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1476 Treatment Outcomes of Childhood Picalm:MLLT10+ Acute Leukemias: An International Retrospective Study

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Clinical Research, pediatric, Diseases, Myeloid Malignancies, Study Population, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Catherine Mark, MD1*, Edward A. Kolb, MD2, Bianca F. Goemans, MD, PhD3, Soheil Meshinchi, M.D., Ph.D.4, Brenda Gibson5*, Anke K. Bergmann, MD6*, Christine J. Harrison, PhD, FRCPath7, Cornelis Jan Pronk, MD, PhD8,9*, Hélène Lapillonne, MD, PhD10*, Guy Leverger11*, Evangelia Antoniou, MD12, Andishe Attarbaschi13*, Michael Dworzak, MD, PhD14*, Jan Stary, MD15*, Daisuke Tomizawa, MD, PhD16, Monika Lejman17*, Kjeld Schmiegelow, MD, DMSc18, Henrik Hasle, MD, PhD19, Brooklyn Joyce20*, Markus Schneider, PhD21* and Oussama Abla, MD22

1Toronto Hospital for Sick Children, Toronto, ON, Canada
2Division of Oncology, Nemours Alfed I. duPont Hospital For Children, Wilmington, DE
3Prinses Maxima Centrum, Utrecht, Netherlands
4Fred Hutchinson Cancer Center, Seattle, WA
5The Royal Hospital for Children, Glasgow, United Kingdom
6Department of Human Genetics, Hannover Medical School (MHH), Hannover, Germany
7Leukaemia Research Cytogenetics Group, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, ENG, United Kingdom
8Lund University, Lund, SWE
9Childhood Cancer Center, Skane University Hospital, Lund, Sweden
10Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
11APHP, Paris, France
12Department of Pediatrics III, University Hospital Essen, Essen, Germany
13Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria
14Department of Pediatrics, St. Anna Children's Hospital and Cancer Research Institute, Medical University of Vienna, Vienna, Austria
15Dept. of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
16Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
17Children's University Hospital, Lublin, Poland
18The Institute of Clinical medicine, The Faculty of Medicine, University of Copenhagen, Hellerup, Denmark
19Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark
20Toronto Hospital for Sick Children, Toronto, Canada
21Department of Pediatrics III, University Children’s Hospital Essen, University Duisburg-Essen, Essen, Germany
22Hospital for Sick Children Division of Hematology, Toronto, ON, Canada

Introduction: Acute leukemia with translocation t(10;11)(p12-13;q14-21) results in generation of the PICALM:MLLT10 fusion gene, and is distinct from t(10;11)(p11-13;q23) which gives rise to KMT2A (formerly MLL) gene rearrangement. Defective PICALM function leads to aberrant hematopoiesis, while defective MLLT10 function impairs chromatin-mediated gene regulation. The PICALM:MLLT10 gene has been reported in patients with Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) predominantly T-cell, Acute Undifferentiated Leukemia (AUL) and Mixed Phenotype Acute Leukemia (MPAL). MLLT10 interacts directly with DOT1L in a complex that regulates the methylation of H3K79. MLLT10 fusions are thought to misdirect DOT1L to the promoters of HOXA genes, leading to hypermethylation of H3K79. This hypermethylation causes constitutive activation of HOXA activity and prevents cell maturation and differentiation. The clinico-biological characteristics, response to conventional treatments, and survival outcomes of childhood PICALM:MLLT10+ leukemias are poorly understood.

Methods: This was an international, multicenter, retrospective cohort study. Data were submitted by ten International-BFM (I-BFM) study Group-AML and ALL committees and by the Children`s Oncology Group (COG)-AML Study committee. For study inclusions, patients were required to be ≤ 21 years of age at diagnosis, diagnosed between January 1995 and December 2019 with de novo ALL, AML, AUL or MPAL and PICALM:MLLT10 fusion-positive. Patients with KMT2A-rearranged leukemia or acute promyelocytic leukemia were excluded. Kaplan Meier curves were employed for survival analysis with Cox proportional hazard modelling to compare effect of AML vs ALL therapy, and receipt of hematopoietic stem cell transplant (HSCT) vs no HSCT, on survival. Pearson’s Chi Squared was employed as a non-parametric measure to determine the effect of end of induction-1 (EIO-1) MRD positive vs negative status on incidence of relapse. P value cut-off for data to reach statistical significance was <0.05.

Results: Ninety-eight children with acute leukemia were included, 60 were males. Median age at diagnosis was 12 years (IQR:9-14.8 years) and median initial white cell count was 40.5 x 109/L (IQR:13.8-168.9). Fifty-five (55.6%) patients were diagnosed with T-ALL, 39 (39.4%) with AML, while precursor-B ALL, AUL and MPAL were each diagnosed in single patients; 1 subtype diagnosis was unknown. Ten (10.1%) patients presented with CNS disease and 13 (13.1%) presented with non-CNS extramedullary manifestations. Of 66 with cytogenetic/molecular data available, 33 (50%) had additional cytogenetic-molecular aberrations; NOTCH1, WT1 and RAS pathway mutations predominated. Most patients received an initial chemotherapy regimen guided by their disease immunophenotype: 58/98 (58.6%) received an ALL-like chemotherapy regimen upfront, 38 (38.4%) received an AML-like regimen, 1 (1.0%) a hybrid regimen, 1 initial chemotherapy regimen was unknown. Five-year event-free survival (EFS) was 50.4% (CI 39.1-64.9). For AML patients, 5-year EFS was 22.5% (CI 9.75-52.0) and for ALL 67.7% (CI 54.2-84.7), p=<0.001. Five-year overall survival (OS) was 56.3% (CI 46.3-68.5). For AML patients, 5-year OS was 26.7% (CI 13.3-53.6) and for ALL 75.7% (CI 64.6-88.8), p=<0.001. Thirty-eight patients died, 22 (57.9%) deaths were disease-related, 4 (10.5%) treatment-related. Patients who received HSCT in CR1, demonstrated a trend towards an inferior 5-year EFS (23.7% vs 56.5%) and OS (42.6% vs 64.5%) than those who did not; however, analysis was limited by small sample size. Four (22.2%) HSCT recipients had ALL but most, 14 (77.8%), had AML, which may account for the unfavourable outcomes associated with HSCT. There was no statistically significant difference in rate of relapse in the EOI-1 MRD-positive compared with MRD-negative patients (p=0.49). Of those who relapsed, 25 (75.8%) had an isolated bone marrow relapse, 3 (9.1%) isolated CNS, 3 (9.1%) other sites and, for 2 patients, site of relapse was unknown.

Conclusions: Children with PICALM:MLLT10+ AML have inferior 5-year EFS and OS outcomes compared to their T-ALL counterparts. MRD status at EOI-1 was not predictive of relapse. Targeted therapies with DOT1L inhibitors or DNA demethylating agents should be explored, particularly for patients with AML.

Disclosures: Tomizawa: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schmiegelow: Medscape: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Novo Nordisk: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

*signifies non-member of ASH