The addition of a tyrosine kinase inhibitor to intensive chemotherapy significantly improves outcome in de novo BCR::ABL1+ acute myeloid leukemia treated with intensive chemotherapy
Abstract
Abstract Introduction: De novo BCR::ABL1+ acute myeloid leukemia (AML) is a distinct and rare entity (0.1%-3% of AML), classified as adverse-risk in the ELN 2022 classification (Döhner H et al., Blood 2022). However, we recently published the favorable outcome of 18 de novo BCR::ABL1+ AML from the French DATAML registry treated with imatinib + intensive chemotherapy (IC) (Gondran C et al., Blood Cancer Journal 2024): CR/CRi, 94.4%; 3-year OS, 77%; that compared favorably to intermediate- and adverse-risk AML. To confirm these results, we performed a multicentric European retrospective data collection of de novo BCR::ABL1+ AML characteristics, treatment data and outcome. Methods: Inclusion criteria for this retrospective study were: adult AML with ≥ 20% bone marrow blasts, BCR::ABL1+or t(9;22)(q34.1;q11.2), with no history of previous chronic myeloid leukemia (even if < 6 months) and no prior exposition to BCR::ABL1 tyrosine kinase inhibitor (TKI), who were treated with IC +/- TKI. Acute leukemia of ambiguous lineage were excluded. Results: We collected the data of 250 patients with de novo BCR::ABL1+ AML diagnosed from March 1999 to December 2024. 212 patients were treated with IC: 89 with IC alone and 123 with IC + TKI. Median age was 54 years and 67 patients (32%) were older than 60. Forty-three patients (28.5%) presented with splenomegaly. The median WBC was 45.109/L (29 in the IC arm vs. 53 in the IC + TKI arm). One hundred and fifteen patients (60%) had additional chromosomal abnormalities, 28 (15%) had a monosomal karyotype and 62 (32%) had complex abnormalities. BCR::ABL1 isotype was p210 in 80% and p190 in 20%. Molecular data were available for the most recent patients: the co-occurring mutations present in more than 10% of cases were: RUNX1 (N=32/100: 32%), BCOR (N=11/82: 13%), ASXL1 (N=10/79: 13%), WT1 (N=9/72: 13%), DNMT3A (N=8/73: 11%), and NPM1 (N=15/147: 10%); a TP53 mutation was found in 7% (N=5/77). IC was a 7+3 including daunorubicin+cytarabine in 107 patients (59%), idarubicin+cytarabine in 59 patients (36%) or another scheme in 14 (8%). In the IC + TKI arm, imatinib was added in 66 patients (54%; 400-800 mg/day), dasatinib in 40 patients (33%; 100-140 mg/day), ponatinib in 11 patients (9%; 15-45 mg/day), and nilotinib in 6 patients (5%; 600-800 mg/day). Response assessment was available in 78 patients in IC arm and 122 patients in IC + TKI arm. Composite complete remission (CR/CRi) was achieved in 52 patients (66.7%) in the IC arm, and 110 patients (90.2%) in the IC + TKI arm (P<0.0001). 28.2% and 9.0% of patients had primary refractory disease in the IC and IC + TKI arm, respectively (p<0.001). 97 patients (59.9%) were transplanted in CR1 (26 patients [50%] in IC arm and 71 patients [64.5%] in IC + TKI arm, P=0.077). The relapse rate was 28% in the IC arm and 18% in the IC + TKI arm (P=0.159). With a median follow-up of 66.7 months, the 3-year and 5-year OS were 42.1% and 38.5% in the IC arm and 70.9% and 62.9% in the IC + TKI arm (P<0.0001). The median OS was 20.5 months in the IC arm and not reached in the IC + TKI arm. The 3-year and 5-year RFS were 52.1% and 49.3% in the IC arm and 73.0% and 67.1% in the IC + TKI arm (P=0.0095). The 3-year and 5-year EFS were 32.1% and 30.4% in the IC arm and 66.7% and 61.4% in the IC + TKI arm (P<0.0001). Of note, in the IC + TKI arm, 26 out of 39 patients (67%) who were not transplanted did not relapse and had a median OS of 65.8 months. In multivariate analyses, the addition of TKI to IC was significantly and independently associated with an improvement in CR/CRi rate (OR: 4.74 [2.17-10.35]; P<0.001), in OS (HR: 0.40 [0.27-0.62]; P<0.001), in EFS (HR 0.37 [0.25-0.55]; P<0.001) and RFS (HR: 0.42 [0.23-0.75]; P=0.004) adjusted for confounding factors including allo-HSCT as time-dependent variable. The other independent poor predictive factors were: age older than 60 years for OS and EFS; and WBC over 50.109/L, IC regimen different than 7+3 and absence of alloSCT for RFS. Conclusions: The addition of a TKI significantly improves the outcome of de novo BCR::ABL1+ AML treated with intensive chemotherapy, and should be a standard of care for this entity. This study should lead to the revision of the current ELN AML genetic risk classification, as this entity no longer deserves to be classified as adverse.
Article Details
Authors (69)
Sarah Bertoli
Niklas Landberg
Emilie Berard
Camille Gondran
1Centre Hospitalo-universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Université de Toulouse, Hematology, Toulouse, France
Laetitia Largeaud
1CHU de Toulouse Institut Universitaire du Cancer - Toulouse Oncopole, Laboratoire d'Hématologie, Toulouse, France
Véronique De Mas
3Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, INSERM U1037, Centre National de la Recherche Scientifique U5077, Toulouse, France
Pierre-Yves Dumas
Arnaud Pigneux
Audrey Bidet
21Laboratory of Hematology, Bordeaux University Hospital, Bordeaux, France
Sylvain Garciaz
5Institut Paoli-Calmettes, Marseille, France
Ludovic Gabellier
18Department of Hematology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
Gabrielle Roth-Guepin
2Fi LMC, Lyon, France
Corentin Orvain
8CHU d'Angers, Hematology, Angers, France
Pierre Peterlin
12Department of Hematology, Centre Hospitalier Universitaire de Nantes, Nantes, France
Rudy Birsen
6Service d'Hématologie Clinique, Hôpital Cochin, AP-HP, Paris, France, Paris, France
Magda Alexis
26Service d’Hématologie, Centre Hospitalier Régional d’Orléans, Orléans, France
Martin Carré
Emmanuelle Tavernier
Marion Boissard Simonet
18Hôpital Jean Minjoz, CHU Besançon, Besançon, France
Chantal Himberlin
18Hôpital Robert Debré, Hématologie Clinique, Reims, France
Marc Maynadié
11Regystry of hematological malignancies of cote d'or, Dijon, France
Kamel Laribi
13CH du mans, Le Mans, France
Cécile Moluçon-Chabrot
22CHU de Clermont-Ferrand, Clermont-Ferrand, France
Amine Belhabri
19Service d’Hématologie, Centre Léon-Bérard, Lyon, France
Samy Chraibi
21Department of Hematology, Centre Hospitalier Universitaire de Nîmes, Nîmes, France
Quentin Cabrera
7Centre Hospitalier Universitaire de la Réunion Site SUD (Terre Sainte), Service d'hématologie, Saint-Pierre, France
Delphine Lebon
10CHU Amiens Picardie, Unité d'Hématologie clinique et Thérapie Cellulaire, Amiens, France
Emmanuel Raffoux
Thomas Cluzeau
15Service d’Hématologie, Centre Hospitalier Universitaire de Nice, Nice, France
Jean-Baptiste Micol
28Gustave-Roussy, université Paris-Saclay, Department of Hematology, Villejuif, France
Mathieu Leclerc
8Hôpital Henri Mondor, Service d'Hématologie Clinique et de Thérapie Cellulaire, Créteil, France
Céline Berthon
29Service d’Hématologie, Centre Hospitalier Universitaire de Lille, Hôpital Claude-Huriez, Lille, France
Hervé Dombret
Gunnar Juliusson
Anna Robelius
Sören Lehmann
Martin Jädersten
Lovisa Wennström
Pau Montesinos
Hospital Universitari i Politecnic La Fe, Valencia, Spain
Carmen Botella
Hematology Department. Hospital General Universitario Dr. Balmis, Alicante, Spain
Juan Miguel Bergua Burgues
Hospital San Pedro de Alcántara. Cáceres, Caceres, Spain
Raimundo Garcia
39Hospital General Universitario de Castellón, Castellón de la Plana, Spain., Hematology Department, Castellón de la Plana, Spain
Josefina Serrano
University Hospital Reina Sofia. IMIBIC. UCO, Cordoba, Spain
Mariluz Amigo
41Hospital Universitario Morales Messeguer, Murcia, Spain
Patricia Garcia Ramirez
42Hospital U. Príncipe de Asturias, Alcalá de Henares, Alcalá de Henares, Spain
Claudia Sossa
23Clínica FOSCAL, Bucaramanga, Colombia
Juan Manuel Alonso-Domínguez
Princess Margaret Cancer Centre, Toronto, Ma, Canada
Hartmut Döhner
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
Konstanze Döhner
12University Hospital of Ulm, Ulm, Germany
Daniela Späth
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
Michael Kuhn
Claudia Lengerke
Hans-Jörg Tischler
48Department of Hematology and Oncology, University Hospital of Minden, Minden, Germany, Minden, Germany
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Leo Ruhnke
27Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany
Christian Thiede
7University Hospital, Dresden University of Technology, Dresden, Germany
Andreas Burchert
6Universitätsklinikum Gießen und Marburg, Marburg, Germany
Hubert Serve
Carsten Mueller-Tidow
1Heidelberg Myeloma Center and German-speaking Myeloma Multicenter Group (GMMG), Heidelberg University Hospital, Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg, Germany
Claudia Baldus
7Department of Hematology, Kiel University Hospital, Kiel, Germany
Jurjen Versluis
4Erasmus MC Cancer Institute, Rotterdam, Netherlands
Peter Valk
6Erasmus MC, Rotterdam, Netherlands
Daniel Kristensen
55Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
Anne Stidsholt Roug
55Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
Jiri Mayer
6Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University Brno, Brno, Czech Republic
Mika Kontro
Pia Ettala
58Department of Clinical Hematology and Stem Cells Transplantation Unit, Turku University Hospital and University of Turku, Turku, Finland
Vladimir Lazarevic
Christian Récher