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The role of clonal hematopoiesis as driver of therapy-related myeloid neoplasms after autologous stem cell transplantation

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Abstract

Therapy-related myeloid neoplasm (t-MN) is a threatening complication of autologous stem cell transplantation (ASCT). Detecting clonal hematopoiesis (CH) mutations in cryopreserved cells before ASCT has been associated with a higher risk of t-MN, but the evolution of molecular abnormalities from pre-ASCT to t-MN, within the same patient, remains to be elucidated. We evaluated the mutational profile of 19 lymphoma/myeloma patients, at both pre-ASCT and t-MN diagnosis, using a targeted NGS approach; 26 non-developing t-MN control patients were also studied pre-ASCT. At ASCT, we found a higher frequency of CH in patients developing t-MN (58%) than in those who did not (23%) (P = 0.029); mutations in epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (PPM1D, RAD21, TP53, and STAG2) were the most represented. At t-MN, CH increased to 82% of patients. Cumulative mutational burden and variant allele frequency (VAF) also increased at t-MN. CH clones detected at ASCT were found at t-MN in eight out of 16 patients, mainly with stable VAF. Among the new driver mutations appeared at t-MN, TP53 increased from one to 13 mutations, in nine patients; being associated with complex karyotype. Mutations in transcription factor (RUNX1, CEBPA) and intracellular signaling genes (FLT3, RAS genes) also increased from three to 17 mutations in eight patients, presenting with a normal karyotype. Overall, we found that preexisting CH at ASCT rarely causes t-MN directly, but may rather facilitate the appearance of new mutations, especially those involving TP53, RUNX1, and RAS, that can drive the evolution to t-MN of at least two distinct types.

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Author notes

  1. D.G. and D.B. contributed equally to this work.

Authors and Affiliations

  1. Hematology, ASST Spedali Civili di Brescia, Brescia, Italy

    Doriana Gramegna, Chiara Cattaneo, Alessandro Re, Angelo Belotti, Erika Borlenghi, Margherita Sciumè, Rosa Daffini, Alessandra Tucci & Giuseppe Rossi

  2. Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili Di Brescia, Brescia, Italy

    Diego Bertoli, Silvana Archetti & Duilio Brugnoni

  3. Laboratory for Stem Cells Manipulation and Cryopreservation, Department of Transfusion Medicine, ASST Spedali Civili Di Brescia, Brescia, Italy

    Camillo Almici & Rosanna Verardi

  4. Clinical Chemistry Laboratory, Cytogenetics and Molecular Genetics Section, Diagnostic Department, ASST Spedali Civili Di Brescia, Brescia, Italy

    Gaetana Lanzi

  5. Clinical Research Development and Phase I Unit, ASST Spedali Civili Di Brescia, Brescia, Italy

    Aldo M. Roccaro

Authors
  1. Doriana Gramegna
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  2. Diego Bertoli
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Contributions

Doriana Gramegna identified patients, collect and analyzed the data, wrote the manuscript; Diego Bertoli designed and performed the experiments, analyzed and interpreted NGS data, wrote the manuscript; Chiara Cattaneo designed the study, identified patients, collect and analyzed the data, wrote the manuscript; Camillo Almici and Rosanna Verardi collected and managed stem cells; Alessandro Re, Angelo Belotti, Erika Borlenghi, Margherita Sciumè, Rosa Daffini and Alessandra Tucci identified and managed patients, collected clinical data; Gaetana Lanzi, Silvana Archetti and Duilio Brugnoni contributed to NGS analysis; Aldo Maria Roccaro critically revised the manuscript; Giuseppe Rossi conceived and designed the study, analyzed and interpreted data, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Diego Bertoli.

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Ethics approval and consent to participate

The study was approved by the local Ethical Committee (NP3985). Patients provided written informed consent in accordance with the Declaration of Helsinki.

Conflict of interest

Aldo Maria Roccaro has served on advisory board for Amgen, Celgene, Janssen, Takeda and has received research funding from AstraZeneca, European Hematology Association, Fondazione AIRC, Fondazione Regionale per la Ricerca Biomedica – ERA-NET Transcan-2. The remaining authors declare that they have no financial interests.

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Gramegna, D., Bertoli, D., Cattaneo, C. et al. The role of clonal hematopoiesis as driver of therapy-related myeloid neoplasms after autologous stem cell transplantation. Ann Hematol 101, 1227–1237 (2022). https://doi.org/10.1007/s00277-022-04806-x

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  • DOI: https://doi.org/10.1007/s00277-022-04806-x

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