VH gene mutation status and cellular drug resistance in chronic lymphocytic leukaemia

Objective: B-cell chronic lymphocytic leukaemia (B-CLL) can be divided into two clinical entities based on the immunoglobulin variable heavy chain (V-H) gene mutation status, as cases with unmutated V-H genes display a more aggressive disease with shorter survival time than mutated cases. The aim of this study was to investigate whether differences in cellular drug resistance could give an explanation for these divergent clinical courses. Methods: The V-H gene mutation status was analysed in patients with previously untreated B-CLL using V-H gene family-specific PCR amplification and nucleotide sequencing. In vitro sensitivity to cytarabine, fludarabine, cladribine, doxorubicin, idarubicin, vincristine, cyclophosphamide, melphalan and prednisolone was assessed using the non-clonogenic in vitro assay, fluorometric microculture cytotoxicity assay. Results: The V-H genes and in vitro drug resistance were successfully analysed in 46 cases, revealing that 25 (54%) cases showed unmutated and 21 (46%) cases mutated V-H genes. Interestingly, the unmutated group generally tended to be more chemosensitive than the mutated group with significant differences for cytarabine and prednisolone (P less than or equal to 0.01). Conclusion: The propensity of inferior drug response in mutated B-CLL may reflect a more differentiated disease than in unmutated B-CLL. We conclude that the difference in prognosis between B-CLL cases with unmutated and mutated V-H genes could not be explained by difference in cellular drug resistance.