CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900

Abstract

We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25(POS) myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25(POS) patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25(NEG) cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITD(POS) AML was restricted to CD25(POS) patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25(POS) status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25(POS) status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.

Figure 1

Kaplan-Meier estimates of OS by CD25 expression in the patient cohort with detailed mutational data (n = 396). CD25^NEG (CD25⁻) patients are depicted in the solid curve (n = 321), whereas CD25^POS (CD25⁺) patients are depicted as a dashed curve (n = 75).

Figure 2

Kaplan-Meier estimates of OS according to integrated-risk status, based on cytogenetic and mutational classification, in CD25^POS versus CD25^NEG patients. Data are shown for the OS of patients with intermediate risk (A; CD25^NEG n = 108, CD25^POS n = 30) or (B) with unfavorable (high) risk (CD25^NEG n = 97, CD25^POS n = 43). (C) The composite shows that OS in CD25^POS intermediate risk (IR) patients was not significantly different from that in CD25^POS or CD25^NEG high-risk (HR) patients (P = .091). Solid lines depict CD25^NEG patients, and dashed lines depict CD25^POS patients. Only 1 CD25^POS patient was low risk (LR).

Figure 3

Effect of CD25 cell-surface marker expression on the integrated (combined cytogenetic and mutational) risk classification of AML. (A) Effect of CD25 on our previously published risk allocation that was determined by mutational profiling and redefined a substantial proportion of patients who by cytogenetic analysis (left) carried intermediate risk to favorable risk or unfavorable risk categories (middle). When we incorporated CD25 expression into the integrated (combined cytogenetic and mutational status) risk stratification algorithm, an additional 11% of intermediate-risk patients were reallocated to the unfavorable-risk class. The favorable-risk group was unaffected by CD25 because of the rare occurrence of CD25 in favorable-risk patients. In each risk category, the percentage of patients in that cohort and their 3 years' OS are given. (B) Kaplan-Meier estimates of OS for the final risk groups, stratified by integrated risk (cytogenetic and mutational) and CD25 expression status.

Figure 4

Kaplan-Meier estimates of OS for FLT3-ITD−positive patients in all integrated risk groups by CD25 status. Data are shown for FLT3-ITD–positive/CD25^NEG (CD25⁻; solid line, n = 63) vs FLT3-ITD−positive/CD25^POS patients (CD25⁺; dashed line, n = 57).

Figure 5

Kaplan-Meier estimates of OS by FLT3 mutation status in CD25^NEG patients. Data are shown for overall survival in CD25^NEG patients with FLT3 wild type (dashed line, n = 258) compared with CD25^NEG patients positive for FLT3-ITD (solid line, n = 63).

Figure 6

GEP of CD25^POS AML in all integrated risk groups. (A) 2-dimensional hierarchical clustering of differentially expressed genes between CD25^POS (blue) and CD25^NEG (red) AML cases. Each column represents a patient, and each row represents a gene. (B) Gene set enrichment analysis using previously reported leukemia stem cell signatures as gene sets showing significant enrichment of the 2 reported signatures in CD25 expression profiles.