Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome

Yusuke Hara, Norio Shiba, Kentaro Ohki, Ken Tabuchi, Genki Yamato, Myoung Ja Park, Daisuke Tomizawa, Akitoshi Kinoshita, Akira Shimada, Hirokazu Arakawa, Akiko M. Saito, Nobutaka Kiyokawa, Akio Tawa, Keizo Horibe, Takashi Taga, Souichi Adachi, Tomohiko Taki, Yasuhide Hayashi

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)394-404
Number of pages11
JournalGenes Chromosomes and Cancer
Volume56
Issue number5
DOIs
Publication statusPublished - May 1 2017

Fingerprint

Leukemia, Megakaryoblastic, Acute
Pediatrics
Acute Myeloid Leukemia
Disease-Free Survival
Survival

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. / Hara, Yusuke; Shiba, Norio; Ohki, Kentaro; Tabuchi, Ken; Yamato, Genki; Park, Myoung Ja; Tomizawa, Daisuke; Kinoshita, Akitoshi; Shimada, Akira; Arakawa, Hirokazu; Saito, Akiko M.; Kiyokawa, Nobutaka; Tawa, Akio; Horibe, Keizo; Taga, Takashi; Adachi, Souichi; Taki, Tomohiko; Hayashi, Yasuhide.

In: Genes Chromosomes and Cancer, Vol. 56, No. 5, 01.05.2017, p. 394-404.

Research output: Contribution to journalArticle

Hara, Y, Shiba, N, Ohki, K, Tabuchi, K, Yamato, G, Park, MJ, Tomizawa, D, Kinoshita, A, Shimada, A, Arakawa, H, Saito, AM, Kiyokawa, N, Tawa, A, Horibe, K, Taga, T, Adachi, S, Taki, T & Hayashi, Y 2017, 'Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome', Genes Chromosomes and Cancer, vol. 56, no. 5, pp. 394-404. https://doi.org/10.1002/gcc.22444
Hara, Yusuke ; Shiba, Norio ; Ohki, Kentaro ; Tabuchi, Ken ; Yamato, Genki ; Park, Myoung Ja ; Tomizawa, Daisuke ; Kinoshita, Akitoshi ; Shimada, Akira ; Arakawa, Hirokazu ; Saito, Akiko M. ; Kiyokawa, Nobutaka ; Tawa, Akio ; Horibe, Keizo ; Taga, Takashi ; Adachi, Souichi ; Taki, Tomohiko ; Hayashi, Yasuhide. / Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. In: Genes Chromosomes and Cancer. 2017 ; Vol. 56, No. 5. pp. 394-404.
@article{54c97423d8a54877b8fcdb5ef0c9b605,
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.",
author = "Yusuke Hara and Norio Shiba and Kentaro Ohki and Ken Tabuchi and Genki Yamato and Park, {Myoung Ja} and Daisuke Tomizawa and Akitoshi Kinoshita and Akira Shimada and Hirokazu Arakawa and Saito, {Akiko M.} and Nobutaka Kiyokawa and Akio Tawa and Keizo Horibe and Takashi Taga and Souichi Adachi and Tomohiko Taki and Yasuhide Hayashi",
year = "2017",
month = "5",
day = "1",
doi = "10.1002/gcc.22444",
language = "English",
volume = "56",
pages = "394--404",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome

AU - Hara, Yusuke

AU - Shiba, Norio

AU - Ohki, Kentaro

AU - Tabuchi, Ken

AU - Yamato, Genki

AU - Park, Myoung Ja

AU - Tomizawa, Daisuke

AU - Kinoshita, Akitoshi

AU - Shimada, Akira

AU - Arakawa, Hirokazu

AU - Saito, Akiko M.

AU - Kiyokawa, Nobutaka

AU - Tawa, Akio

AU - Horibe, Keizo

AU - Taga, Takashi

AU - Adachi, Souichi

AU - Taki, Tomohiko

AU - Hayashi, Yasuhide

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85013212329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013212329&partnerID=8YFLogxK

U2 - 10.1002/gcc.22444

DO - 10.1002/gcc.22444

M3 - Article

C2 - 28063190

AN - SCOPUS:85013212329

VL - 56

SP - 394

EP - 404

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 5

ER -