Vascular endothelial growth factor expression in acute myeloid leukemia: a biomarker ready for primetime?

Although dose-intensive chemotherapy and stem cell transplant offer the possibility of cure to adults with acute myeloid leukemia (AML), outcomes remain unsatisfactory for the majority of adults with this malignancy [1]. Indeed, more than 60% of adults with AML die from relapsed disease, such that the primary challenge in this disease remains our ability to identify, prevent and/or treat relapsed disease. As a result, many groups have performed detailed analyses to identify biomarkers which predict relapse in AML, so that patients with high risk disease can be identified early in their disease course and offered more aggressive therapy including allogeneic transplant. This includes recent reports demonstrating that mutational studies can inform risk stratification in AML, and can be used to improve our ability to identify subsets of patients with AML who are unlikely to be cured with standard anti-leukemic therapies [2]. Although these efforts have led to the use of cytogenetic and mutational studies to gain information on risk stratification in AML, our ability to accurately predict prognosis in this disease remains limited at best. One question that remains to be addressed is whether we can identify additional biomarkers that add to our existing risk classification. For example, microRNA profiling [3] has been shown to further expand prognostication in AML; however, to date this has not been adopted in clinical practice.

In this issue of the journal, Guo and colleagues [4] attempted to determine whether a new biomarker, vascular endothelial growth factor (VEGF) expression, can be used to improve prognostication and risk stratification in AML. Previous studies have shown that the expression of VEGF in leukemic blasts in AML and in acute lymphoblastic leukemia (ALL) is associated with adverse outcome [5]. However, the latter study was carried out in a relatively small cohort from a single institution, and as such, Guo and colleagues sought to perform a larger study of the prognostic relevance of VEGF expression [4]. They therefore performed a detailed meta-analysis of all studies which reported VEGF expression, using different modalities, and survival in order to determine the prognostic relevance of VEGF expression in AML. They identified 11 studies with sufficient data, including 1112 patients, which allowed them to assess the prognostic relevance of VEGF expression in a large cohort of patients. Importantly, their analysis showed that high VEGF expression was associated with shorter event-free and overall survival in meta-analysis, suggesting that VEGF expression represents a novel, independent prognostic risk factor in AML. This study provides evidence that VEGF expression may represent a novel biomarker which can be used to inform prognosis in AML. However, these data must be taken with several caveats. First, the different studies in this meta-analysis measured VEGF expression using different mRNA and protein assays; this makes combining the results of these individual studies more challenging, and raises the question of whether future studies should assess VEGF mRNA or protein expression and which assay is most robust. Second, this study did not assess whether VEGF expression can be used to improve current, molecularly based risk classification systems, as was shown previously for CD25 [6], which indeed does provide additive value to integrated cytogenetic/molecular profiling. Finally, and most important, this finding must be validated in independent prospective trials before VEGF expression is adopted as a clinical test for prognostication in AML. Taken together, this study paves the way to determine whether expression of angiogenic factors might provide more information on prognosis in AML.

The other, important aspect of these data relates to the biologic relevance of VEGF expression to AML pathogenesis. Preclinical studies have demonstrated the relevance of angiogenesis to the pathogenesis of epithelial malignancies, which was then validated by the demonstration that VEGF-targeted therapies improve outcomes in solid tumors, particularly in renal cell carcinoma. However, the role of aberrant angiogenesis in AML pathogenesis remains less clear. Indeed, given recent studies suggesting the importance of the vascular niche to normal and malignant hematopoiesis, one hypothesis is that VEGF expression on AML blasts stimulates vessel formation, which then creates a “feed forward” loop and stimulates leukemic proliferation in vivo. These biologic possibilities require further study, and it remains to be seen whether this process can be therapeutically targeted in vivo. These data also suggest the possibility that patients with high risk disease, marked by high VEGF expression, might represent a subset of patients in whom we can intervene with specific, targeted therapies, as is being studied for patients with FLT3 or c-Kit mutant AML in trials combining tyrosine kinase inhibition with chemotherapy in patients with these specific mutant disease alleles. Specifically, there are now agents which can target VEGF through small molecule and immunologic approaches, and it would be of importance to determine whether these agents might offer efficacy in preclinical and clinical studies in VEGF-overexpressing AML. We look forward to future studies of VEGF expression and outcome in AML, and to clinical trials of anti-angiogenic therapies in subsets of patients with high VEGF expression and poor-risk AML.

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