| Abstract: |
Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcomes; however, only FLT3-internal tandem duplication (ITD) mutation and adverse karyotype are currently used for risk stratification because of inconsistent results and uncertainty about how other factors should influence treatment, particularly given the strong prognostic effect of postinduction measurable residual disease (MRD). Here, we analyzed a large group of patients with NPM1 mutations (NPM1mut) AML enrolled in prospective trials (National Cancer Research Institute [NCRI] AML17 and AML19, n = 1357) to delineate the impact of baseline molecular and clinical features, postinduction MRD status, and treatment intensity on the outcome. FLT3-ITD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01-1.63), DNMT3A (HR, 1.65; 95% CI, 1.32-2.05), WT1 (HR, 1.74; 95% CI, 1.27-2.38), and non-ABD NPM1mut (HR, 1.64; 95% CI, 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients who achieved MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD-negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the high-risk molecular subgroups. © 2024 American Society of Hematology |
| Keywords: |
adolescent; adult; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; young adult; gene mutation; major clinical study; overall survival; genetics; mutation; leukemia, myeloid, acute; clinical feature; mortality; cancer radiotherapy; antineoplastic agent; nuclear protein; antineoplastic combined chemotherapy protocols; cytogenetics; cancer research; nuclear proteins; hematologic malignancy; minimal residual disease; neoplasm, residual; wt1 protein; drug therapy; granulocyte colony stimulating factor; therapy; dna (cytosine 5) methyltransferase; hematologic disease; induction chemotherapy; cumulative incidence; dna methyltransferase 3a; cd135 antigen; nucleophosmin; wt1 proteins; acute myeloid leukemia; fms-like tyrosine kinase 3; gemtuzumab; very elderly; dna sequencing; humans; prognosis; human; male; female; article; patient history of chemotherapy; flt3 protein, human; real time reverse transcription polymerase chain reaction; dna (cytosine-5-)-methyltransferases; npm1 protein, human; dnmt3a protein, human; wt1 protein, human
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