs":["agile","ivosidenib"]}],"pipeline":["venetoclax","idea-shortened-venetoclax","myelomatch","g8-geriatric-screening","geriatric-assessment"],"openProblems":["How long venetoclax needs to be given, and whether MRD-negative patients can stop.","Whether fit older patients do better with venetoclax-azacitidine than with intensive chemotherapy.","Infections and cytopenias that keep older patients in hospital during a treatment meant to be gentle."],"parent":"aml"},"route":"/cancers/aml-older-unfit/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"aml-flt3","kind":"cancer","name":"FLT3-mutated acute myeloid leukaemia","route":"/cancers/aml-flt3/"},{"id":"aml-idh","kind":"cancer","name":"IDH1- and IDH2-mutated acute myeloid leukaemia","route":"/cancers/aml-idh/"},{"id":"aml-npm1-kmt2a","kind":"cancer","name":"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia","route":"/cancers/aml-npm1-kmt2a/"},{"id":"aml-secondary","kind":"cancer","name":"Secondary and therapy-related acute myeloid leukaemia","route":"/cancers/aml-secondary/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"bcl2-inhibitors","kind":"technology","name":"BCL-2 inhibitors","route":"/technologies/bcl2-inhibitors/"},{"id":"g8-geriatric-screening","kind":"technology","name":"G8 geriatric screening tool","route":"/technologies/g8-geriatric-screening/"},{"id":"geriatric-assessment","kind":"technology","name":"Geriatric assessment","route":"/technologies/geriatric-assessment/"},{"id":"transfusion-support","kind":"technology","name":"Transfusion support and anaemia management","route":"/technologies/transfusion-support/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"}],"pathway":[{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"}],"term":[{"id":"aml-myelodysplasia-related","kind":"term","name":"AML with myelodysplasia-related gene mutations (AML-MR)","route":"/terms/aml-myelodysplasia-related/"},{"id":"eln-risk","kind":"term","name":"ELN 2022 risk classification","route":"/terms/eln-risk/"},{"id":"hma","kind":"term","name":"Hypomethylating agents (azacitidine, decitabine)","route":"/terms/hma/"},{"id":"tumor-lysis-syndrome","kind":"term","name":"Tumour lysis syndrome (TLS)","route":"/terms/tumor-lysis-syndrome/"}],"trial":[{"id":"nct07743112","kind":"trial","name":"A Phase 2 Study of MAX-40279 Combined With Venetoclax and Azacitidine in Unfit Newly Diagnosed Acute Myeloid Leukemia","route":"/trials/nct07743112/"},{"id":"nct06389292","kind":"trial","name":"A Pivotal Study of APG-2575 (Lisaftoclax) Combined With Azacitidine in the Treatment of Acute Myeloid Leukemia","route":"/trials/nct06389292/"},{"id":"nct06852222","kind":"trial","name":"A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)","route":"/trials/nct06852222/"},{"id":"nct05520567","kind":"trial","name":"A Study of Gilteritinib, Venetoclax and Azacitidine as a Combined Treatment for People Newly Diagnosed With Acute Myeloid Leukemia","route":"/trials/nct05520567/"},{"id":"nct06456463","kind":"trial","name":"A Study of Tagraxofusp in Combination With Venetoclax and Azacitidine in Adults With Untreated CD123+ Acute Myeloid Leukemia Who Cannot Undergo Intensive Chemotherapy","route":"/trials/nct06456463/"},{"id":"agile","kind":"trial","name":"AGILE","route":"/trials/agile/"},{"id":"nct05907057","kind":"trial","name":"An Open-label Phase 3b Study of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy.","route":"/trials/nct05907057/"},{"id":"nct02781883","kind":"trial","name":"Clinical Trial of BP1001 in Combination With With Venetoclax Plus Decitabine in AML","route":"/trials/nct02781883/"},{"id":"nct05601726","kind":"trial","name":"First-in-human Study Aiming to Characterize the Safety, Tolerability, Pharmacokinetic and Preliminary Signs of Activity of ABD-3001 in Refractory or Relapsed AML and High Risk MDS Adult Patients","route":"/trials/nct05601726/"},{"id":"nct04093505","kind":"trial","name":"Gemtuzumab Ozogamicin in Induction and Glasdegib in Postremission Therapy in Patients With AML (Acute Myeloid Leukemia)","route":"/trials/nct04093505/"},{"id":"myelomatch","kind":"trial","name":"myeloMATCH","route":"/trials/myelomatch/"},{"id":"quazar-aml-001","kind":"trial","name":"QUAZAR AML-001","route":"/trials/quazar-aml-001/"},{"id":"nct03603795","kind":"trial","name":"Study Impact on Outcome of Eltrombopag in Elderly Patients with Acute Myeloid Leukemia Receiving Induction Chemotherapy","route":"/trials/nct03603795/"},{"id":"nct02665065","kind":"trial","name":"Study of Iomab-B vs. Conventional Care in Older Subjects With Active, Relapsed or Refractory Acute Myeloid Leukemia","route":"/trials/nct02665065/"},{"id":"nct05079230","kind":"trial","name":"Study of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Participants With Acute Myeloid Leukemia","route":"/trials/nct05079230/"},{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/"}],"paper":[{"id":"paper-agile-ivosidenib-azacitidine-nejm-2022","kind":"paper","name":"AGILE: ivosidenib plus azacitidine for newly diagnosed IDH1-mutated AML in patients unfit for intensive chemotherapy","route":"/key-papers/paper-agile-ivosidenib-azacitidine-nejm-2022/"},{"id":"paper-aza-aml-001-dombret-blood-2015","kind":"paper","name":"AZA-AML-001: azacitidine versus conventional care in older patients with acute myeloid leukaemia and more than 30 percent blasts","route":"/key-papers/paper-aza-aml-001-dombret-blood-2015/"},{"id":"paper-eln-2022-aml-dohner-blood-2022","kind":"paper","name":"ELN 2022: diagnosis and management of acute myeloid leukaemia in adults","route":"/key-papers/paper-eln-2022-aml-dohner-blood-2022/"},{"id":"paper-quazar-aml-001-wei-nejm-2020","kind":"paper","name":"QUAZAR AML-001: oral azacitidine maintenance for acute myeloid leukaemia in first remission","route":"/key-papers/paper-quazar-aml-001-wei-nejm-2020/"},{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","kind":"paper","name":"VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy","route":"/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"cpx-351","kind":"drug","name":"CPX-351 (liposomal daunorubicin-cytarabine)","route":"/drugs/cpx-351/"},{"id":"cytarabine","kind":"drug","name":"Cytarabine","route":"/drugs/cytarabine/"},{"id":"cytarabine-7-3","kind":"drug","name":"Cytarabine + anthracycline ('7+3')","route":"/drugs/cytarabine-7-3/"},{"id":"decitabine","kind":"drug","name":"Decitabine","route":"/drugs/decitabine/"},{"id":"gilteritinib","kind":"drug","name":"Gilteritinib","route":"/drugs/gilteritinib/"},{"id":"glasdegib","kind":"drug","name":"Glasdegib","route":"/drugs/glasdegib/"},{"id":"hydroxyurea","kind":"drug","name":"Hydroxyurea (hydroxycarbamide)","route":"/drugs/hydroxyurea/"},{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"},{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"},{"id":"quizartinib","kind":"drug","name":"Quizartinib","route":"/drugs/quizartinib/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"idea":[{"id":"idea-shortened-venetoclax","kind":"idea","name":"Shorter venetoclax courses in unfit AML","route":"/ideas/idea-shortened-venetoclax/"}],"pairing":[{"id":"venetoclax-plus-hma","kind":"pairing","name":"Venetoclax + hypomethylating agent","route":"/pairings/venetoclax-plus-hma/"}],"person":[{"id":"herve-dombret","kind":"person","name":"Hervé Dombret","route":"/people/herve-dombret/"}]}}