The Prognostic Significance of Combined Expression of ZAP-70 and CD38 in Chronic Lymphocytic Leukemia.

BACKGROUND: Following gene expression profiling which compared the two well established prognostic markers in CLL, ZAP-70 and CD38 with unmutated and mutated IgVH, ZAP-70 has emerged as the most promising surrogate marker for the IgVH mutation status. CD38 expression has also been suggested as a surrogate marker for the IgVH mutation status.

AIM: We aimed to investigate the impact of ZAP-70 and CD38 expressions as well as their combined expressions on the treatment outcome and survival of our CLL patients.

PATIENTS AND METHODS: This study included 50 CLL patients as well as10 normal volunteers as a control group. All patients were subjected to complete work up and immunophenotyping to confirm the diagnosis. ZAP-70 and CD38 expressions were studied in (CD19+, CD5+) B cells. Results were expressed as percent expression and mean flourecent index (MFI). Results were correlated to the treatment outcome and survival as well as to other prognostic markers of CLL including TLC, Hb level, platelets count, modified Rai staging at diagnosis, P53 and BCL 2.

RESULTS: A significant association was found between ZAP-70 percent expression and the diffuse pattern of bone marrow infiltration (p<0.002) as well as the P53 percent expression (p=0.005). A Significant increase in serum levels of LDH and B2M in ZAP-70 positive as compared to negative groups was detected (p=0.049 and 0.007 respectively). A higher number of non-responding patients was reported in the ZAP70 positive as compared to ZAP70 negative group (p<0.001). ZAP-70 percent expression was significantly associated with shorter time to disease progression (TDP) and shorter overall survival (p=0.025 and 0.029 respectively). A significant increase in serum levels of B2M in CD38 percent positive as compared to negative group was encountered (p=0.045). CD38-MFI showed a significant associations to advanced modified Rai staging at diagnosis (p=0.019) and to higher serum levels of both LDH and B2M (p=0.03 and 0.05 respectively). CD38, either expressed as a percentage or as MFI, showed a significant association with the non-responders (p=0.034 and 0.006 respectively). There was a significant inverse relation between CD38 expression and time to disease progression (p=0.033) while no significant relation was encountered with overall survival (p=0.197). Combined expression of both markers, ZAP-70+ /CD38+ was reported in 5 patients (10%) while ZAP-70- /CD38- expression was encountered in 24 patients (48%). Patients with either ZAP-70+ or CD38+ represented 42% of the cases (21 patients).There were significant differences between the three groups and the initial response to chemotherapy (p=<0.001) and the pattern of bone morrow infiltration (p=0.015), while no significant relation was found with age, sex, modified Rai staging at diagnosis or BCL2 percent expression. Patients with combined expression of ZAP-70 and CD38 had significantly shorter TDP and overall survival (p<0.001 and 0.03 respectively).

CONCLUSION: ZAP-70 is one of the most important prognostic markers in CLL, it appears to be more predictive of disease progression and poor outcome than CD38 expression. Semi quantification of the CD38 antigen by flowcytometry greatly improves the prognostic value of its expression. The combination of ZAP-70 and CD38 increases the prognostic power of either alone.

KEY WORDS: CLL - Prognostic factors - ZAP 70 and CD38.