Sensitivity of B-CLL to Cell Death Induction by Anticancer Drugs Is Independent of the Immunoglobulin Heavy Chain Variable Genes (IgHv) Mutation Status.

B-type chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease. Unmutated immunoglobulin (Ig) VH genes, i.e. a post-germinal center genotype, are associated with a more aggressive natural course of disease. To explore the impact of Ig variable region hypermutation on response to cytotoxic therapies we analyzed the sensitivities to a panel of cytotoxic modalities by use of the DiSC assay that measures cell death. These data were compared to the Ig VH mutation status in 113 B-CLL patients. 29 patients exhibited IgHV hypermutation (age 66.3±1.8 years, 18 male, 11 female) whereas 84 patients (age 62.2±1.1, 66 male, 18 female) were of pre-germinal center B-cell origin. Hypermutated samples were from Binet stage A in 11 cases (unmutated 12), Binet stage B in 5 cases (14), Binet stage C in 10 cases (44), and in stage A/B in 2 cases (10 cases), Chi-square test p=0.02. 11/29 patients with Ig VH hypermutation and 54 of the 84 of the patients with unmutated B-CLL had received prior chemotherapy. Ig VH hypermutation had no impact in the percentage of surviving cells after 92 hours for ionizing irradiation (IR, 2 Gy by a 137Cs source) (hypermutated, 35.3%±8.2, unmutated 34.2%±4.5). Furthermore, there was no significant difference for the log LC90 values for chlorambucil (Mann-Whitney U test, p=0.22), doxorubicin (p=0.86), fludarabine (p=0.36), and mafosfamide (p=0.49). Interestingly, the log LC90 value for methylprednisolone showed a significant difference and was lower in the unmutated (n=83, mean±SEM 0.8±0.13) as compared to the hypermutated samples(n=29, 1.36±0.2; p=0.038). Conclusions: The mutation status of the IgHV gene segment does not appear to be responsible for differences in the response to various drug treatments in B-CLL. Vice versa, differences in gene expression that were described in hypermutated versus unmutated B-CLL do not seem to impact on drug sensitivity profiles. Thus, both DiSC assay result and VH Gene hypermutation are valuable independent prognostic markers.