The Restricted V_H-Gene Usage Is of Prognostic Value in B-Cell Chronic Lymphocytic Leukemia.

In B-cell chronic lymphocytic leukemia (B-CLL) the mutation status of the immunoglobulin variable heavy chain gene (V_H) is known as a prognostic factor. We have investigated if specific V_H-gene usage is of additional prognostic importance regarding survival. Peripheral blood samples from 147 B-CLL patients were analysed for V_H usage. Recombinations occurring in at least 5% of cases were studied in depth. The most frequently used V_H-gene segments were V_H1-69 (10.9%), V_H3-7 (7.5%), V_H3-30 (6.8%), V_H4-34 (6.8%), V_H3-21 (6.1%), V_H3-23 (6.1%), and V_H3-33 (5.4%). The V_H gene usage was compared with mutation status, cytogenetic abnormalities and survival. Comparison with age matched controls reveals the restricted V_H gene usage in B-CLL. V_H gene usage showed a distinct prognostic value (p=0.01) when the patients using V_H genes with bad prognosis were grouped together (V_H1-69, V_H3-21, V_H3-23 and V_H3-33; 43% of these patients died) and were compared with the patients using V_H genes with a relatively good prognosis (V_H3-7, V_H3-30 and V_H4-34; mortality rate of only 13%). The prognostic significance holds true when all patients were included (p=0.03). Also the mutation status (p=0.04) and cytogenetics (p=0.03) showed a prognostic significance. The V_H gene usage did not correlate with mutation status, nor with cytogenetics. On the contrary mutation status and cytogenetics were strongly correlated (p<0.00001). These findings are highly suggestive for V_H gene usage to offer additional prognostic information to the other well established prognostic parameters. In conclusion, a bias to the specific V_H gene segments involved in B-CLL supports the concept that B-CLL arises from B cells driven by specific antigens/superantigens which is different from a stochastic event in the elderly B-cell population. Moreover, the immunoglobulin specificity reveals specific subgroups with differing prognosis.