Despite a startling separation of chronic lymphocytic leukemia (CLL) into two clinically different diseases with average survivals of 8 years and 25 years, the mutational status of immunoglobulin variable region (IGHV) genes has not entered routine clinical practice to assess prognosis, although its assessment is regarded as an essential for clinical trials. Instead, surrogates that may be measured by flow cytometry have been sought. Measurements of the expression of CD38 and ZAP-70 have been the most popular assays for prognosis although both are in their own ways unsatisfactory. Many other candidates have emerged, but none has been universally endorsed. As the assay for IGHV mutations has been standardized the level of difficulty has diminished and as greater numbers of cases have been assessed it has become clear that there is even more information to be gathered from the study of the sequence of IGHV genes. It has been recognized that stereotypy within CLL is associated with more specific clinical features than mere longevity and an even greater heterogeneity has been revealed. It seems clear that the search for surrogacy is futile and that IGHV mutational status should become a routine investigation in CLL.
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