-Author name in bold denotes the presenting author
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Clinically Relevant Abstract denotes an abstract that is clinically relevant.

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520 ATM Germline Pathogenic Variants Affect Treatment Outcomes in Children with Acute Lymphoblastic Leukemia/Lymphoma and Ataxia TelangiectasiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Progress Through Collaboration: Impactful Cooperative Efforts to Optimize Care for ALL
Hematology Disease Topics & Pathways:
Genetic Disorders, Diseases, Lymphoid Malignancies
Sunday, December 10, 2023: 12:45 PM

Sarah Elitzur, MD1, Ruth Shiloh, PhD1*, Jan Loeffen, MD, PhD2*, Agata Pastorczak, MD, PhD3*, Masatoshi Takagi, MD, PhD4, Simon Bomken, MD, PhD5*, Andre Baruchel, MD6, Stephane Ducassou, MD, PhD7*, Nizar Mahlaoui, MD, PhD8,9*, Marion Strullu, MD, PhD10,11*, Thomas Lehrnbecher, MD12*, Kjeld Schmiegelow, MD, DMsc13*, Oussama Abla, MD14, Liliia Anderzhanova, MD15*, Nira Arad-Cohen, MD16*, Itziar Astigarraga, MD, PhD17*, Miriam Ben-Harosh, MD18*, Francesco Ceppi, MD19, Nicole Bodmer, MD20*, Triantafyllia Brozou, MD21*, Luciano Dalla-Pozza, MD22, Gabriele Escherich, MD23*, Roula Farah, MD24*, Amber Gibson, DO25*, Henrik Hasle26, Julieta Hoveyan, MD27*, Elad Jacoby, MD28, Janez Jazbec, MD, PhD29*, Alexandra Kolenova, MD, PhD30, Jelena Lazic, MD, PhD31*, Luca Lo Nigro, MD32, Lane Miller, MD33*, Vassilios Papadakis, MD, PhD34*, Lucie Pecheux, MD35*, Marta Pillon, MD, PhD36*, Ifat Sarouk, MD37*, Jan Stary, MD, DSc38*, Eftichia Stiakaki, MD39*, Sarah K Tasian, MD40, Thai Hoa Tran, MD41, Marek Ussowicz, MD, PhD42*, Jose Jaime Verdu-Amoros, MD43*, Anna Wakulinska, MD44*, Joanna Zawitkowska, MD, PhD45*, Dominique Stoppa-Lyonnet, PhD46,47,48*, Malcolm Taylor, PhD49*, Yosef Shiloh, PhD50*, Shai Izraeli, MD1, Ronit Nirel, PhD51*, Veronique Minard-Colin, MD, PhD52*, Andishe Attarbaschi, Prof., MD53* and Arndt Borkhardt, MD21

1Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Tel Aviv University, Petah Tikva, Israel
2Princess Máxima Center for Pediatric Oncology, Utrecht, Utrecht, NLD
3Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
4Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
5Newcastle University, Newcastle Upon Tyne, GBR
6Hôpital Robert Debré, Paris, France
7Service d'onco-hématologie pédiatrique, Hôpital Pellegrin Tripode, Bordeaux, FRA
8Pediatric Hematology, Immunology and Rheumatology Department, Hopital Necker-Enfants Malades, Paris, France
9French National Reference Center for Primary Immune Deficiencies (CEREDIH), Paris, France
10INSERM UMR 1131, Institut De Recherche St Louis, Paris, FRA
11Hôpital Robert Debré, APHP, Paris, France
12Department of Pediatrics, Division of Hematology, Oncology and Hemostaseology, Goethe University Frankfurt, Frankfurt/Main, Germany
13Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark
14Hospital For Sick Children, Toronto, ON, Canada
15Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
16Department of Pediatric Hemato-Oncology, Rambam Health Care Campus, Haifa, ISR
17Hospital Universitario Cruces, Barakaldo, ESP
18Soroka Medical Center, Beer Sheva, Israel
19CHUV University Hospital, Lausanne, VD, Switzerland
20Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
21Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
22The Children's Hospital at Westmead, Westmead, Australia
23Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
24Saint George Hospital, Beirut, Lebanon
25Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX
26Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
27Pediatric Cancer and Blood Disorders Center, Immune Oncology Research Institute, Yerevan, Armenia
28Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
29University Children's Hospital, Faculty of Medicine, University of Ljubljan, Ljubljana, SVN
30Commenius Univ. Children's Hospital, Bratislava, SVK
31University Children's Hospital, School of Medicine University of Belgrade, Belgrade, SRB
32Azienda Policlinico OVE - Center of Pediatric Hematology Oncology, Catania, Italy, Italy
33Cancer and Blood Disorders, Children's Minnesota, Minneapolis, MN
34Agia Sofia Children's Hospital, Athens, Marousi, GRC
35Stollery Children Hospital, University of Alberta, Edmonton, Canada
36University of Padova, Padova, ITA
37Pediatric Pulmonology Unit and Ataxia Telangiectasia Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
38Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University/University Hospital Motol, Prague, Czech Republic
39University Hospital of Heraklion, Heraklion Crete, AL, GRC
40Children's Hospital of Philadelphia, Philadelphia, PA
41CHU Sainte Justine, Montreal, QC, Canada
42Wroclaw Medical University, Wroclaw, POL
43University Hospital Valencia, Valencia, Spain
44The Children's Memorial Health Institute, Warsaw, Poland
45Medical University of Lublin, Lublin, POL
46Department of Genetics, Institut Curie, Paris, FRA
47Inserm U830, Paris, France
48Université Paris Cité, Paris, France
49Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
50Department of Human Molecular Genetics and Biochemistry, Tel Aviv University School of Medicine, Tel Aviv, Israel
51Department of Statistics and Data Science, Hebrew University, Jerusalem, ISR
52Gustave Roussy, Villejuif, France
53Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria

Introduction Ataxia telangiectasia (A-T) is a multisystem disorder caused by biallelic germline pathogenic variants (PV) in the ATM gene. An important feature of A-T is an increased predisposition to cancer with a reported incidence of 25%, primarily attributed to hematological malignancies. Patients with A-T and cancer are usually excluded from therapeutic clinical trials, limited information thus exists concerning their treatment outcomes and toxicity profiles and consequently, optimal management strategies are unclear and an unmet need. In this multinational study, we aimed to investigate the characteristics and outcomes of leukemia and lymphoma in a large cohort of children with A-T and to determine risk factors which impact treatment outcome in order to generate consensus and data-based prospective treatment recommendations.

Methods This study of patients aged ≤25 years with A-T and hematological malignancies was conducted through the International BFM Study Group. Patient data were collected from medical records, including specific patient comorbidities. Each reported ATM PV identified in the cohort was classified as null (resulting in complete loss of ATM activity) or hypomorphic (allowing residual ATM activity) according to the expected functional activity of the ATM protein and published functional studies. Patients with reported ATM PV were then classified as Group A (two null PV) or Group B (at least one hypomorphic PV).

Results We report 202 pediatric and adolescent/young adult patients with A-T and hematological malignancies from 25 countries. The cohort included 82 patients with ALL/LBL (41%), predominantly (85%) of T-cell lineage, 91 with mature B-cell lymphomas (45%), 21 with Hodgkin lymphoma (10%) and 8 with other hematological malignancies (4%) (Fig 1). Of 111 patients with classifiable germline ATM variants, 82 (74%) were classified as Group A and 29 as Group B (26%). The distribution of patients with Group A and Group B germline ATM PV differed considerably between tumor types with 44% of the patients with lymphoblastic leukemia/lymphoma classified as Group B vs. 5% of those with mature B cell lymphomas (p<.001). In total, 185 patients (92%) treated with curative intent were included in the outcome analyses, 135 (73%) of whom were treated with attenuated therapy regimens. Four-year OS and EFS for the entire cohort were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Surprisingly, cure rates of patients with A-T and malignancy did not appear to improve significantly with therapy modernization over the last four decades with 4-year EFS rates of 41.6% (95% CI 26.6-65), 49.6% (95% CI 38.8-63.4) and 48.0% (95% CI 37.4-61.7) for those treated before 2000, between 2000-2009 and since 2010, respectively (p=.54). The major cause of treatment failure for the entire cohort was treatment-related mortality (TRM) with a 4-year cumulative incidence of 32.8% (95% CI 19.5-32.4), followed by progressive cancer in 14.5% (95% CI 10-19.8) and second malignancy in 4.9% (95% CI 13.1-85.8) (Fig 2). We identified factors that were significantly associated with survival for this unique patient population. Older age had a significantly deleterious effect upon survival with 4-year EFS rates of 69.1% (95%CI 55.9-85.4), 45.3% (95% CI 34.5-59.4), 39.8% (95% CI 25-63.2), and 33.7% (95% CI 20.8-54.6) for children aged ≤5 years, 5-10 years, 10-15 years and ≥15 years, respectively (p=.003). The type of germline ATM PV also had a significant impact: 4-year EFS for patients with Group B ATM PV was 78.7% (95% CI 63.7-97.2) vs. 39.4% (95% CI 29-53.3) for Group A (p<.001). Group A PV were associated with an increased TRM (OR 9.3; 95% CI 1.6-180.1; p=.042) and decreased EFS (HR .371 95% CI 16.6-82.6; p=.009).

Conclusions We demonstrate in this first comprehensive international study that leukemia and lymphoma in children with A-T are curable. While the standard treatment stratification system for patients with hematological malignancies without A-T focuses upon cancer relapse/progression as the main cause of treatment failure, TRM was the main cause of therapy failure in patients with A-T and was strongly associated with the underlying germline ATM variant type. This study further fulfills an unmet need for international collaboration and provides a platform for data-based guidelines for a novel risk stratification system and optimal therapy selection for this unique patient population.

Disclosures: Elitzur: Medison Pharma: Honoraria; Jazz Pharmaceuticals: Honoraria. Baruchel: AstraZeneca: Other: honoraria for advisory board participation but given to my institution; Servier: Honoraria, Research Funding; Clinigen: Honoraria; Serb: Other: honoraria for advisory board participation; Jazz: Other: honoraria for advisory board participation. Schmiegelow: Medscape: Other: Speaker's fee; Amgen: Other: Speaker's fee; Servier: Honoraria, Other: Educational grants; Jazz Pharmaceuticals: Honoraria; Illumina: Honoraria. Abla: Springworks Therapeutics: Consultancy, Honoraria. Jacoby: Novartis: Honoraria, Speakers Bureau; Medison: Speakers Bureau. Lo Nigro: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinigen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tasian: Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Research Funding; Incyte Corporation: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: travel support . Tran: Servier: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Minard-Colin: Adaptimmune Therapeutics plc: Consultancy; BMS: Consultancy; Roche: Consultancy; Aztra: Consultancy. Attarbaschi: JazzPharma: Honoraria.

*signifies non-member of ASH