Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial

Anne Bouvier (1) , Jean-Francois Hamel (2, 3) , Jacques Delaunay (4) , Eric Delabesse (5, 6) , Pierre-Yves Dumas (7, 8) , Marie-Pierre Ledoux (9) , Pierre Peterlin (10) , Isabelle Luquet (11) , Gabrielle Roth Guepin (12) , Claude Eric Bulabois (13) , Maria Pilar Gallego Hernanz (14) , Gaelle Guillerm (15) , Romain Guieze (16) , Yosr Hicheri (17) , Celestine Simand (9) , Chantal Himberlin (18) , Mathilde Hunault-Berger (1, 19, 20) , Marc Bernard (21) , Eric Jourdan (22) , Denis Caillot (23) , Veronique Dorvaux (24) , Emmanuelle Tavernier (25) , Etienne Daguindau (26) , Anne Banos (27) , Mario Ojeda-Uribe (28) , Emmanuel Gyan (29, 30, 31) , Magda Alexis (32) , Jean-Pierre Marolleau (33, 34) , Pascal Turlure (35) , Didier Bouscary (36, 37) , Catherine Humbrecht , Hacene Zerazhi (38) , Marie-Christine Bene (10) , Arnaud Pigneux (8) , Martin Carre (13) , Norbert Ifrah (3, 39) , Odile Blanchet (40, 3) , Norbert Vey (41, 42) , Christian Recher (43) , Pascale Cornillet-Lefebvre (44)

1 CRCINA-ÉQUIPE 7 - Innate Immunity and Immunotherapy
2 Irset - Institut de recherche en santé, environnement et travail
3 CHU Angers - Centre Hospitalier Universitaire d'Angers
4 Hôpital privé du Confluent [Nantes]
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 CHU Toulouse [Toulouse]
7 CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France.
8 Biothérapies des maladies génétiques et cancers
9 ICANS - Institut de Cancérologie de Strasbourg Europe
10 CHU Nantes - Centre hospitalier universitaire de Nantes
11 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
12 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
13 CHU - Centre Hospitalier Universitaire [Grenoble]
14 Service d'Hématologie [CHU Poitiers]
15 CHU - BREST - Hôpital Morvan - CHRU de Brest
16 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
17 CHRU Montpellier - Hôpital Saint Eloi
18 CHU Reims - Centre Hospitalier Universitaire de Reims
19 FHU GOAL - Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers]
20 Service des maladies du sang [Angers]
21 CHU Pontchaillou [Rennes]
22 Département d'Hématologie [CHU Nîmes]
23 CHU Dijon
24 CHR Metz-Thionville - Centre hospitalier régional Metz-Thionville
25 Institut de Cancérologie de la Loire Lucien Neuwirth
26 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
27 Le CHCB, Centre Hospitalier de la Côte Basque
28 CH E.Muller Mulhouse - Centre Hospitalier Emile Muller [Mulhouse]
29 GICC EA 7501 - Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...]
30 LNOx - ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx)
31 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
32 CHRO - Centre Hospitalier Régional d'Orléans
33 CHU Amiens-Picardie
34 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
35 Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges]
36 Hôpital Cochin [AP-HP]
37 IC UM3 (UMR 8104 / U1016) - Institut Cochin
38 Centre Hospitalier Henri Duffaut (Avignon)
39 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
40 Centre de Ressources Biologiques [CHU Angers]
41 Institut Paoli-Calmettes
42 CRCM - Centre de Recherche en Cancérologie de Marseille
43 Service d'Hématologie [CHU Toulouse]
44 Service d'Hématologie Biologique [Hôpital Robert Debré, Paris]

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m(2) of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.

Domaines: Sciences du Vivant [q-bio]

Anne Bouvier, Jean-Francois Hamel, Jacques Delaunay, Eric Delabesse, Pierre-Yves Dumas, et al.. Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial. European Journal of Haematology, 2021, 107 (1), pp.111-121. ⟨10.1111/ejh.13626⟩. ⟨hal-03604930⟩