Acute myeloid leukemia

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study

Abstract

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITDhigh/NPM1WT mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.

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Fig. 1: LAM-SA 2007 molecular workflow.
Fig. 2: LAM-SA 2007 mutation pattern.
Fig. 3: Mutations associations classified as gene categories as defined by Bullinger et al. [16], NPM1, signalization, DNA methylation, splicing, chromatin, transcription factors, cohesin, and antioncogenes.
Fig. 4: Circos plots of gene categories showing the profiles of co-mutations.
Fig. 5: Clinical responses (OS and EFS) to lomustine (lomustine) according to the ELN2017 risk classification.

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Acknowledgements

We thank physicians from participating centers as well as central and local data managers for collecting and monitoring patients’ data. We thank Filothèque members for the conservation of patients samples; Catherine Lacombe, Rachid Boulghana, Laure Cabaret, Ségolène Diry, Krishshanthi Sinnadurai, and Shari Dini Mohamed.

French Innovative Leukemia Organization

J.-P. Marolleau26, A. Aleme26, F. Orsini-Piocelle27, N. Cadoux27, N. Ifrah28, M. Hunault28, C. Marie28, A. Al Jijakli29, G. Lepeu30, H. Zerazhi30, M. Beyrne30, A. Banos31, S. Labarrere31, E. Deconinck32, M. Peria32, A. El Yamani33, O. Kadiri33, B. Choufi34, M. Brument34, A. Pigneux35, T. Leguay35, P.-Y. Dumas35, C. Berthou36, G. Guillerm36, G. Drugmanne36, O. Tournilhac37, G. Roy37, B. Audhuy38, S. Camara38, D. Caillot39, M. Grandjean39, J.-Y. Cahn40, C.-E. Bulabois40, B. Fief40, N. Vey41, C. Ladraa41, V. Dorvaux42, M. Hagopian42, N. Fegueux43, C. Fenoll43, V. Sabadash43, M. Ojeda44, C. Haby44, F. Witz45, C. Bonmati45, M. Lhuire45, J. Delaunay46, P. Peterlin46, L. Airiau46, L. Mannone47, I. Touitou47, E. Jourdan48, D. Umuhire48, M. Alexis49, O. Michel49, F. Dreyfus50, D. Bouscary50, A. Cheung50, L. Sanhes51, F. Touhami51, E. Ribas51, M. Puyade52, M.-P. Gallego-Hernanz52, N. Hugon52, C. Himberlin53, L. Maggi53, T. Lamy54, A. Testu54, E. Tavernier55, S. Marchand55, B. Lioure56, C. Kravanja56, L. Benboubker57, D. Nollet57, M. Attal58, C. Recher58, A. Sarry58, A. Lhermitte59, G. Yrica59, D. Schwartz59, N. Le Montagner59, C. Fenoll59, V. Sabadash59, D. Nollet59, L. Auvray59, R. Delepine59, A. Fayault59

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Correspondence to Eric Delabesse.

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Largeaud, L., Cornillet-Lefebvre, P., Hamel, J. et al. Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study. Leukemia (2020). https://doi.org/10.1038/s41375-020-01031-1

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