The division of B-CLL into stable and progressive disease was noted in the 1960's, and today, it is generally agreed that there are two subsets of CLL based on IgVH gene mutational status. Patients with unmutated immunoglobulin V genes (approximately 40%) form one subset while patients with mutated immunoglobulin V genes form the other subset. There is no evidence that the subsets change from one into the other. The unmutated subset is three times as common in men while the mutated subset is equally common in men and women.
These two subsets of CLL have separate and distinct natural histories. Early stage patients with unmutated immunoglobulin V genes have a median life expectancy of 8 years, while those with mutated immunoglobulin V genes have a median survival of twenty-five years. It is not correct to assume that all CLL patients with mutated immunoglobulin V genes are smoldering, since some cases do progress to advanced stage disease. However, it is very likely that all cases of smoldering CLL are confined to patients with mutated immunoglobulin V genes.
The best specimens for testing IgVH gene mutational status are the peripheral blood and the bone marrow. To be absolutely certain, both should be evaluated since there are patients who express this mutation in the marrow, but not in the peripheral blood. The best test for IgVH mutational status involves sequencing of IgVH genes. Another option is single-cell reverse transcription-polymerase chain reaction (RT-PCR). Both of these procedures are expensive and are not readily available. For this reason, researchers look for surrogate markers that are strong predictors of IgVH mutational status.
Some researchers believe CD38 is an accurate surrogate for IgVH mutational status--patients with less than 20 percent CD38+ B-CLL cells are likely to have mutated immunoglobulin V genes while patients with greater than 20 percent CD38+ B-CLL cells are likely to have unmutated immunoglobulin genes. This is a matter of ongoing debate as it appears that there is approximately a 30% discordance between the assays. Moreover, in 25% of cases the expression of CD38 changes during the course of the disease. Serum thymidine kinase level is thought to be another surrogate marker where >15 U/l has proved to be a strong predictor of mutational status.