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Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial

Leukemia volume 29, pages 2438–2441 (2015)Cite this article

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Core binding factor acute myeloid leukemia (CBF-AML), characterized by the chromosomal abnormalities of t(8;21) (AML1-ETO) or inv(16)/t(16;16) (CBFB-MYH11), is the most frequent subtype in pediatric AML. Although CBF-AML is generally classified as a low-risk group, in a recent analysis of 154 patients with CBF-AML participating in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 trial (2006–2010), 29.9% of the patients relapsed within 3 years.1 This finding suggests that a population of the CBF-AML patients had other risk factors that could account for their poor outcome. The KIT gene, located on chromosome 4, encodes a type III receptor tyrosine kinase activated by stem cell factor (SCF), and leads to cell survival, migration and proliferation.2 In adults with CBF-AML, gain-of-function mutations of KIT are risk factors.3, 4, 5, 6, 7 These mutations cluster in exon 8 (encoding the extracellular domain of KIT), exon 17 (encoding the activation loop of the tyrosine kinase domain) and occasionally in exon 10 or 11 (encoding the transmembrane domain and the juxtamembrane domain, respectively). Among these mutations, KIT exon 17 D816 mutations have been shown to confer a poor prognosis to adult patients with t(8;21).3, 4, 7 In pediatric CBF-AML, some studies8, 9, 10 found no clinical impact of KIT mutations, whereas Shimada et al.11 and Manara et al.12 studying the prognostic impact of KIT mutations in pediatric t(8;21) AML both concluded that KIT mutations may be poor prognostic factors (Supplementary Table S1). These retrospective studies, however, could be influenced by selection bias of the cytogenetic subtype. Therefore, a further validation study that includes all of the targeted cytogenetic subtypes (t(8;21) and inv(16)/t(16;16)) and KIT mutations in a larger cohort is necessary to elucidate any involvement of KIT mutations in the prognosis of pediatric CBF-AML.

In this study, we analyzed KIT mutations in 138 pediatric CBF-AML patients participating in the JPLSG AML-05 trial whose complementary DNA (cDNA) from their diagnostic bone marrow samples were available; 107 patients carried a t(8;21) rearrangement and 31 an inv(16). KIT mutations in exons 8, 10, 11 and 17 were screened using direct sequencing of cDNA.11 Event-free survival (EFS) was measured from the time of diagnosis to the last follow-up or the first event (failure to achieve remission, relapse, secondary malignancy or death), and overall survival (OS) was measured from the time of diagnosis to death. The 3-year probability of EFS (pEFS) and the 3-year probability of OS (pOS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Differences between cumulative incidence of relapse (CIR) curves were compared using Gray’s test. Statistical analyses were performed with STATA software (version 13.0; StataCorp LP, College Station, TX, USA) and R software (version 3.0.2, The R Foundation for Statistical Computing, Vienna, Austria).

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Acknowledgements

This work was supported by a grant for a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (H26-061).

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Authors and Affiliations

  1. Department of Pediatrics, Kyoto University, Kyoto, Japan

    M Tokumasu & T Heike

  2. Department of Hematology/Oncology, Gunma Children’s Medical Center, Shibukawa, Japan

    C Murata, K Ohki & Y Hayashi

  3. Department of Pediatrics, Okayama University, Okayama, Japan

    A Shimada

  4. Clinical Research Center, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan

    A M Saito & K Horibe

  5. Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan

    J Fujimoto

  6. Human Health Sciences, Kyoto University, Kyoto, Japan

    M Nagao, H Itoh, Y Kamikubo & S Adachi

  7. Department of Pediatrics, Fukuoka-Higashi Medical Center, National Hospital Organization, Koga, Japan

    H Nakayama

  8. Department of Pediatrics, St Marianna University School of Medicine, Kawasaki, Japan

    A Kinoshita

  9. Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    D Tomizawa

  10. Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan

    T Taga

  11. Department of Pediatrics, National Hospital Organization, Osaka Medical Center, Osaka, Japan

    A Tawa

  12. Department of Pharmacoepidemiology, Kyoto University, Kyoto, Japan

    S Tanaka

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  1. M Tokumasu
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  2. C Murata
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  15. T Taga
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  16. A Tawa
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  17. S Tanaka
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  18. T Heike
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  19. S Adachi
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Correspondence to S Adachi.

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Tokumasu, M., Murata, C., Shimada, A. et al. Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia 29, 2438–2441 (2015). https://doi.org/10.1038/leu.2015.121

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