TO THE EDITOR:
Mutations in the nucleophosmin 1 (NPM1) gene are among the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and have been associated with a favorable prognosis.1,2 In 2019, in a large international collaborative study, we have reported that cytogenetic abnormalities are important determinants of outcome in NPM1-mutated (NPM1mut) AML.3 We showed that intensively treated patients with NPM1mut AML and coexisting adverse-risk cytogenetics shared the same unfavorable prognosis as their NPM1 wild-type (NPM1WT) counterparts. This was a new finding, because the European LeukemiaNet (ELN) 2017 classification considered the NPM1mut status (in the absence of an FLT3-ITD mutation with a high allelic ratio) favorable regardless of accompanying chromosomal abnormalities, in full analogy to core-binding factor AML.4 As a consequence, in the recently published ELN 2022 genetic risk classification of AML, the presence of adverse-risk cytogenetics now defines adverse-risk in NPM1mut AML.5 Other key changes made to the previous ELN classification included the addition of further disease-defining recurrent cytogenetic abnormalities to the adverse-risk group [ie, t(3q26.2;v) and t(8;16)(p11;p13)]. In turn, hyperdiploid karyotypes with multiple (≥3) trisomies or polysomies in the absence of structural abnormalities are no longer considered as complex karyotypes.5,6 Even though the combination of an NPM1 mutation with adverse chromosomal aberrations is a rare event (∼3%), the impact of cytogenetics in NPM1mut AML has important implications for postremission treatment decisions.
To explore whether the unfavorable impact of adverse-risk karyotype abnormalities in NPM1mut AML holds true when applying updated ELN 2022 definitions for cytogenetic risk, we reevaluated the data set from our previous study.3 Among 2426 patients with NPM1mut AML (and no FLT3-ITD mutation with a high allelic ratio), 426 patients (17.6%) had an abnormal karyotype, including 341 patients (14.1%) with intermediate-risk, and 71 patients (2.9%) with adverse-risk chromosomal abnormalities. Chromosomal abnormalities were regrouped from adverse- to intermediate-risk in 12 of 83 (14%) patients with NPM1mut AML because of the reclassification of hyperdiploid karyotypes. Given the rarity of cooccurrence of 2 disease-defining recurrent genetic abnormalities, cases with t(8;16) or t(3q26.2;v) were not found among the 2426 patients with NPM1mut AML. In NPM1mut AML, adverse cytogenetics according to ELN 2022 remained associated with lower complete remission rates (87.7%, 85.3%, and 66.2% for normal, aberrant-intermediate, and adverse karyotypes, respectively; P < .001), inferior 5-year event-free survival (52.4%, 44.4%, and 17.3% for normal, aberrant-intermediate, and adverse karyotypes, respectively; P < .001; Figure 1), overall survival (40.6%, 35.9%, and 15.6% for normal, aberrant-intermediate, and adverse karyotypes, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.3%, and 53.3% for normal, aberrant-intermediate, and adverse karyotypes, respectively; P < .001). Similar outcome was observed for patients with NPM1mut and patients with NPM1WT with adverse cytogenetics (all end points P > .10). Importantly, adverse karyotype remained predictive for inferior outcome of allogeneic hematopoietic stem cell transplantation in first complete remission in patients with NPM1mut AML (hazard ratio, 0.22; 95% confidence interval, 0.06-0.79; P for interaction = .0093). In sensitivity analyses excluding the 448 patients with FLT3-ITD–mutated AML, nearly identical results emerged (data not shown) because only 3 patients had a concomitant FLT3-ITD mutation in combination with an adverse-risk karyotype.
In summary, adverse-risk cytogenetics remained significantly associated with unfavorable prognosis in patients with NPM1mut AML when applying refined ELN 2022 definitions, supporting the recent categorization of NPM1mut AML with adverse-risk cytogenetics as adverse risk.
This study was performed in accordance with the Declaration of Helsinki. All registries were approved by the local institutional review boards, and written informed consent was obtained from all patients through the participating centers.
Acknowledgments
The authors thank all participating patients, hospitals, and investigators contributing data to the Acute Leukemia French Association, Australasian Leukaemia and Lymphoma Group, Czech Leukemia Study Group for Life, Fred Hutchinson Cancer Research Center, MD Anderson Cancer Center, Programa Español para el Tratamientode las Hemopatias Malignas, Study Alliance Leukemia, Swedish AML Registry, and Toulouse-Bordeaux DATAML database trials or registries.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, grant 470563736) (L.A.).
Authorship
Contribution: L.A. and C.S. designed the study and wrote the initial draft of the manuscript; and all authors analyzed data and approved the final version of the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Linus Angenendt, Department of Medicine A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany; e-mail: linus.angenendt@ukmuenster.de.
References
Author notes
Data are available on request from the corresponding author, Linus Angenendt (linus.angenendt@ukmuenster.de).
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