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 - Anderzhanova, Liliia
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 - Stoppa-Lyonnet, Dominique
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
UR - http://www.scopus.com/inward/record.url?scp=85199688867&partnerID=8YFLogxK
U2 - 10.1182/blood.2024024283
DO - 10.1182/blood.2024024283
M3 - Article
C2 - 38917355
VL - 144
SP - 1193
EP - 1205
JO - Blood
JF - Blood
SN - 0006-4971
IS - 11
ER -