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

Laetitia Largeaud (1, 2) , Pascale Cornillet-Lefebvre (3) , Jean-François Hamel (4, 5) , Pierre-Yves Dumas (6, 7) , Naïs Prade (1, 2) , Stéphanie Dufrechou (1, 2) , Julien Plenecassagnes (8) , Isabelle Luquet (9) , Odile Blanchet , Anne Banos (10) , Marie Béné (11) , Marc Bernard (12) , Sarah Bertoli (9) , Caroline Bonmati (13) , Luc Matthieu Fornecker (14) , Romain Guièze (15) , Lamya Haddaoui (16) , Mathilde Hunault (5) , Jean Christophe Ianotto (17) , Eric Jourdan (18, 19) , Mario Ojeda , Pierre Peterlin , Norbert Vey (20, 21) , Hacene Zerazhi , Hicheri Yosr , Ariane Mineur , Jean-Yves Cahn , Norbert Ifrah , Christian Récher , Arnaud Pigneux , Eric Delabesse , J.-P. Marolleau , A. Aleme , F. Orsini-Piocelle , N. Cadoux , Norbert Ifrah , Mathilde Hunault , C. Marie , A. Al Jijakli , G. Lepeu , Hacene Zerazhi , M. Beyrne , Anne Banos , S. Labarrere , E. Deconinck , M. Peria , A. El Yamani , O. Kadiri , B. Choufi , M. Brument , Arnaud Pigneux , T. Leguay , Pierre-Yves Dumas , C. Berthou , G. Guillerm , G. Drugmanne , O. Tournilhac , G. Roy , B. Audhuy , S. Camara , D. Caillot , M. Grandjean , Jean-Yves Cahn , C.-E. Bulabois , B. Fief , Norbert Vey (20, 21) , C. Ladraa , V. Dorvaux , M. Hagopian , N. Fegueux , C. Fenoll , V. Sabadash , Mario Ojeda , C. Haby , F. Witz , Caroline Bonmati , M. Lhuire , J. Delaunay , Pierre Peterlin , L. Airiau , L. Mannone , I. Touitou , Eric Jourdan , D. Umuhire , M. Alexis , O. Michel , F. Dreyfus , D. Bouscary , A. Cheung , L. Sanhes , F. Touhami , E. Ribas , M. Puyade , M.-P. Gallego-Hernanz , N. Hugon , C. Himberlin , L. Maggi , T. Lamy , A. Testu , E. Tavernier , S. Marchand , B. Lioure , C. Kravanja , L. Benboubker , D. Nollet , M. Attal , Christian Récher , A. Sarry , A. Lhermitte , G. Yrica , D. Schwartz , N. Le Montagner , C. Fenoll , V. Sabadash , D. Nollet , L. Auvray , R. Delepine , A. Fayault

1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
3 Service d'Hématologie Biologique [Hôpital Robert Debré, Paris]
4 Irset - Institut de recherche en santé, environnement et travail
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France.
7 Biothérapies des maladies génétiques et cancers
8 Institut Claudius Regaud
9 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
10 CHCB - Centre Hospitalier de la Côte Basque
11 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
13 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
14 Département d'Oncologie et Hématologie [Strasbourg]
15 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
16 IC UM3 (UMR 8104 / U1016) - Institut Cochin
17 BREST - Hémato Clinique - Département d'Hématologie Clinique
18 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
19 UM - Université de Montpellier
20 Service d’Hématologie [Institut Paoli Calmettes, Marseille]
21 CRCM - Centre de Recherche en Cancérologie de Marseille

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.

Domains: Cancer

Laetitia Largeaud, Pascale Cornillet-Lefebvre, Jean-François Hamel, Pierre-Yves Dumas, Naïs Prade, et al.. Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study. Leukemia, 2021, 35 (5), pp.1291-1300. ⟨10.1038/s41375-020-01031-1⟩. ⟨hal-03623649⟩