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International Journal of Hematology

, Volume 107, Issue 5, pp 586–595 | Cite as

Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study

  • Akira Shimada
  • Yuka Iijima-Yamashita
  • Akio Tawa
  • Daisuke Tomizawa
  • Miho Yamada
  • Shiba Norio
  • Tomoyuki Watanabe
  • Takashi Taga
  • Shotaro Iwamoto
  • Kiminori Terui
  • Hiroshi Moritake
  • Akitoshi Kinoshita
  • Hiroyuki Takahashi
  • Hideki Nakayama
  • Katsuyoshi Koh
  • Hiroaki Goto
  • Yoshiyuki Kosaka
  • Akiko Moriya Saito
  • Nobutaka Kiyokawa
  • Keizo Horibe
  • Yusuke Hara
  • Kentaro Oki
  • Yasuhide Hayashi
  • Shiro Tanaka
  • Souichi Adachi
Original Article

Abstract

Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42.2 and 36.8%, respectively. The 5-year disease-free survival rate among 29 patients without induction failure was 58.4%. We defined the allelic ratio (AR) of FLT3-ITD to WT > 0.7 as high. Significant differences were found in OS (AR-high, 20% vs. AR-low, 66%, p < 0.001) and EFS (13 vs. 50%, p = 0.004). All five patients with concurrent NPM1 mutations survived, while seven of eight patients who expressed the NUP98-NSD1 chimera failed to achieve 1CR and died. Multivariate analysis revealed that AR > 0.7 and expression of the NUP98-NSD1 chimera strongly impacted OS and EFS. Although all the AMLFLT3-ITD patients received HSCT at 1CR, the treatment outcome of AMLFLT3-ITD patients did not improve compared with those in a previous study. Heterogeneity was observed among AMLFLT3-ITD patients.

Keywords

AML FLT3-ITD Childhood Alleric ratio NUP98-NSD1 

Abbreviations

FLT3

fms-related tyrosine kinase 3

ITD

Internal tandem duplication

HSCT

Hematopoietic stem cell transplantation

CR

Complete remission

OS

Overall survival

DFS

Disease-free survival

EFS

Event-free survival

AR

Allelic ratio

Notes

Acknowledgements

We thank all doctors involved for participating in the JPLSG AML-05 study. This work was supported by a Grant for Clinical Cancer Research and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour, and Welfare of Japan, and Japan Agency for Medical Research and Development (AMED). We thank Ryan Chastain-Gross, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Authors Contributions

Shimada A and Tomizawa D reviewed the data analysis and interpretation and were the main authors of the manuscript. Shimada A, Tawa A (principle investigator), Tomizawa D, Taga T, Iwamoto S, Terui K, Moritake H, Kinoshita A, Takahashi T, Nakayama H and Adachi S are the member of the AML committee and participated actively in the study conception and design of the AML-05 study. Iijima-Yamashita Y, Yamada M, Norio S, Hara Y, and Oki K performed the genetic analysis. Hayashi Y organized the genetic analysis. Koh K, Goto H, and Kosaka Y contributed to the recruitment of the patients. Kiyokawa N is responsible for specimen banking center. Saito AM and Horibe K are responsible for data center. Watanabe T and Tanaka S performed statistical analysis. Adachi S and Horibe K contributed to financial and administrative support of the AML-05 study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

12185_2017_2395_MOESM1_ESM.docx (21 kb)
Supplemental Figure 1 The clearance of bone marrow blasts after single induction course in complete remission (CR) vs. non-CR group. The median blast  % dropped from 75.5% (29.4–93.9%) at BMA1 to 1.1% (0.2–17.2%) at BMA2 in the CR group vs. 85.8% (67.3–92.1%) at BMA1 to 30.6% (2.8–69.0%) at BMA2 in the non-CR group (p < 0.001) (DOCX 21 kb)
12185_2017_2395_MOESM2_ESM.docx (37 kb)
Supplemental Figure 2 Plot of receiver operating characteristic curve, depicting the allelic ratio (AR) of fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). We defined the cutoff value as 0.7 (DOCX 37 kb)
12185_2017_2395_MOESM3_ESM.docx (23 kb)
Supplementary material 3 (DOCX 22 kb)

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Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Akira Shimada
    • 1
    • 2
  • Yuka Iijima-Yamashita
    • 2
  • Akio Tawa
    • 3
  • Daisuke Tomizawa
    • 4
  • Miho Yamada
    • 2
  • Shiba Norio
    • 5
  • Tomoyuki Watanabe
    • 6
  • Takashi Taga
    • 7
  • Shotaro Iwamoto
    • 8
  • Kiminori Terui
    • 9
  • Hiroshi Moritake
    • 10
  • Akitoshi Kinoshita
    • 11
  • Hiroyuki Takahashi
    • 12
  • Hideki Nakayama
    • 13
  • Katsuyoshi Koh
    • 14
  • Hiroaki Goto
    • 15
  • Yoshiyuki Kosaka
    • 16
  • Akiko Moriya Saito
    • 2
  • Nobutaka Kiyokawa
    • 17
  • Keizo Horibe
    • 2
  • Yusuke Hara
    • 21
  • Kentaro Oki
    • 17
  • Yasuhide Hayashi
    • 18
  • Shiro Tanaka
    • 19
  • Souichi Adachi
    • 20
  1. 1.Department of Pediatric Hematology/OncologyOkayama University HospitalOkayamaJapan
  2. 2.National Hospital Organization, Clinical Research CenterNagoya Medical CenterNagoyaJapan
  3. 3.Department of Pediatrics, National Hospital OrganizationOsaka Medical CenterOsakaJapan
  4. 4.Division of Leukemia and LymphomaChildren’s Cancer Center, National Center for Child Health and DevelopmentTokyoJapan
  5. 5.Department of PediatricsYokohama City UniversityYokohamaJapan
  6. 6.Department of Nutritional ScienceAichi Gakuin UniversityNisshinJapan
  7. 7.Department of PediatricsShiga Medical UniversityOtsuJapan
  8. 8.Department of PediatricsMie UniversityTsuJapan
  9. 9.Department of PediatricsHirosaki UniversityHirosakiJapan
  10. 10.Department of PediatricsMiyazaki UniversityMiyazakiJapan
  11. 11.Department of Pediatrics, School of MedicineSt. Marianna UniversityKawasakiJapan
  12. 12.Department of PediatricsToho University Omori Medical CenterTokyoJapan
  13. 13.Department of PediatricsKyushu Cancer CenterFukuokaJapan
  14. 14.Department of Hematology/OncologySaitama Children’s Medical CenterSaitamaJapan
  15. 15.Department of Hematology/OncologyKanagawa Children’s Medical CenterYokohamaJapan
  16. 16.Department of Hematology/OncologyKobe Children’s Medical CenterKobeJapan
  17. 17.Department of Pediatric Hematology and Oncology ResearchNational Center for Child Health and DevelopmentTokyoJapan
  18. 18.Department of Hematology/OncologyGunma Children’s Medical CenterShibukawaJapan
  19. 19.Department of Clinical Biostatistics, Graduate School of MedicineKyoto UniversityKyotoJapan
  20. 20.Department of Human Health ScienceKyoto UniversityKyotoJapan
  21. 21.Department of PediatricsGunma UniversityMaebashiJapan

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