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582 NUTM1-Rearranged Infant and Pediatric B Cell Precursor Acute Lymphoblastic Leukemia: A Good Prognostic Subtype Identified in a Collaborative International StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Insights in Genomics, MRD, and Toxicities
Hematology Disease Topics & Pathways:
ALL, Leukemia, Diseases, Lymphoid Malignancies, Clinically relevant
Monday, December 7, 2020: 9:00 AM

Judith M. Boer, PhD1,2, Maria Grazia Valsecchi, PhD3*, Femke M. Hormann, MSc1,2*, Zeljko Antic, MD4*, Marketa Zaliova, MD, PhD5, Claire Schwab, PhD6*, Giovanni Cazzaniga, PhD7*, Chloé Arfeuille, MD8*, Hélène Cavé, PharmD, PhD9*, Andishe Attarbaschi, MD10*, Sabine Strehl, PhD11*, Gabriele Escherich, MD12*, Toshihiko Imamura, MD, PhD13, Kentaro Ohki, MD, PhD14*, Tanja A. Gruber, MD, PhD15, Rosemary Sutton, BSc MSc PhD16*, Agata Pastorczak17*, Tim Lammens, PhD18,19*, Frederic Lambert, MD20*, Chi Kong Li, MD21, Enrique Carrillo de Santa Pau, PhD22*, Steve Hoffmann, MD, PhD23*, Anja Möricke, MD24*, Christine J. Harrison, PhD, FRCPath6, Monique L. Den Boer, PhD1,2,25, Paola De Lorenzo7,26*, Ronald W. Stam, PhD1*, Anke K. Bergmann, MD, PhD4* and Rob Pieters, MD, PhD, MSc1

1Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
2Oncode Institute, Utrecht, Netherlands
3Centro Operativo di Ricerca Statistica, Fondazione Tettamanti, Monza, Italy
4Institute of Human Genetics, Medical School Hannover, Hannover, Germany
5CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
6Leukaemia Research Cytogenetics Group, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
7Tettamanti Research Center, Pediatric Clinic, University of Milan-Bicocca, Monza, Italy
8Department of Genetics, Robert Debré Hospital and University of Paris, Paris, France
9Institut de Recherche St Louis, Université de Paris, INSERM U1131, Paris, France
10Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
11CCRI, Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
12Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
13Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
14Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
15Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
16Children's Cancer Institute Australia, University of NSW, Randwick, NSW, Australia
17Department of Pediatric Oncology and Hematology, Medical University of Lodz, Lodz, CA, Poland
18Cancer Research Institute Ghent (CRIG), Ghent, Belgium
19Department of Pediatric Hemato-oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
20Centre Hospitalier Universitaire de Liège, Liege, Belgium
21Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong
22Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, Madrid, Spain
23Computational Biology, Leibniz Institute on Ageing-Fritz Lipmann Institute (FLI), Jena, Germany
24Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
25Erasmus MC-Sophia Children's Hospital, Department of Pediatric Oncology/Hematology, Rotterdam, Netherlands
26Centro Operativo di Ricerca Statistica, Fondazione Tettamanti, School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy

Background and Aims

A novel genetic subtype of B cell precursor acute lymphoblastic leukemia (B-ALL) is characterized by rearrangement of NUTM1 (NUTM1r) on 15q14 resulting in fusion of NUTM1 to one of several partner genes such as CUX1, ACIN1, BRD9, and IKZF1. The downstream effects of NUTM1r include upregulation of the proto-oncogene BMI1 and specific fusions also induce transcription of the HOXA gene cluster (Hormann et al. Haematologica 2019; Li et al. PNAS 2018). This novel subtype is rare in children, but appears to be more prevalent among infants negative for KMT2A rearrangement (KMT2Ar) based on the frequency of karyotypic 15q aberrations (De Lorenzo et al. Leukemia 2014). This international collaborative study aimed to determine the frequency of NUTM1r in infant and pediatric cohorts, and to characterize the demographic, clinical and molecular features of NUTM1r-positive B-ALL.

Patients and Methods

Interfant-related study groups provided NUTM1 screening results for KMT2Ar-negative Interfant-99 and -06 cases with karyotypic 15q aberration, normal karyotype, or missing karyotype. Additionally, NUTM1r-positive cases of any age were collected from the study groups united in the Ponte di Legno consortium. The identified NUTM1r-positive children were diagnosed between 1995-2019, infants (≤365 days of age) included in the Interfant-99 or 06 trials were diagnosed between 2000-2016, and remaining infants between 1986-2019. The techniques used for the detection of NUTM1r were break-apart FISH, RNA sequencing, and RT-PCR. Event-free survival (EFS) and overall survival (OS) were estimated according to Kaplan-Meier, standard error according to Greenwood, and the curves were compared by log-rank test.


We identified 81 NUTM1r cases, including 35 Interfant-enrolled infants, 10 other infants and 36 children. NUTM1r was reported to be rare among pediatric B-ALL with an estimated frequency range of 0.28-0.86%. The median age among NUTM1r-positive children was 4.5 years (range 1-15). Among KMT2Ar-negative infants the frequency of NUTM1r was 21.7%. Of NUTM1r-positive infants, 54% were <6 months at diagnosis (median 5.6, range 0.4-11.0 months) compared with 16% in the remaining KMT2Ar-negative infants (median 9.3, range 0.1-11.9; p<0.0001). Other baseline characteristics (WBC, gender, prednisone poor response) were similar between NUTM1r-positive and -negative infants.

Of the NUTM1r-positive cases, all achieved complete remission, 82% had minimal residual disease <10e-4 at the end of induction, and no patient received stem cell transplant in first remission. The 4-year EFS was 100% in Interfant-enrolled NUTM1r-positive patients versus 74% (95% CI 65.1-81.0, p=0.001) in the remaining KMT2Ar-negative cases (n=126). The better outcome was confirmed also after adjusting for WBC, gender and prednisone response (p=0.0001). The 4-year OS were 100% and 88.0% (95% CI 80.5-92.7) for NUTM1r-positive and other KMT2Ar-negative infant cases, respectively (p-value=0.04). Children and non-Interfant-enrolled infants treated on different treatment protocols showed 89.4% (95% CI 78.6-1) 4-year EFS and 100% 4-year OS.

In order of frequency, NUTM1 fusion partners were ACIN1 (30.4%), CUX1 (21.7%), BRD9 (17.4%), ZNF618 (13%), AFF1 (4.3%), SLC12A6 (4.3%), IKZF1 (2.9%), and three novel partners: ATAD5 (2.9%), CHD4 (1.4%) and RUNX1 (1.4%). Infants mainly showed fusions with ACIN1, CUX1, BRD9 and AFF1, associated with HOXA9 upregulation. Older infants and children showed both HOXA-upregulating and non-HOXA-upregulating fusions. Epigenetic profiling showed a distinct pattern of DNA methylation and histone modification of the HOXA gene cluster region in leukemic cells of an ACIN1-NUTM1 pediatric case compared with KMT2Ar-positive and KMT2Ar/NUTM1r-negative pediatric cases.


NUTM1r ALL was identified as the second largest subtype in infants, found in 21.7% of KMT2Ar-negative infant B-ALL, representing 5-7% of total infant ALL, and associated with excellent outcome on Interfant standard risk protocols. The favorable outcome was confirmed in the Ponte di Legno cohort of infant and pediatric NUTM1r-positive patients enrolled on different treatment protocols over more than two decades. We conclude that NUTM1r ALL is a favorable genetic subtype in infants and children and possibly eligible for treatment reduction.

Disclosures: No relevant conflicts of interest to declare.

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