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

Sarah Elitzur; Ruth Shiloh; Jan L C Loeffen; Agata Pastorczak; Masatoshi Takagi; Simon Bomken; André Baruchel; Thomas Lehrnbecher; Sarah K Tasian; Oussama Abla; Nira Arad-Cohen; Itziar Astigarraga; Miriam Ben-Harosh; Nicole Bodmer; Triantafyllia Brozou; Francesco Ceppi; Liliia Chugaeva; Luciano Dalla-Pozza; Stéphane Ducassou; Gabriele Escherich; Roula Farah; Amber Gibson; Henrik Hasle; Julieta Hoveyan; Elad Jacoby; Janez Jazbec; Stefanie Verena Junk; Alexandra Kolenova; Jelena Lazic; Luca Lo Nigro; Nizar Mahlaoui; Lane H Miller; Vassilios Papadakis; Lucie Pecheux; Marta Pillon; Ifat Sarouk; Jan Stary; Eftichia Stiakaki; Marion Strullu; Thai Hoa Tran; Marek Ussowicz; Jaime Verdu-Amorós; Anna Zofia Wakuliñska; Joanna Zawitkowska; Dominique Stoppa-Lyonnet; Alexander Malcolm Taylor; Yosef Shiloh; Shai Izraeli; Véronique Minard-Colin; Kjeld Schmiegelow; Ronit Nirel; Andishe Attarbaschi; Arndt Borkhardt

doi:10.1182/blood.2024024283

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

Sarah Elitzur^*, Ruth Shiloh, Jan L C Loeffen, Agata Pastorczak, Masatoshi Takagi, Simon Bomken, André Baruchel, Thomas Lehrnbecher, Sarah K Tasian, Oussama Abla, Nira Arad-Cohen, Itziar Astigarraga, Miriam Ben-Harosh, Nicole Bodmer, Triantafyllia Brozou, Francesco Ceppi, Liliia Chugaeva, Luciano Dalla-Pozza, Stéphane Ducassou, Gabriele EscherichRoula Farah, Amber Gibson, Henrik Hasle, Julieta Hoveyan, Elad Jacoby, Janez Jazbec, Stefanie Verena Junk, Alexandra Kolenova, Jelena Lazic, Luca Lo Nigro, Nizar Mahlaoui, Lane H Miller, Vassilios Papadakis, Lucie Pecheux, Marta Pillon, Ifat Sarouk, Jan Stary, Eftichia Stiakaki, Marion Strullu, Thai Hoa Tran, Marek Ussowicz, Jaime Verdu-Amorós, Anna Zofia Wakuliñska, Joanna Zawitkowska, Dominique Stoppa-Lyonnet, Alexander Malcolm Taylor, Yosef Shiloh, Shai Izraeli, Véronique Minard-Colin, Kjeld Schmiegelow, Ronit Nirel, Andishe Attarbaschi, Arndt Borkhardt

^*Corresponding author for this work

Department of Paediatrics and Adolescent Medicine

2 Citations (Scopus)

Abstract

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Original language	English
Journal	Blood
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood.2024024283
Publication status	E-pub ahead of print - 25 Jun 2024

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10.1182/blood.2024024283

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Elitzur, S., Shiloh, R., Loeffen, J. L. C., Pastorczak, A., Takagi, M., Bomken, S., Baruchel, A., Lehrnbecher, T., Tasian, S. K., Abla, O., Arad-Cohen, N., Astigarraga, I., Ben-Harosh, M., Bodmer, N., Brozou, T., Ceppi, F., Chugaeva, L., Dalla-Pozza, L., Ducassou, S., ... Borkhardt, A. (2024). ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies. Blood. Advance online publication. https://doi.org/10.1182/blood.2024024283

Elitzur, S, Shiloh, R, Loeffen, JLC, Pastorczak, A, Takagi, M, Bomken, S, Baruchel, A, Lehrnbecher, T, Tasian, SK, Abla, O, Arad-Cohen, N, Astigarraga, I, Ben-Harosh, M, Bodmer, N, Brozou, T, Ceppi, F, Chugaeva, L, Dalla-Pozza, L, Ducassou, S, Escherich, G, Farah, R, Gibson, A, Hasle, H, Hoveyan, J, Jacoby, E, Jazbec, J, Junk, SV, Kolenova, A, Lazic, J, Lo Nigro, L, Mahlaoui, N, Miller, LH, Papadakis, V, Pecheux, L, Pillon, M, Sarouk, I, Stary, J, Stiakaki, E, Strullu, M, Tran, TH, Ussowicz, M, Verdu-Amorós, J, Wakuliñska, AZ, Zawitkowska, J, Stoppa-Lyonnet, D, Taylor, AM, Shiloh, Y, Izraeli, S, Minard-Colin, V, Schmiegelow, K, Nirel, R, Attarbaschi, A & Borkhardt, A 2024, 'ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies', Blood. https://doi.org/10.1182/blood.2024024283

@article{6892a1e7ec224434877e0f9cfaf1eb34,

title = "ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies",

abstract = "Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.",

author = "Sarah Elitzur and Ruth Shiloh and Loeffen, {Jan L C} and Agata Pastorczak and Masatoshi Takagi and Simon Bomken and Andr{\'e} Baruchel and Thomas Lehrnbecher and Tasian, {Sarah K} and Oussama Abla and Nira Arad-Cohen and Itziar Astigarraga and Miriam Ben-Harosh and Nicole Bodmer and Triantafyllia Brozou and Francesco Ceppi and Liliia Chugaeva and Luciano Dalla-Pozza and St{\'e}phane Ducassou and Gabriele Escherich and Roula Farah and Amber Gibson and Henrik Hasle and Julieta Hoveyan and Elad Jacoby and Janez Jazbec and Junk, {Stefanie Verena} and Alexandra Kolenova and Jelena Lazic and {Lo Nigro}, Luca and Nizar Mahlaoui and Miller, {Lane H} and Vassilios Papadakis and Lucie Pecheux and Marta Pillon and Ifat Sarouk and Jan Stary and Eftichia Stiakaki and Marion Strullu and Tran, {Thai Hoa} and Marek Ussowicz and Jaime Verdu-Amor{\'o}s and Wakuli{\~n}ska, {Anna Zofia} and Joanna Zawitkowska and Dominique Stoppa-Lyonnet and Taylor, {Alexander Malcolm} and Yosef Shiloh and Shai Izraeli and V{\'e}ronique Minard-Colin and Kjeld Schmiegelow and Ronit Nirel and Andishe Attarbaschi and Arndt Borkhardt",

note = "Copyright {\textcopyright} 2024 American Society of Hematology.",

year = "2024",

month = jun,

day = "25",

doi = "10.1182/blood.2024024283",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

}

TY - JOUR

T1 - ATM germline 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, André

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, Stéphane

AU - Escherich, Gabriele

AU - Farah, Roula

AU - Gibson, Amber

AU - Hasle, Henrik

AU - Hoveyan, Julieta

AU - Jacoby, Elad

AU - Jazbec, Janez

AU - Junk, Stefanie Verena

AU - Kolenova, Alexandra

AU - Lazic, Jelena

AU - Lo Nigro, Luca

AU - Mahlaoui, Nizar

AU - Miller, Lane H

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-Amorós, Jaime

AU - Wakuliñska, Anna Zofia

AU - Zawitkowska, Joanna

AU - Stoppa-Lyonnet, Dominique

AU - Taylor, Alexander Malcolm

AU - Shiloh, Yosef

AU - Izraeli, Shai

AU - Minard-Colin, Véronique

AU - Schmiegelow, Kjeld

AU - Nirel, Ronit

AU - Attarbaschi, Andishe

AU - Borkhardt, Arndt

PY - 2024/6/25

Y1 - 2024/6/25

N2 - Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated 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. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

UR - http://www.scopus.com/inward/record.url?scp=85199688867&partnerID=8YFLogxK

U2 - 10.1182/blood.2024024283

DO - 10.1182/blood.2024024283

M3 - Journal article

C2 - 38917355

SN - 0006-4971

JO - Blood

JF - Blood

ER -

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

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