Prognostic impact of the AML ELN2022 risk classification in patients undergoing allogeneic stem cell transplantation

Abstract

For most patients with acute myeloid leukemia (AML), an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the diagnosis and risk classification in AML based on genetic factors at diagnosis as well as a dynamic adjustment (reclassification) according to the measurable residual disease (MRD) status for the favorable and intermediate risk groups. Validation of the ELN2022 risk classification has not been reported. We retrospectively analyzed 522 AML patients who received an HSCT at a median age of 59 (range 16-76) years. For patients with adequate material available and in remission prior to HSCT (n = 229), the MRD status was evaluated. Median follow-up after HSCT was 3.0 years. ELN2022 risk at diagnosis was in 22% favorable, in 26% intermediate, and in 52% adverse. ELN2022 risk at diagnosis is associated with the cumulative incidence of relapse/progression (CIR), event-free survival (EFS), and overall survival (OS) in the whole patient cohort, as well as the subgroup of patients transplanted in first remission. However, the risk stratification based on the ELN2022 classification did not significantly improve outcome prognostication in comparison to the ELN2017 classification. In our study, the newly added group of patients with myelodysplasia-related gene mutations did not have adverse outcomes. Re-classifying these patients into the intermediate risk group and adjusting the grouping for all AML patients by MRD at HSCT, led to a refined and improved risk stratification, which should be validated in independent studies.

Fig. 1. Risk distribution and outcomes according to the ELN2022 genetic risk groups at diagnosis.

A Transition plot of risk distribution between the ELN2017 and ELN2022 risk stratification systems at diagnosis. B Cumulative incidence of relapse, C Event-free survival, and D Overall survival according to the ELN2022 genetic risk groups in the whole patient cohort (n = 522).

Fig. 2. Outcomes according to the ELN2022 genetic risk groups at diagnosis within patients transplanted in first morphologic remission (n = 337).

A Cumulative incidence of relapse, B Event-free survival, and C Overall survival.

Fig. 3. Event-free survival within the three ELN2022 risk groups at diagnosis according to the different genetic characteristics.

A In favorable ELN2022 risk AML patients (n = 114), B in intermediate ELN2022 risk AML patients (n = 121), and C in adverse ELN2022 risk AML patients (n = 271). Note: P values for subgroup comparisons: ELN2022 favorable risk: CBF vs NPM1^mut P = 0.05, CBF vs CEBPA bZIP^mut P = 0.09, NPM1^mut vs CEBPA bZIP^mut P = 0.70; ELN2022 intermediate risk: FLT3-ITD AR <0.5 vs FLT3-ITD AR >0.5 P = 0.30, FLT3-ITD AR >0.5 vs t(9;11) P = 0.20, FLT3-ITD AR >0.5 vs other cytogenetics P = 0.20, FLT3-ITD AR <0.5 vs t(9;11) P = 0.30, FLT3-ITD AR <0.5 vs other cytogenetics P = 0.70, t(9;11) vs other cytogenetics P = 0.50). ELN2022 adverse risk: ELN2017 defined high-risk mutations vs myelodysplasia-related gene mutation P = 0.30, ELN2017 defined high-risk mutations (i.e., mutations in the genes: ASXL1, RUNX1, and TP53) vs complex karyotype P = 0.02, ELN2017 defined high-risk mutations vs other adverse risk karyotypes P = 0.40, myelodysplasia-related gene mutation vs complex karyotype P < 0.001, myelodysplasia-related gene mutation vs other adverse risk karyotypes P = 0.09, complex karyotype vs other adverse risk karyotypes P = 0.04.

Fig. 4. Outcomes according to the MRD-adjusted ELN2022 risk groups (favorable: ELN2022 favorable or intermediate + MRD^neg at HSCT; intermediate: ELN2022 favorable or intermediate + MRD^pos at HSCT, adverse: ELN2022 adverse).

A Transition plot for patients’ distribution from diagnosis to HSCT, B Cumulative incidence of relapse, C Event-free survival, and D Overall survival in patients transplanted in CR/CRi (n = 327).

Fig. 5. Outcomes according to the proposed refinement of the ELN2022 risk groups at diagnosis and MRD-adjusted at HSCT.

A Transition plot for patients distribution from the ${\mathrm{ELN2022}}_{\mathrm{at}\mathrm{diagnosis}}$ risk to the ${\mathrm{ELN2022}}_{\mathrm{at}\mathrm{diagnosis}}^{\mathrm{refined}}$. B ROC curves comparison for suffering an event (relapse or death) within 1 year after HSCT between the ${\mathrm{ELN2022}}_{\mathrm{at}\mathrm{diagnosis}}$ and the ${\mathrm{ELN2022}}_{\mathrm{at}\mathrm{diagnosis}}^{\mathrm{refined}}$risk groups, C Event-free survival according to the three ${\mathrm{ELN2022}}_{\mathrm{at}\mathrm{diagnosis}}^{\mathrm{refined}}$ risk groups, D Transition plot for patients distribution from the ${\mathrm{ELN2022}}_{\mathrm{MRD-adjusted}}$ risk to the ${\mathrm{ELN2022}}_{\mathrm{MRD-adjusted}}^{\mathrm{refined}}$ risk at HSCT, E ROC curves comparison for suffering an event (relapse or death) within 1 year after HSCT between the ${\mathrm{ELN2022}}_{\mathrm{MRD-adjusted}}$ and the ${\mathrm{ELN2022}}_{\mathrm{MRD-adjusted}}^{\mathrm{refined}}$ risk groups at HSCT, and F Event-free survival according to the three ${\mathrm{ELN2022}}_{\mathrm{MRD-adjusted}}^{\mathrm{refined}}$risk groups at HSCT.