Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts

Abstract

PURPOSE Nucleophosmin 1 ( NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene ( FLT3) is absent ( FLT3-ITDneg) or present with a low allelic ratio ( FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. METHODS We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/ FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. RESULTS Among 2,426 patients with NPM1mut/ FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/ FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. CONCLUSION Karyotype abnormalities are significantly associated with outcome in NPM1mut/ FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/ FLT3-ITDneg/low AML.

White Blood Cell Count Nadir and Duration of Aplasia Do Not Associate with Treatment Outcome in Adult Patients with Acute Myeloid Leukemia Undergoing Intensive Chemotherapy

“…Although molecular profile is associated with an appropriate risk stratification of AML patients treated with intensive chemotherapy, a large proportion with an a priori favorable risk shows a poor prognosis [2]. Therefore, there is an urgent need for the identification of new clinical markers to improve the classification risk of AML patients [6][7][8]. Several studies evaluated the deepness of aplasia and the early clearance of neoplastic cells in the bone marrow as possible surrogate markers for response.…”

Molecular Detection of Minimal Residual Disease before Allogeneic Stem Cell Transplantation Predicts a High Incidence of Early Relapse in Adult Patients with NPM1 Positive Acute Myeloid Leukemia

“…Some limitations of the current study need to be considered, including the absence of evidence regarding the most clinically significant time points and MRD thresholds to be considered, but also with respect to the correlation of MRD with other known prognostic indicators, such as coexisting molecular mutations [1]. In addition, in NPM1 mutated patients, we documented the presence of additional chromosomal abnormalities only in five patients, and this prevents us from evaluating the recently described, negative prognostic impact associated with this finding [31]. We believe that our data must be corroborated by further analysis performed on a larger group of patients.…”

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

“…Additional chromosomal abnormalities are detected in 15% of AML with an NPM1 mutation. In a recent analysis, the presence of a complex karyotype in AML with an NPM1 -mutated gene, with negative or low burden FLT -ITD, was associated with lower response rates and shorter survival despite earlier reports showing no impact on prognosis [ 71 , 72 , 73 ].…”