Publication

Genetic alterations and MRD refine risk assessment within KMT2A-rearranged B-cell precursor ALL in adult: a GRAALL study.

Journal Paper/Review - Aug 18, 2023

Units
PubMed
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Citation
Kim R, Bergugnat H, Pastoret C, Pasquier F, Raffoux E, Larcher L, Passet M, Grardel N, Delabesse E, Kubetzko S, Caye-Eude A, Meyer C, Marschalek R, Lafage-Pochitaloff M, Thiebaut-Bertrand A, Balsat M, Escoffre-Barbe M, Blum S, Baumann M, Banos A, Straetmans N, Gallego-Hernanz M, Chalandon Y, Graux C, Soulier J, Leguay T, Hunault-Berger M, Huguet F, Lhéritier V, Dombret H, Boissel N, Clappier E. Genetic alterations and MRD refine risk assessment within KMT2A-rearranged B-cell precursor ALL in adult: a GRAALL study. Blood 2023
Type
Journal Paper/Review (English)
Journal
Blood 2023
Publication Date
Aug 18, 2023
Issn Electronic
1528-0020
Brief description/objective

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of co-mutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in three consecutive GRAALL trials, 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%, p=0.001) and OS (28.1% vs 60.7%, p=0.006). We next analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG)/T-cell receptor (TR) rearrangements and KMT2A genomic fusion as markers. In approximately one third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. By contrast, KMT2A-based MRD was highly reliable and was strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR 7.1% and OS 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.