Like somatic mutations of IGHV, CD38 expression identifies two subgroups of CLL patients with different clinical outcomes; this distinction is based on the percentage of CD38+ leukemic cells within a CLL clone. In the majority of studies, the threshold is considered as ≥ 30% CD38+ clonal members. The 2 patient subgroups that result from this cut-off point differ clinically in several ways, including overall survival, time to first treatment, bias toward male gender, number of leukemic cells with atypical morphology, extent and level of adenopathy, lactate dehydrogenase and β2-microglobulin levels, and absolute lymphocyte counts. These subgroups also differ in responsiveness to various therapies.
Combining CD38 with other prognostic markers, such as ZAP-70 and CD49d, provides complementary prognostic information. Because these molecules are components of the same functional network, their interrelated biologic roles probably explain these observations.
The past decade has highlighted several molecular differences between CD38+ and CD38− members of the same clone, including expression of specific activation markers, which reflect quantitative and temporal differences in response to stimulation. CD38+ CLL cells express high levels of CD69 and HLA-DR, both indicative of recent activation. CD38 also marks a cellular subset enriched in Ki-67+ and ZAP-70+ cells, more efficiently responding to surface IgM cross-linking. Both features are apparently independent of the percentage of CD38-expressing cells within the original clone. In addition, CD38+ CLL clones display enhanced ability to migrate in response to CXCL12, to transduce BCR-mediated signals, and to respond to anti-IgM and anti-IgD antibody-mediated crosslinking. The genetic signature characterizing CD38+ and CD38− members of the same clone revealed higher VEGF and Mcl-1 levels in CD38+ cells, pointing to a survival advantage from microenvironmental interactions.