KIT Mutations Confer Worse Prognosis in Core Binding Factor Leukemias
KIT Mutations Confer Worse Prognosis in Core Binding Factor Leukemias
Abstract & Commentary
By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Core binding factor (CBF) AML (eg, inversion 16 and translocation 8;21) has generally been considered favorable risk although the 50% long-term survival demonstrates the need for better delineating high-risk subsets. In this study, pre-treatment samples from 110 CBF AML patients enrolled in CALGB trials were analyzed for mutations at exon 8 and 17 of the KIT gene. The authors found an increased relapse risk associated with mutated KIT, primarily related to exon 17 mutations. Survival was worse for the subset with inv(16) but not t(8;21). Although the data require validation, mutated KIT holds promise to identify a high-risk subset of CBF AML.
Source: Paschka P, et al. Adverse prognostic significance of KIT mutations in Adult Acute Myeloid Leukemia with inv(16) and t(8;21): A Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24:3904-3911.
The prognostic heterogeneity for acute myeloid leukemia (AML) has lead to various strategies to assign risk. Among those, pre-treatment chromosomal abnormalities detected by cytogenetic analysis have gained widespread acceptance, especially to direct post-remission therapy.1 Genetic abnormalities leading to aberrant subunits of core-binding factor (CBF), such as inv(16)(p13;q22), t(16;16)(p13;q22), and t(8;21)(q22;22)2 are relatively frequent and confer a relatively favorable outcome. Nevertheless, the 5-year survival of 50% among CBF AML indicates a substantial number of patients still succumb to the disease,3 demonstrating a need to further delineate adverse prognostic subsets among CBF AML. Recent data suggest a mutated KIT gene (mutKIT) as a candidate in identifying a high-risk subset.4 Common sites for mutKIT in CBF AML include exon 17 and exon 8.
Paschka and colleagues analyzed 110 patients with AML harboring the core binding factor mutations of inv16 and t(8;21) who were enrolled in several CALGB treatment protocols. In general, patients received fairly uniform induction (cytarabine, +/- etoposide) and consolidation (high-dose cytarabine). KIT mutations in exon 17 and 8 were identified by HPLC and confirmed by direct sequencing.
KIT gene mutations were identified in 29 of 110 patients. Specifically, 18/61 (29.5%) with inv16 and 11/49 (22%) with t(8;21) harbored mutKIT. MutKIT was associated with older age, male sex, and peripheral blood blasts in inv(16) but not in t(8;21). The median age was 38 years for wild-type KIT and 49 years for mutKIT (P = 0.001). Although the CR rates were not lower for mutKIT, the cumulative incidence of relapse was significantly worse for mutKIT in inv16 (P = 0.05) and t(8;21) (P = 0.017). MutKIT predicted for inferior survival among inv16 (P = 0.009) but not t(8;21). The increase in relapse for inv 16 arose primarily from mutKIT in exon 17 as opposed to exon 8.
Commentary
This study of a relatively large number of AML patients harboring the core binding factor mutations of inv(16) and t(8;21) shows an association with increased relapse and possibly inferior survival for those with concurrent mutations in KIT. Although both exon 17 and exon 8 were analyzed, the data suggest most of the adverse impact is related to exon 17 mutations. The relapse rate was six times higher for mutKIT at exon 17 compared to non-mutated KIT for inv(16). The relapse rates were also higher among the t(8;21) patients with mutKIT, of whom 9/11 had exon 17 mutations. The data are consistent with another recent study suggested the adverse impact of mutKIT may primarily relate to exon 17 mutations.4
One strategy should the results be validated would be to consider more aggressive post-remission therapy, such as hematopoietic transplant. This may be particularly appealing to the extent the initial complete remission rates were not affected by mutational status. Targeted therapy may be an even more appealing approach. KIT mutations result in a tyrosine kinase gain of function and thus represent obvious targets for tyrosine kinase inhibitors. Dampening some enthusiasm, the authors note that activity of TK inhibitors vary depending on the precise mutation which may be a major challenge for designing clinical trials.
An important limitation in this study is the limited adjustment for age. Most of the multivariable analysis only adjusted for peripheral blood blasts and sex. Older age is strongly associated with adverse prognosis in AML, even among good-risk cytogenetic subgroups. The median age was one decade greater in the mutKIT patients. It may be that the adverse impact of age is due to mutated KIT or, alternatively, older age confounds the association and that mutKIT may not necessarily have any independent adverse impact once considering older age. While the authors propose screening for mutated KIT among CBF AML, the prognostic relevance still requires validation in larger studies employing adequate multivariate adjustment. These limitations notwithstanding, KIT mutation analysis holds promise to add to the growing arsenal of genetic mutations enabling more accurate disease characterization of AML and possibly targeting therapies.
References
1. Slovak ML, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075-4083.
2. de Bruijn MF, Speck NA. Core-binding factors in hematopoiesis and immune function. Oncogene. 2004;23:4238-4248.
3. Marcucci G, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705-5717.
4. Cairoli R, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107:3463-3468.
Core binding factor (CBF) AML (eg, inversion 16 and translocation 8;21) has generally been considered favorable risk although the 50% long-term survival demonstrates the need for better delineating high-risk subsets.Subscribe Now for Access
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