What is the overall prognosis for acute myeloid leukemia based on patient age, performance status, cytogenetic/molecular risk category (European LeukemiaNet classification) and treatment approach (intensive 7 + 3 induction, low‑intensity regimens, targeted agents, or allogeneic stem‑cell transplantation)?

Prognosis of Acute Myeloid Leukemia by Risk Stratification

The overall prognosis of AML varies dramatically from >70% 5-year survival in favorable-risk younger patients to <5% in adverse-risk elderly patients, with cytogenetic/molecular classification (ELN criteria) being the strongest predictor of outcomes, followed by age and performance status, which together determine whether intensive 7+3 induction, low-intensity regimens, or allogeneic transplantation should be pursued. 1, 2

Cytogenetic and Molecular Risk Categories (ELN Classification)

Favorable-Risk Disease

• Favorable-risk AML includes t(15;17)/PML-RARA (achieving ~70% cure rate), t(8;21)/RUNX1-RUNX1T1, and inv(16)/CBFB-MYH11, along with NPM1-mutated without FLT3-ITD (or FLT3-ITD allelic ratio <0.5) and biallelic CEBPA mutations 1, 2
• In younger patients (<60 years) with favorable-risk genetics, median overall survival reaches 5.3 years with intensive chemotherapy, and 3-year leukemia-free survival after allogeneic transplant approaches 67.8% 3, 4
• Older patients (≥60 years) with favorable-risk disease still achieve significantly better outcomes than other risk groups, with 3-year leukemia-free survival of approximately 50% after transplant, though this remains inferior to younger favorable-risk patients 3, 5

Intermediate-Risk Disease

• Intermediate-I risk includes cytogenetically normal AML with FLT3-ITD mutation and t(9;11)/MLLT3-MLL, with median OS of 1.1 years in younger patients receiving intensive chemotherapy 1, 4
• Intermediate-II risk encompasses cytogenetically normal AML without favorable or adverse molecular markers, showing median OS of 1.6 years in younger patients—notably better than intermediate-I despite historical grouping 4, 5
• The distinction between intermediate-I and intermediate-II becomes less clinically meaningful in patients ≥60 years, where both subgroups demonstrate similar outcomes with remission rates of 40-50% using standard cytarabine-anthracycline regimens 1, 4
• Critical caveat: Among intermediate-risk patients, FLT3-ITD with high mutant allele burden (≥0.5) predicts high early relapse rates and should prompt consideration of allogeneic transplant in first remission 1, 2

Adverse-Risk Disease

• Adverse-risk cytogenetics include complex karyotype (≥3 unrelated abnormalities, occurring in 10-12% of patients), monosomy 5/del(5q), monosomy 7/del(7q), inv(3)/t(3;3), t(6;9), and non-t(9;11) MLL rearrangements 1, 2
• TP53 mutations, present in approximately two-thirds of complex karyotype cases, confer the worst prognosis with median OS of 0.5 years in younger patients and even shorter survival in older adults 1, 2
• Monosomal karyotype (single monosomy excluding loss of X/Y, or ≥2 monosomies) represents a particularly unfavorable subset with 3-year leukemia-free survival of only 18-24% even with allogeneic transplant 1, 3
• Therapy-related AML (t-AML) and secondary AML from antecedent MDS carry uniformly poor prognosis, with CR rates of only 28% with standard chemotherapy and 3-year OS of approximately 20-30% even with allogeneic transplant 1, 2

Age-Stratified Outcomes

Younger Adults (<60 Years)

• Overall 5-year survival ranges from 30-40% across all risk groups, with linear decline in outcomes as age increases even within this "younger" cohort 2, 6
• The ELN classification maintains clear prognostic separation in younger patients, with significant differences in OS between all four genetic risk groups (favorable, intermediate-I, intermediate-II, adverse) 4, 5
• Treatment-related mortality remains acceptable (<10-15%) with intensive 7+3 induction in younger patients with good performance status (ECOG 0-2) 1

Older Adults (≥60 Years)

• No improvement in outcomes has been documented over the past 3 decades for patients >60 years, in stark contrast to younger patients who have experienced significant survival gains 1
• Patients aged >75 years or those with ECOG performance status >2 experience treatment-related mortality that frequently exceeds any transient response to intensive chemotherapy 1
• Within each ELN risk group, older patients demonstrate significantly worse outcomes than younger patients: favorable-risk OS 49.8% vs 67.8%, intermediate-I 50.7% vs 53.4%, intermediate-II 20.2% vs 65.7%, and adverse-risk 23.8% vs 44.6% at 3 years 3, 5
• Chronological age alone should not determine treatment decisions; performance status, comorbidities, and disease genetics must be integrated using validated predictive models (available at http://www.aml-score.org/ and http://www.amlcompositemodel.org/) 1

Treatment Approach and Prognosis

Intensive 7+3 Induction

• Standard-dose cytarabine (100-200 mg/m² × 7 days) plus anthracycline (3 days) remains the backbone for medically fit patients with favorable or intermediate-risk disease, achieving CR rates of 40-50% in older patients with normal karyotype 1
• Older adults with intact functional status (ECOG 0-2), minimal comorbidity, and de novo AML without unfavorable genetics may benefit from intensive therapy regardless of chronologic age, though outcomes remain inferior to younger patients 1
• Predictive models incorporating performance status, age, platelet count, serum albumin, secondary AML status, WBC, blast percentage, and creatinine achieve AUC of 0.82 for predicting early death after induction 1

Low-Intensity Regimens

• Patients aged >75 years with significant comorbidities generally do not benefit from conventional chemotherapy, with the rare exception of favorable-risk or normal karyotype AML without comorbidities 1
• Low-intensity approaches (hypomethylating agents, low-dose cytarabine) are appropriate for patients with ECOG >2, adverse cytogenetics, therapy-related AML, or antecedent hematologic disorder where intensive therapy carries prohibitive mortality risk 1

Targeted Agents

• FLT3-mutated AML: Addition of midostaurin to 7+3 induction improves outcomes in FLT3-positive disease, though high FLT3-ITD allelic burden still predicts early relapse requiring allogeneic transplant consolidation 1
• Targeted therapies provide modest disease control but limited survival benefit in heavily pretreated or relapsed patients, with gilteritinib achieving median OS of 9.3 months in first relapse but significantly less in subsequent relapses 7

Allogeneic Stem Cell Transplantation

• Allogeneic HSCT offers the best chance for durable remission in intermediate and adverse-risk patients, with 3-year leukemia-free survival of 44-68% depending on risk group and age 3, 8
• Chronological age between 60-75 years is not a reliable predictor of transplant outcome; performance status, comorbidities, and disease genetics are more informative 8
• Post-transplant relapse carries extremely poor prognosis, with 3-year survival of only 4-12% even at first relapse, and median OS of 3-6 months at third recurrence 9, 7
• Reduced-intensity conditioning (RIC) regimens have expanded transplant access to older patients, though relapse incidence remains higher compared to myeloablative conditioning 1

Relapsed Disease Prognosis

• Relapsed AML is stratified by a validated prognostic index incorporating remission duration, cytogenetics at diagnosis, prior transplant, and age at relapse 1
• Favorable relapse risk (9% of patients, score 0-6 points): 1-year survival 70%, 5-year survival 46% 1
• Intermediate relapse risk (25% of patients, score 7-9 points): 1-year survival 49%, 5-year survival 18% 1
• Unfavorable relapse risk (66% of patients, score 10-14 points): 1-year survival 16%, 5-year survival 4% 1
• Relapse within 6 months of initial CR or post-transplant relapse confers the worst prognosis, with median survival of 3-6 months and long-term survival approaching 0% 9, 7

Critical Prognostic Pitfalls

• Elevated WBC at presentation independently predicts worse outcomes across all risk groups 1
• Failure to achieve CR after two induction cycles should reclassify patients as adverse-risk regardless of initial genetic profile 2
• Complex karyotype with TP53 mutation represents the most adverse biology, with outcomes so poor that clinical trial enrollment or palliative approaches should be strongly considered 1, 2
• Secondary cytogenetic abnormalities (e.g., trisomy 8, del(9q)) in the context of favorable translocations generally do not worsen prognosis, with the possible exception of trisomy 22 in inv(16) AML 1