The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS). The classification, available in a free online tool, is easy to apply to routine clinical practice and provides crucial information on survival after allogeneic hematopoietic cell transplantation (alloHCT). Jurjen Versluis, MD, PhD, of Erasmus University Medical Center Cancer Institute in the Netherlands, and colleagues reported that AML60+ can identify patients who will benefit from intensive chemotherapy and alloHCT. The investigators published their findings in the Journal of Clinical Oncology.
Hematologists often diagnose AML in patients older than 60 years, and alloHCT represents the most important curative consolidation therapy for these individuals. However, the treatment is potentially toxic, so hematologists must identify which older patients with AML are most likely to benefit from it. While devised using data from younger patients, the 2017 European LeukemiaNet (ELN2017) and ELN2022 classifications nevertheless segregate older patients with AML into distinct risk groups: favorable, intermediate, and adverse. The classifications do not, however, speak to the survival rates of patients older than 60 years, which can be quite variable.
“This new model works even better compared with previous classification systems for younger patients with AML,” Dr. Versluis said, adding “We hope this one will be used from now on in older patients with AML.”
The retrospective study included 1,910 patients from two cohorts: NCRI-AML18 and HOVON-SAKK. Patients were treated over a 12-year period and had a median age of 67 years (range = 60-84). The investigators found that the patients had a high frequency of poor-risk features, including ELN2022 adverse risk (57.3%) and mutated TP53 (14.4%). Approximately two-thirds (65.3%) had MDS-related cytogenic changes, mutations in genes associated with secondary AML, or a combination of both, while only 9.1% had a clinical diagnosis of secondary AML. The findings are consistent with the fact that AML is a genetically heterogeneous disease, particularly in older patients.
The researchers used a machine learning random survival forest algorithm to determine the importance of patient-specific genetic and cytogenetic variables in the risk stratification of patients for overall survival (OS). The three most important variables at diagnosis in predicting survival were the presence of a TP53 mutation (hazard ratio [HR] = 2.42; 95% CI 1.83-3.21), monosomal karyotype (HR=2.06; 95% CI 1.56-2.7]), and being older than 65 (HR=1.50; 1.31-1.72) of the nine variables identified. Finally, these nine variables were assigned points on the basis of their rounded HRs. Mutated TP53 and monosomal karyotype were assigned three points; being older than 65 was assigned two points; and a white blood cell count higher than 20 × 109/L, male sex, FLT3 internal tandem duplication, and mutations in DNMT3A, ASXL1, and RUNX1 were each assigned one point.
“This is a data-driven risk model, specifically for older patients with AML,” Dr. Versluis said.
He and his colleagues used the top discriminatory variables sequentially in a Cox regression analysis for OS to define the optimal model, after which they identified nine variables and used them to construct four groups with highly distinct four-year OS: favorable, intermediate, poor, and very poor. The favorable-risk group included relatively younger, primarily female patients lacking adverse-risk molecular, cytogenetic features, or both.
Having developed AML60+, the researchers next validated the classification in two cohorts: an AML validation and an HR-MDS test cohort. They noted that the AML development cohort was slightly younger than the AML validation cohort (66 vs. 68 years). The new risk model showed strong prognostic separation of OS in the AML development, AML validation, and HR-MDS test cohorts. The investigators reported that patients classified as AML60+ intermediate- and very poor-risk had significantly improved OS after alloHCT for consolidation treatment. In contrast, the poor-risk subgroup had only slightly improved OS after alloHCT. The authors concluded that AML60+ must be validated in other cohorts and refined as optimal treatment evolves.
The authors noted several limitations of the study, such as its retrospective nature, with multiple patient cohorts treated over a 12-year period and receiving different intensive chemotherapy regimens. Additionally, their analysis did not assess measurable residual disease (MRD) after intensive therapy or pre- or post-alloHCT, so future studies with MRD assessment are needed.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Versluis J, Metzner M, Wang A, et al. Risk stratification in older intensively treated patients with AML [published online ahead of print, 2024 September 4]. J Clin Oncol. doi: 10.1200/JCO.23.02631.
