VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

In chronic lymphocytic leukemia (CLL), biologic risk factors such as Immunoglobulin variable heavy chain gene (V-H) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V-H mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q-, +8q, 11q-, +12q, 13q-, t(14q), 17p-) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V-H mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (P-cor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was Identified at 97% V-H homology (95% confidence interval [CI], 96%-98% homology, P-cor less than or equal to .001) and at 7% CD38 expression (95% Cl, 20%-71% expression, P-cor = .02). In univariate analyses, unmutated V-H genes and high CD38 expression levels predicted for shorter survival times. The overall Incidence of genomic aberrations was similar in the V-H unmutated and V-H mutated subgroups. High-risk genomic aberrations such as 17p- and 11q- occurred almost exclusively in the V-H unmutated subgroup, whereas favorable aberrations such as 13q- and 13q- as single abnormalities were overrepresented In the V-H mutated subgroup. In multivariate analysis, unmutated V-H, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of V-H mutation status and genomic aberrations to predict outcome in CLL. (C) 2002 by The American Society of Hematology.