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. 2025 Jan 14;9(1):39-53.
doi: 10.1182/bloodadvances.2024013648.

AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular

Sandra Castaño-Díez  1   2 , Mònica López-Guerra  1   3 , Inés Zugasti  2   4 , Xavier Calvo  2   5 , Felicitas Isabel Schulz  6 , Alejandro Avendaño  2   7 , Elvira Mora  2   8 , José Falantes  2   9 , Gemma Azaceta  2   10 , Mariam Ibáñez  2   11 , Tzu Chen  2   12 , Cristina Notario  2   13 , Neus Amer  2   14 , Laura Palomo  2   15 , Helena Pomares  2   16 , Jordi Vila  2   17 , Teresa Bernal Del Castillo  2   18 , Carlos Jiménez-Vicente  4 , Daniel Esteban  19 , Francesca Guijarro  1 , José Álamo  1   2 , Albert Cortés-Bullich  4 , Víctor Torrecillas-Mayayo  20 , Ana Triguero  4 , Lucía Mont-de Torres  20 , Ester Carcelero  21 , Aina Cardús  1 , Ulrich Germing  6 , Beate Betz  22 , Maria Rozman  1   2 , Leonor Arenillas  2   5 , Lurdes Zamora  2   19 , María Díez-Campelo  2   7 , Blanca Xicoy  2   19 , Jordi Esteve  4 , Marina Díaz-Beyá  2   4
Affiliations

AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular

Sandra Castaño-Díez et al. Blood Adv. .

Abstract

Mutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2, and NPM1, are rarely found in chronic myelomonocytic leukemia (CMML), and their prognostic significance in CMML has not been clearly identified. In 127 patients with CMML, we have retrospectively analyzed next-generation sequencing and polymerase chain reaction data from bone marrow samples collected at the time of CMML diagnosis. Seven patients harbored CEBPA mutations, 8 FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations, and 11 NPM1 mutations. Patients with CMML harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN) more frequently had the myeloproliferative subtype, a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CMML Prognostic Scoring System molecular classification, mutCFN patients with CMML had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN patients with CMML closely resembled that of patients with AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible. Furthermore, certain targeted therapies approved for use in AML should be considered.

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Conflict of interest statement

Conflict-of-interest disclosure: F.G. is a speaker for AbbVie. J.E. has received consultancy honoraria from AbbVie, Novartis, Astellas, Jazz Pharmaceuticals, Bristol Myers Squibb–Celgene, Pfizer, and Daiichi Sankyo; and research grants from Novartis and Jazz Pharmaceuticals. M.D.-B. has served as a consultant, adviser, or speaker and received travel grants from Bristol Myers Squibb, AbbVie, Astellas, Jazz Pharmaceuticals, Takeda, and Novartis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mutations detected at diagnosis in the entire cohort. Each column corresponds to 1 patient. Each row corresponds to 1 gene. Gray squares indicate wild-type genes. White squares indicate unanalyzed genes. Blue squares represent mutated genes.
Figure 2.
Figure 2.
Survival analysis and incidence of AML transformation of patients with mutCFN vs wtCFN. OS (A) and CIP to AML (B) in mutCFN patients vs wtCFN patients.
Figure 3.
Figure 3.
OS of mutCFN patients receiving (red) or not receiving (blue) alloHSCT.
Figure 4.
Figure 4.
Co-occurrence or exclusivity of genes at diagnosis in the entire cohort. The interaction of genes repeatedly found comutated in the same patient is presented in purple. The interaction of genes observed to be mutually exclusive and those not frequently altered in the same patient is presented in orange. ∗P < .05.
See this image and copyright information in PMC

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