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 ShimadaEmail author
  • 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


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.


AML FLT3-ITD Childhood Alleric ratio NUP98-NSD1 



fms-related tyrosine kinase 3


Internal tandem duplication


Hematopoietic stem cell transplantation


Complete remission


Overall survival


Disease-free survival


Event-free survival


Allelic ratio



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 ( 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)


  1. 1.
    Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94.CrossRefPubMedGoogle Scholar
  2. 2.
    Zwaan CM, Meshinchi S, Radich JP, Veerman AJ, Huismans DR, Munske L, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood. 2003;102:2387–94.CrossRefPubMedGoogle Scholar
  3. 3.
    Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J, et al. Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011;118:5905–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Shimada A, Taki T, Tabuchi K, Taketani T, Hanada R, Tawa A, et al. Tandem duplications of MLL and FLT3 are correlated with poor prognoses in pediatric acute myeloid leukemia: a study of the Japanese childhood AML Cooperative Study Group. Pediatr Blood Cancer. 2008;50:264–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, Reinhardt D, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–61.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Pratcorona M, Brunet S, Nomdedéu J, Ribera JM, Tormo M, Duarte R, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013;121:2734–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Linch DC, Hills RK, Burnett AK, Khwaja A, Gale RE. Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124:273–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Koszarska M, Meggyesi N, Bors A, Batai A, Csacsovszki O, Lehoczky E, et al. Medium-sized FLT3 internal tandem duplications confer worse prognosis than short and long duplications in a non-elderly acute myeloid leukemia cohort. Leuk Lymphoma. 2014;55:1510–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD positive AML with respect to allogeneic hematopoietic stem cell transplantation. Blood. 2014;124:3441–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Shiba N, Ichikawa H, Taki T, Park MJ, Jo A, Mitani S, et al. NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia. Genes Chromosom Cancer. 2013;52:683–93.PubMedGoogle Scholar
  12. 12.
    Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Pratcorona M, Abbas S, Kuipers JE, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118:3645–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Ostronoff F, Othus M, Gerbing RB, Loken MR, Raimondi SC, Hirsch BA, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124:2400–7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sano H, Shimada A, Tabuchi K, Taki T, Murata C, Park MJ, et al. WT1 mutation in pediatric patients with acute myeloid leukemia: a report from the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2013;98:437–45.CrossRefPubMedGoogle Scholar
  15. 15.
    Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Tomizawa D, Tawa A, Watanabe T, Saito AM, Kudo K, Taga T, et al. Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. Int J Hematol. 2013;98:578–88.CrossRefPubMedGoogle Scholar
  17. 17.
    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.Google Scholar
  18. 18.
    Larrosa-Garcia M, Baer MR. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Mol Cancer Ther. 2017;16:991–1001.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rautenberg C, Nachtkamp K, Dienst A, Schmidt PV, Heyn C, Kondakci M, Germing U, Haas R, Kobbe G, Schroeder T. Sorafenib and azacitidine as salvage therapy for relapse of FLT3-ITD mutated AML after allo-SCT. Eur J Haematol. 2017;98:348–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175:496–504.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Iwasaki Y, Nishiuchi R, Aoe M, Takahashi T, Watanabe H, Tokorotani C, et al. Positive minimal residual disease of FLT3-ITD before hematopoietic stem cell transplantation resulted in a poor prognosis of an acute myeloid leukemia. Acta Med Okayama. 2017;71:79–83.PubMedGoogle Scholar
  22. 22.
    Shimada A, Taki T, Koga D, Tabuchi K, Tawa A, Hanada R, et al. High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;96:469–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Sano H, Shimada A, Taki T, Murata C, Park MJ, Sotomatsu M, Tabuchi K, Tawa A, Kobayashi R, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y. RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;95:509–15.CrossRefPubMedGoogle Scholar
  24. 24.
    Hirade T, Abe M, Onishi C, Taketani T, Yamaguchi S, Fukuda S. Internal tandem duplication of FLT3 deregulates proliferation and differentiation and confers resistance to the FLT3 inhibitor AC220 by Up-regulating RUNX1 expression in hematopoietic cells. Int J Hematol. 2016;103:95–106.CrossRefPubMedGoogle Scholar
  25. 25.
    Tian X, Xu Y, Yin J, Tian H, Chen S, Wu D, Sun A. TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1 + and FLT3-ITD− mutations. Int J Hematol. 2014;100:96–104.CrossRefPubMedGoogle Scholar
  26. 26.
    Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97:683–94.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Akira Shimada
    • 1
    • 2
    Email author
  • 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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