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 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.

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Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-991
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Chronic Myeloid Leukemia Treatments
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article

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

Arnaud Pigneux, Pau Montesinos, Audrey Bidet, Christian Thiede et al.
Blood
Chronic Myeloid Leukemia Treatments
article

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

Arnaud Pigneux, Pau Montesinos, Audrey Bidet, Christian Thiede, Laëtitia Largeaud, Emmanuelle Tavernier, Jean‐Baptiste Micol, Christian Récher, Martin Jädersten, Anne Stidsholt Roug, Magda Alexis, Chantal Himberlin, Daniel Tuyet Kristensen, Pierre‐Yves Dumas, Cécile Moluçon‐Chabrot, Rudy Birsen, Pierre Péterlin, Juan Manuel Alonso‐Domínguez, Sylvain Lehmann, Christoph Röllig, Carsten Müller‐Tidow, Gunnar Juliusson, Daniela Späth, Juan Miguel Bergua Burgués, Véronique Mansat‐De Mas, Sylvain Garciaz, Kamel Laribi, Claudia Dorothea Baldus, Jurjen Versluis, Sarah Bertoli, Delphine Lebon, Amine Belhabri, Samy Chraïbi, Josefina Serrano, Konstanze Döhner, Quentin Cabrera, Hervé Dombret, Emmanuel Raffoux, Gabrielle Roth-Guépin, Mika Kontro, Leo Ruhnke, Mathieu Leclerc, Claudia Sossa, Marion Simonet, Andreas Burchert, Peter J.M. Valk, Pia Ettala, Thomas Cluzeau, Céline Berthon, Niklas Landberg, Ludovic Gabellier, Carmen Botella, Martin Carré, Lovisa Wennström, Hubert Serve, Claudia Lengerke, Patricia García Ramírez, Hartmut Döhner, Corentin Orvain, Michael W.M. Kühn, Vladimir Lazarević, Camille Gondran, Marc Maynadié, Emilie Bérard, Raimundo García, Jiří Mayer, M. L. Amigo, Hans‐Joachim Tischler, Anna Robelius
article en

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.

BloodVol. 146(Supplement 1)
Goethe University Frankfurt (DE), Uppsala University (SE), Université d'Orléans (FR), Karolinska University Hospital (SE), University of Helsinki (FI), Université Toulouse III - Paul Sabatier (FR), Université de Bordeaux (FR), Inserm (FR), Philipps University of Marburg (DE), Université de Bourgogne (FR), Universidad de Alcalá (ES), Universidad Autónoma de Bucaramanga (CO), Johannes Gutenberg University Mainz (DE), Université Paris-Est Créteil (FR), University of Erfurt (DE), Université Paris Cité (FR), Heidelberg University (DE), Université de Lille (FR), Helsinki University Hospital (FI), Sahlgrenska University Hospital (SE), Institut Gustave Roussy (FR), Erasmus MC (NL), Turku University Hospital (FI), Aarhus University Hospital (DK), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Hospital Universitari i Politècnic La Fe (ES), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire Henri-Mondor (FR), Centre Hospitalier Universitaire de Toulouse (FR), Hochschule für Angewandte Wissenschaften Kiel (DE), Christian-Albrechts-Universität zu Kiel (DE), Centre Hospitalier Universitaire de Besançon (FR), Städtisches Klinikum Dresden (DE), Hospital General Universitario Morales Meseguer (ES), Sorbonne Paris Cité (FR), Hôpital Cochin (FR), Centre Hospitalier Universitaire de Montpellier (FR), University Medical Center of the Johannes Gutenberg University Mainz (DE), Centre Hospitalier Universitaire Amiens-Picardie (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), University Hospital Brno (CZ), Centre Hospitalier Universitaire de Nîmes (FR), Centre Léon Bérard (FR), Centre Hospitalier Universitaire de Reims (FR), Bordeaux Population Health (FR), Hospital Universitario Príncipe de Asturias (ES), Laboratoire de Thermique et Energie de Nantes (FR), Department of Medical Sciences (RU), Hospital San Pedro de Alcántara (ES), Centre Hospitalier Universitaire d'Angers (FR), CHU Dijon Bourgogne (FR), Hôpital l'Archet (FR), Hôpital Cardiologique du Haut-Lévêque (FR), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Centre Hospitalier du Mans (FR), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Hospital Universitario Fundación Jiménez Díaz (ES), Peuplements végétaux et bioagresseurs en milieu tropical (RE), Hospital General Universitario de Alicante Doctor Balmis (ES), Skåne University Hospital (SE), Institut Universitaire de Recherche Clinique (FR), Centre de Recherche en Cancérologie de Marseille (FR), Centre hospitalier universitaire d'Orléans (FR), University Hospital Ulm (DE), Centre Hospitalier Universitaire de Saint-Étienne (FR), University Hospital Carl Gustav Carus (DE), Johannes Wesling Klinikum Minden (DE), Hochschule für Technik und Wirtschaft Dresden – University of Applied Sciences (DE), BoRdeaux Institute of onCology (FR), Technische Universität Dresden (DE), University of Tübingen (DE), Heidelberg University (US), Université Grenoble Alpes (FR), Université de Reims Champagne-Ardenne (FR), Nantes Université (FR)
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Chronic Myeloid Leukemia Treatments
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