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.
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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
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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.
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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.
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This research was (partially) supported by the Practical Research for Innovative Cancer Control grant from the Japan Agency for Medical Research and Development, AMED.
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12185_2017_2395_MOESM1_ESM.docx
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
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)
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Shimada, A., Iijima-Yamashita, Y., Tawa, A. et al. Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study. Int J Hematol 107, 586–595 (2018). https://doi.org/10.1007/s12185-017-2395-x
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DOI: https://doi.org/10.1007/s12185-017-2395-x