Date Published: January 15, 2016
Publisher: Public Library of Science
Author(s): Wenlan Chen, Hui Xie, Hongxiang Wang, Li Chen, Yi Sun, Zhichao Chen, Qiubai Li, Ken Mills.
The prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia (CBF-AML), including inv(16) and t(8;21) AML, is uncertain. We performed a systematic review and meta-analysis of the effect of KIT mutations on the complete remission (CR) and relapse rates and overall survival (OS) of CBF-AML. PubMed, Embase, Web of Science, and the Cochrane Library were searched and relevant studies were included. Negative effect was indicated on relapse risk of CBF-AML (RR [relative risk], 1.43; 95%CI [confidence interval], 1.20–1.70) and t(8;21) AML (RR, 1.70; 95% CI, 1.31–2.21), not on OS of CBF-AML (RR, 1.09; 95% CI, 0.97–1.23), CR (OR [odds ratio], 0.95; 95% CI, 0.52–1.74), relapse risk (RR, 1.12; 95% CI, 0.90–1.41) or OS (RR, 1.03; 95% CI, 0.90–1.18) of inv(16) AML. Subgroup analysis of t(8,21) AML showed negative effect of KIT mutations on CR (OR, 2.03; 95%CI: 1.02–4.05), relapse risk (RR, 1.89; 95%CI: 1.51–2.37) and OS (RR, 2.26; 95%CI: 1.35–3,78) of non-Caucasians, not on CR (OR, 0.61; 95%CI: 0.19–1.95) or OS (RR, 1.12; 95%CI: 0.90–1.40) of Caucasians. This study indicates KIT mutations in CBF-AML to be included in the initial routine diagnostic workup and stratification system of t(8,21) AML. Prospective large-scale clinical trials are warranted to evaluate these findings.
Acute myeloid leukemia (AML) with recurrent t(8;21)(q22;q22) [abbreviated as t(8;21)] and inv(16)(p13q22)/t(16;16)(p13;q22) [abbreviated as inv(16)] genetic abnormalities are termed as core-binding factor (CBF)-AML. To date, patients with CBF-AML are generally recognized as a favorable cytogenetic AML sub-group . However, approximately 50% of patients with CBF-AML remain incurable, and markers are required to refine the risk stratification of patients at diagnosis and to optimize their treatment . KIT mutations, as potential molecular markers, are found in 12–46% of t(8;21) patients and 9–53% of inv(16) patients [3–8]. Observational studies have assessed the impact of KIT mutations on the prognosis of t(8;21) and inv(16) AML [3, 5–8]; however, data concerning the prognostic significance of KIT mutations have been conflicting thus far. Some studies have shown that the KIT mutation is significantly associated with decreased remission duration and overall survival (OS) in CBF-AML patients [4, 5, 8–12], whereas other studies have shown that KIT mutations have no obvious effect on CBF-AML clinical outcomes as a group or in subgroups [7, 13–17]. Although the current data do not support the use of KIT mutational status in clinical guidance (in terms of therapeutic interventions), the data have been included in the National Comprehensive Cancer Network Guidelines as a prognostic marker, where the KIT mutation can transform CBF-AML patients from favorable-risk AML to intermediate-risk AML . In contrast, the International European Leukemia Net currently does not recommend testing KIT mutational status as part of an initial routine diagnostic workup [19, 20]. This inconsistency is based on the current prognostic data of KIT mutations in CBF-AML patients. Thus, we performed a systematic review and meta-analysis of published studies to investigate the prognostic significance of KIT mutations in CBF-AML patients.
This study reports the first meta-analysis (to our knowledge) evaluating the impact of KIT mutations on the prognosis of CBF-AML, summarizing the results of 11 studies involving 1 380 CBF-AML patients. Based on the current controversy regarding the prognostic significance of KIT mutations in CBF-AML, we primarily focused on CBF-AML as one group and sought to determine whether the clinical outcomes are associated with KIT mutations. We found that the KIT mutations had no effect on CR, as previously reported [8, 17, 39, 43], but they resulted in a significantly increased relapse risk. However, it has been reported that KIT mutations play different clinical roles in the inv(16) and t(8,21) AML subtypes [5, 6, 8, 9, 17, 39], and these two CBF-AML subtypes should be considered as distinct entities. Therefore, we performed a subgroup meta-analysis of the clinical outcomes of these subtypes. The KIT mutations did not affect the CR of inv(16) or t(8,21) AML, and the KIT mutation-related relapse risk of t(8,21) AML was significantly increased, but it was not increased in inv(16) AML, indicating that the increased relapse risk of CBF-AML may be due to the risk of t(8,21) AML but not inv(16) AML. Furthermore, in inv(16) AML, the OS was not significantly affected by the KIT mutations; however, the OS tended to be shorter in t(8,21) AML patients with KIT mutations. To date, inv(16) and t(8,21) AML have been considered to have relatively favorable prognoses and to have been treated similarly. However, with the distinct effects of KIT mutations in our subgroup analyses, CBF-AML with KIT mutations should be regarded as distinct and heterogeneous entities with different outcomes.