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Molecular indicators of prognosis in mantle cell lymphoma in the era of R-hyper-CVAD: Still an open issue

Mantle cell lymphoma (MCL) is a well recognized lymphoproliferative disorder characterized by the overexpression of the Cyclin D1 gene, which results from the t(11;14)(q13;q32) translocation [1]. The disease is characterized by generalized lymphadenopathy, with frequent involvement of the spleen, bone marrow, and gastrointestinal tract. Although patients show a high response rate to first line therapy, their disease-free survival is short and prognosis is poor. Neither high dose therapy [2] nor the addition of rituximab to standard CHOP regimen [3] seems to improve the outcome. Conversely, R-hyper-CVAD was indicated by Romaguera et al. [4] as the new standard of treatment in MCL, considering the optimal response rate, both in terms of magnitude (97%) and quality (CR and uCR 87%) and, more importantly, in light of the 3-year failure-free and overall survival rates of 64% and 82%, respectively. Recently, gene expression profiling analysis using DNA microarrays demonstrated the unique genomic signature of MCL [5]. Roughly 150 genes, involved in cell proliferation, gene transcription and drug resistance, are differently regulated in MCL as compared with other non-germinal center B-cell lymphomas, such as small lymphocytic lymphoma and marginal zone lymphoma. Interestingly, genes encoding for membrane transporters and implicated in drug resistance, i.e. glutatione-S-transferase p (GSTp) and MDR/ATP-binding cassette (ABC) membrane proteins (ABCG2 and ABCC5), were found to be over-expressed. Galimberti and co-workers tested the expression of topoisomerase iia, glutathione-s-transferasep (GSTp) and ABCG2 (BCRP) and of MRD1 by real-time quantitative PCR in a relatively small cohort of MCL treated according to R-hyper-CVAD regimen [6]. The Galimberti study aimed to ascertain whether the expression of the above mentioned genes, all involved in the resistance of drugs commonly employed in MCL therapy, predict the type of response to therapy and/or the clinical outcome. Although all MCL cases expressed ABCG2 and MRD1 and 17/20 (85%) GSTp and Topoisomerase IIa, only ABCG2 resulted over-expressed in MCL patients when their mRNA levels were weighed against those of both healthy donors and of CD5þ/ CD20þ tonsillar lymphocytes. Notably, the levels of expression of the 4 genes failed to cluster cases with different response to treatment and clinical outcome. These findings could be strictly associated with the expected high response rate (87.5%, in Galimberti series) of the R-Hyper-CVAD which possibly offset gene-induced chemo-resistance, though it may be due to the relatively small number of cases in this study. This latter hypothesis is also supported by the fact that a trend for a longer progression-free survival was appreciated in those cases with low ABCG2 levels. These remain tentative results and need further investigation in a larger series of cases. Moreover, if the ABCG2 over-expression could influence drug resistance, on the other hand it might reflect an increased level of angiogenesis, which seems to have an important role in the pathogenesis of MCL. In fact, as reported by Maliepaard et al., ABCG2 is highly expressed in the endothelium [7], raising the question on a possible link between its expression and levels of angiogenesis in MCL. Should these hypotheses be confirmed, ABCG2 determination would allow an early identification of patients with poor prognosis who could benefit from the use of thalidomide, an anti-angiogenetic drug active against MCL cells of relapsed patients [8].