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-␣) 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. (Blood. 2012;120(11):2297-2306) IntroductionIncreasingly, recurrent genetic aberrations govern the prognostication of the acute leukemias, including the large group of patients who present with acute myeloid leukemia (AML) without apparent cytogenetic abnormalities. A steadily growing catalog of molecular lesions has led to the development of outcome-based classification systems that incorporate information on perturbed pathogenetic pathways and inform us about potential therapeutic targets. [1][2][3][4] In the context of this evolving molecular risk assessment, antigenexpression profiles have been identified as surrogates for certain leukemic genotypes. Furthermore, a few single antigens per se have been found to be predictive of clinical response. In most cases, however, the prognostic power of antigens has not been disassociated from underlying genetic determinants.The prognostic impact of antigens, such as CD1a and CD13, in T-lineage acute lymphoblastic leukemia (ALL) 5 has been linked to molecular subgroups with the activation of specific transcription factors and with unique gene expression signatures, reflecting distinct stages of maturation. 6 In acute promyelocytic leukemia (APL), expression of the T cell-affiliated antigen, CD2, in association with S-isoform PML/RAR␣, 7 confers inferior prognosis. 8 CD2 POS S-isoform POS APL is distinguishable from other isoforms on the basis of gene-expression profiling (GEP) 9 and has been posited to be derived from an immature leukemia stem cell (LSC). 10 Su...

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

“…[3][4][5] A similar study also showed that high STAT5 activity corresponds to poorer overall and relapse-free survival in AML. 38 In addition, the evaluation of CD25-positive populations prior, during, and after induction chemotherapy showed that a majority of poorly responding patients demonstrated an increased percentage of CD25-positive cells at day 7 and day 21 after initiation of induction chemotherapy.…”

“…2 In several retrospective studies investigating CD25 as a prognostic marker in AML using an immunophenotyping approach, a higher percentage of CD25-positive cells (.10% or .20%) in leukemic blasts were found to correlate with poor overall and relapse-free survival. [3][4][5] Here we demonstrated that a higher mRNA expression level of CD25 also correlates with poor overall survival (Figure 2Di, CD25). Because CD25 is a prominent candidate gene in the responder signature for PIM inhibitors with potential clinical relevance, we wanted to assess whether subpopulations of primary leukemic blasts from patients with differential expression of CD25 display unique response to PIM inhibitors.…”

“…2 Furthermore, retrospective studies have demonstrated that patients with a higher percentage of CD25-positive blasts manifest poor overall survival or relapse-free survival. [3][4][5] Because CD25 is a well-established STAT5-regulated gene, high CD25 expression could likely be a result of hyperactivation of STAT5. 6 STAT5 transcription factors, represented by isoforms STAT5A and STAT5B, are known to be crucial in both normal hematopoiesis and hematological malignancies.…”

Nonbiological factors affecting survival in younger patients with acute myeloid leukemia

“…13,14 Recurrent mutations in IDH, AXL receptor tyrosine kinase (ASXL), DNMT3a, TET2, MLL, and PHF6 have recently been identified, for which the prognostic effect is being actively investigated in combination with previously described cytogenetic and molecular features. [15][16][17] Several groups have attempted to build models incorporating important patient-related and disease-related factors to provide prognostic and predictive systems for patients undergoing intensive chemotherapy. 18 However, to the best of our knowledge, none of these models have integrated nonbiological factors (NBFs) such as employment, education, income, health insurance, and marital status, which may affect how one accesses and interacts with health care and, ultimately, clinical outcomes.…”

Novel signaling axis in CML-initiating cells

“…The authors of the current study showed that CD25 expression is higher in the accelerated phase (AP) and even further increased in the blast crisis (BC) phase of human CML than in the chronic phase ( Figure 6E, Kobayashi et al 1 ). Because the myeloid BC in CML resembles AML, and CD25 is also considered a prognostic factor for AML development, 9,10 an interesting hypothesis triggered by these observations is that CD25 may mark or promote human CML advancement in the AP or BC stage. If so, the IL2/CD25 axis may not regulate the initiation of human CML but may contribute to disease progression.…”