title: Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.
abstract: Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.|Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Yusuke
authors.identifier: 0000-0001-7271-3454
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.|Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.|Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Tabuchi
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.|Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Yamato
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.
authors.forename: Myoung-Ja
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Pediatrics, St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Department of Pediatrics, Okayama University Hospital, Okayama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Akiko M
authors.initials: AM
authors.lastname: Saito
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kiyokawa
authors.affiliation: Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Tawa
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Human Health Sciences Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.affiliation: Department of Hematology and Oncology, Gunma Children's Medical Center, Shibukawa, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.|Gunma Red Cross Blood Center, Maebashi, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion