Hierarchical cluster analysis of immunophenotype classify AML patients with NPM1 gene mutation into two groups with distinct prognosis

Abstract

BackgroundThe prognostic implication of immunophenotyping in acute myeloid leukemia (AML) patients with NPM1 mutation remains unclear.MethodsNinety-four of 543 AML patients diagnosed with NPM1 mutation between 1987 and 2007 were studied. The expression of surface antigens on leukemic cells was evaluated with respect to clinical manifestations and outcomes. In order to validate the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were analyzed.ResultsNinety-four patients with NPM1 mutations and complete immunophenotyping data were enrolled for a hierarchical cluster analysis and the result was correlated with clinico-laboratory characteristics. Clustering analysis divided the patients with NPM1 mutations into the following two groups: group I, CD34(−)/CD7(−), but with variable expression of HLA-DR; and group II, HLA DR(+)/CD34(+)/CD7(+). With a median follow-up of 53 months, the group II patients had a significantly shorter relapse-free survival (RFS, median: 3 vs. 23 months, p = 0.006) and overall survival (OS, median: 11 vs. 40 months, p = 0.02) than group I patients. Multivariate analysis of variables, including clinico-laboratory data and other gene mutations revealed that the immunophenotypic cluster is an independent prognostic factor (RFS, p = 0.002; OS, p = 0.024). In order to confirm the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were validated. Hierarchical cluster analysis also showed two distinct clusters, group I patient showed significant better RFS (p = 0.021), and OS (p = 0.055). In total, we stratified 130 NPM1-mutant patients, by FLT3-ITD mutation and immunophenotypic cluster into distinct prognostic groups (RFS, p < 0.001 and OS, p = 0.017).ConclusionsAmong NPM1-mutated AML, the antigen expression pattern of HLADR(+) CD34(+) CD7(+) is associated with a poor prognosis, independent to the FLT3-ITD mutation.

Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children’s Oncology Group protocol AAML0531

“…Historically, relationships among immunophenotype, genotype, morphology, and outcome have been loosely correlated, 23 – 27 with phenotypic associations hinging largely on the expression of a single antigen. 28 , 29 Although previous studies have performed clustering analysis of immunophenotypic data to identify small subgroups of patients with poor prognosis, 30 – 32 such studies have not evaluated a sufficiently large cohort of uniformly treated patients. By defining the IEP as a continuous variable, patients with similar global immunophenotypic patterns can be grouped together with hierarchical clustering, thus providing a focal point to correlate continuous and categorical test results.…”

Prevalence and Clinical Significance of FLT3 and NPM1 Mutations in Acute Myeloid Leukaemia Patients of Assam, India

“…This could be one of the reasons which affected the overall survival in patients with NPM1 type A mutation in our study group. Previous studies demonstrated that high WBC count, cytogenetic abnormalities, older age, association with FLT3-ITD [44,45], expressions of HLA-DR, CD34 and CD7 [46] also have a significant impact on survival in patients with NPM1 mutation. Due to our limited number of cases of patients with NPM1 type B and type D mutation we could not statistically compare the above parameters with NPM1 type A mutation.…”

Correlation of Next-Generation Sequencing Based Genotypic Profiles with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia

“…LSCs are in the relatively silent cell cycle G0 phase and highly express the drug-resistant e ux transporter P-glycoprotein (PGP) or multidrug-resistant protein (MDR1). (11,37) Chen CY et al (17) clustered immunophenotyping in 94 NPM1 mut patients and divided them into two categories according to CD34, CD7 and HLA-DR, showing that the prognosis of type-class characterized by CD34 (+) /HLA-DR (+) /CD7 (+) was signi cantly poorer versus the type-class CD34 (−) /CD7 (−) . However, their results may be affected by the biased distribution of concurrent FLT3-ITD, which has a positive correlation with CD34 and CD7.…”

“…(14) Immunophenotype is not only used in the differential diagnosis of AML, but also has prognostic value. The CD34 (+) (11,15), leukemic stem cells (LSCs) phenotype CD34 (+) /CD38 (−) /CD123 (+) (16), APL-like phenotype CD34 (−) /HLA-DR (−) /MPO (str+) (12) and clustered type-phenotype CD34 (+) /HLA-DR (+) /CD7 (+) (17) have been reported to convey prognostic effects on NPM1 mut AML. However, data on genetic information were less integrated into analysis in those relatively earlier studies.…”