What is the prognosis for acute myeloid leukemia (AML)?

Prognosis for Acute Myeloid Leukemia

The prognosis of AML is highly heterogeneous, with overall 5-year survival ranging from less than 10% in adverse-risk elderly patients to over 70% in favorable-risk younger patients, primarily determined by cytogenetic abnormalities, molecular mutations, patient age, and treatment response. 1

Overall Survival by Age Group

The single most powerful patient-related prognostic factor is age, which independently predicts both treatment-related mortality and disease outcomes 2, 1:

• Pediatric patients (<18 years): 60-75% 5-year survival 1
• Younger adults (18-60 years): 30-40% 5-year survival 1
• Older adults (>60 years): Significantly worse outcomes, with median age at diagnosis of 67-71 years 2, 1
• Elderly patients (≥75 years): Comprise approximately one-third of diagnoses with particularly poor prognosis 2

The mortality rate in the general population is approximately 4-6 deaths per 100,000 per year 2. An estimated 10,920 patients will die of AML annually in the United States 2.

Cytogenetic Risk Stratification

Cytogenetics represent the most powerful predictor of response to induction therapy and survival 2, 1. The European LeukemiaNet classification divides patients into three risk categories:

Favorable-Risk Cytogenetics (Best Prognosis)

The following abnormalities confer favorable prognosis 2, 1:

• t(15;17)(q22;q21)/PML-RARA (acute promyelocytic leukemia): Approximately 70% cure rate with ATRA-based therapy 2
• t(8;21)(q22;q22)/RUNX1-RUNX1T1: Core binding factor AML 2, 1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11: Core binding factor AML with myelomonocytic differentiation and eosinophilia 2, 1

Intermediate-Risk Cytogenetics

This category includes 2, 1:

• Normal karyotype (cytogenetically normal AML) without favorable molecular markers 2
• t(9;11)(p22;q23)/MLLT3-MLL 2, 1
• Isolated trisomy 8 2

Adverse-Risk Cytogenetics (Worst Prognosis)

The following abnormalities predict poor outcomes 2, 1:

• Complex karyotype (≥3 unrelated chromosomal abnormalities): Occurs in 10-12% of patients and consistently associated with very poor outcome 2
• Monosomy 5 or deletion 5q 2
• Monosomy 7 or deletion 7q 2
• inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1: Associated with 3-year overall survival of only 8.8% in newly diagnosed patients and 5-year survival of 6% without transplant 3
• t(6;9)(p23;q34)/DEK-NUP214 2
• t(v;11)(v;q23)/MLL rearrangements (excluding t(9;11)) 2

Molecular Genetic Refinement of Prognosis

Within cytogenetically normal AML, molecular mutations critically refine prognosis 2, 1, 4:

Favorable Molecular Markers

• NPM1 mutation WITHOUT FLT3-ITD or with FLT3-ITD allelic ratio <0.5 2, 1
• Biallelic CEBPA mutations 2, 1, 4

Adverse Molecular Markers

• FLT3-ITD with high mutant allele burden (≥0.5 allelic ratio): Predicts high and early relapse rate 2, 1, 4
• TP53 mutations: Frequently associated with complex karyotype and confer worst prognosis 2, 1
• RUNX1, ASXL1, DNMT3A mutations: Associated with adverse outcomes 1, 4
• KIT mutations in core binding factor AML: Worsen otherwise favorable prognosis 1, 4

Secondary and Therapy-Related AML

Therapy-related AML (t-AML) and AML evolved from prior MDS carry uniformly poor prognosis 2, 1:

• t-AML accounts for 5-20% of all AML cases 2
• Associated with prior exposure to alkylating agents, topoisomerase inhibitors, or radiotherapy 2
• Disease course is generally progressive and more resistant to conventional cytotoxic therapies than de novo AML 2
• Remains an independent adverse prognostic factor even after adjusting for cytogenetics 1

Treatment Response and Relapse Prognosis

Complete remission rates vary substantially by risk group and treatment intensity 2, 1:

• Favorable-risk patients: Higher CR rates with chemotherapy alone
• Intermediate and adverse-risk patients: Lower CR rates, often requiring allogeneic stem cell transplantation for cure 2

Relapsed AML carries extremely poor prognosis 1:

• Favorable relapse risk (first remission >6 months, favorable cytogenetics): 1-year survival 70%, 5-year survival 46% 1
• Duration of first remission <6 months: Worst prognostic factor for relapse 1
• Post-transplant relapse: 3-year survival only 4-12% even at first relapse 5
• Third or subsequent relapse: Median survival approximately 4 months with 30-day mortality risk ≥14% with intensive salvage 5

Critical Prognostic Pitfalls

Several factors worsen prognosis beyond genetic features 2, 6:

• Elevated white blood cell count at presentation: Associated with worse outcomes 2, 6
• Poor performance status and comorbidities: Predict higher treatment-related mortality, particularly in elderly patients 2
• Failure to achieve CR after 2 induction cycles: Should reclassify patients as adverse-risk regardless of initial genetic profile 2
• Body mass index outside normal range: Associated with increased mortality incidence 6

Minimal Residual Disease Monitoring

MRD assessment provides independent prognostic information beyond initial risk stratification 1:

• Flow cytometry-based MRD monitoring is increasingly used, particularly in favorable-risk subgroups 2, 1
• MRD positivity after treatment predicts higher relapse risk 1