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

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

Kim Rathana, Bergugnat Hugo, Pastoret Cedric, Pasquier Florence, Raffoux Emmanuel, Larcher Lise, Passet Marie, Grardel Nathalie, Delabesse Eric, Kubetzko Susanne, Caye-Eude Aurélie, Meyer Claus, Marschalek Rolf, Lafage-Pochitaloff Marina, Thiebaut-Bertrand Anne, Balsat Marie, Escoffre-Barbe Martine, Blum Sabine, Baumann Michael, Banos Anne, Straetmans Nicole, Gallego-Hernanz Maria-Pilar, Chalandon Yves, Graux Carlos, Soulier Jean, Leguay Thibaut, Hunault-Berger Mathilde, Huguet Françoise, Lhéritier Véronique, Dombret Hervé, Boissel Nicolas, Clappier Emmanuelle

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.