ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

TY - JOUR

T1 - ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

AU - Elitzur, Sarah

AU - Shiloh, Ruth

AU - Loeffen, Jan L C

AU - Pastorczak, Agata

AU - Takagi, Masatoshi

AU - Bomken, Simon

AU - Baruchel, Andre

AU - Lehrnbecher, Thomas

AU - Tasian, Sarah K

AU - Abla, Oussama

AU - Arad-Cohen, Nira

AU - Astigarraga, Itziar

AU - Ben-Harosh, Miriam

AU - Bodmer, Nicole

AU - Brozou, Triantafyllia

AU - Ceppi, Francesco

AU - Chugaeva, Liliia

AU - Dalla Pozza, Luciano

AU - Ducassou, Stephane

AU - Escherich, Gabriele

AU - Farah, Roula

AU - Gibson, Amber

AU - Hasle, Henrik

AU - Hoveyan, Julieta

AU - Jacoby, Elad

AU - Jazbec, Janez

AU - Junk, Stefanie

AU - Kolenova, Alexandra

AU - Lazic, Jelena

AU - Lo Nigro, Luca

AU - Mahlaoui, Nizar

AU - Miller, Lane

AU - Papadakis, Vassilios

AU - Pecheux, Lucie

AU - Pillon, Marta

AU - Sarouk, Ifat

AU - Stary, Jan

AU - Stiakaki, Eftichia

AU - Strullu, Marion

AU - Tran, Thai Hoa

AU - Ussowicz, Marek

AU - Verdu-Amoros, Jaime

AU - Wakulinska, Anna

AU - Zawitkowska, Joanna

AU - Stoppa-Lyonnet, Dominique

AU - Taylor, A Malcolm

AU - Shiloh, Yosef

AU - Izraeli, Shai

AU - Minard-Colin, Veronique

AU - Schmiegelow, Kjeld

AU - Nirel, Ronit

AU - Attarbaschi, Andishe

AU - Borkhardt, Arndt

N1 - © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

PY - 2024/9/12

Y1 - 2024/9/12

N2 - Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

AB - Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

KW - Humans

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - Child

KW - Ataxia Telangiectasia/genetics

KW - Male

KW - Female

KW - Adolescent

KW - Hematologic Neoplasms/genetics

KW - Child, Preschool

KW - Germ-Line Mutation

KW - Infant

KW - Young Adult

KW - Adult

U2 - 10.1182/blood.2024024283

DO - 10.1182/blood.2024024283

M3 - SCORING: Journal article

C2 - 38917355

VL - 144

SP - 1193

EP - 1205

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 11

ER -