Damle et al. (5) suggested that expression of surface CD38 on CLL cells gave the same information as IgV gene mutations and might be a surrogate assay. However, in an analysis of 145 of our patients, although there was a highly significant association between CD38 expression and unmutated IgVH genes, for individual patients there were important discordances (77). Fifteen patients with unmutated IgVH genes had less than 30% of cells expressing CD38, and 26 patients with mutated IgVH genes had more than 30% of cells expressing CD38. The number of patients with discordant results for the two assays was 41/145 (28.3%). Discordant markers occurred as frequently in patients with stable disease as in those with progressive disease.

In a multivariate analysis of IgVH status, CD38 positivity, Binet stage, typical or atypical morphology, progressive or stable disease (progressive disease included a lymphocyte doubling time of less than 12 mo as one of the criteria), and the two commonest karyotypic abnormalities, trisomy 12 and abnormalities at 13q14, only stage, IgVH status, and CD38 positivity were independent prognostic factors (77).

Perhaps of more importance, CD38 expression did not remain constant throughout the course of the disease. Several patterns of CD38 positivity may be seen. Although in some cases all the cells are CD38-positive or CD38-negative, in many cases a mixture of CD38-positive and -negative cells is seen. The composition of this mixture changed in 24.4% of cases examined. In most cases, changes in CD38 expression were associated with treatment of the CLL, with a suggestion that chemotherapy selectively kills CD38-negative cells. In one patient the recovering cells after several rounds of chemotherapy were strongly CD38-positive, and the morphology of the cells had become atypical. In one case, stopping all therapy was associated with a recovery of CD38-negative cells. However, we also saw increases in the proportion of CD38-positive cells in patients with progressive disease without treatment (77).

In two of our patients, changes in the proportion of cells expressing CD38 were not associated with progression. One had stable disease but developed recurrent chest infections; the other developed concurrent chronic myelomonocytic leukemia. As the monocyte count rose, the expression of CD38 by the lymphocytes fell.

CD38 is a type II trans-membrane glycoprotein that acts as a complex ectoenzyme with ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities (78). In the B-cell compartment, CD38 is not a lineage marker, but it is expressed at times during B-cell development when cell-to-cell interactions are crucial to development (79). Examples include an early bone marrow precursor cell, cells in the germinal center, and plasma cells (80). All the factors that signal its upregulation are as yet unknown, but they include both a- and y-interferon (81). From the foregoing, it might be expected that expression of CD38 on b-cell CLL cells could vary, not only with disease progression, but also with the presence of intercurrent illness.

Because of the variability of CD38, it is risky to use it as a prognostic factor in early stage A disease. Nevertheless, patients who have both CD38-positive cells and unmutated IgVH genes have a worse prognosis than those who are discordant for these markers (77). The independence of CD38 as an independent prognostic factor was lost when the series was extended to 215 patients, and loss or mutation of the p53 gene was included in the prognostic factors examined (82).

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