ZAP-70 Expression in Chronic Lymphocytic Leukemia (CLL) Is Independent of Rai Stage: A Retrospective Review of 38 Patients (pts).

ZAP-70 is a tyrosine kinase protein involved in T cell signaling, overexpression of which is associated with a poor prognosis in CLL. Clinical information on 32 pts with CLL, and 6 pts with prolymphocytic transformation (PLT) followed at our institution was retrospectively reviewed for Rai stage, ZAP-70, CD38, FISH and response to treatment to determine the prognostic association among these factors. Ages ranged from 37 to 78 (median 59). 5/32 pts with CLL had received prior initial therapy, while 17/19 pts had not. They eventually were all treated with fludarabine based regimens either as salvage or upfront. The remaining 8/32 had not required therapy. Response to therapy was correlated with ZAP-70 expression as measured by immunohistochemistry using a monoclonal antibody to ZAP-70 (clone 2F3.2).17/32 patients (53%) were ZAP-70 positive, as were 3/6 (50%) of the patients with PLT. Of the patients with CLL who were ZAP-70 positive, 5 (30%) were stage 0-II, and 12 (70%) were stage III/IV, while18% did not require therapy. Of the 13 who were treated there were 4 (31%) CR, and 5 (38%) PR. Of the patients who were ZAP-70 negative, 50% (7/14) had stages 0-II and 50% had stage III/IV disease. 5/14(36%) were not treated. Of the 9 who were treated there were 2 CR 22%, and 7 PR 78% (p=0.01). 3 PLT patients were previously treated for CLL with fludarabine-based combinations. When they required therapy for PLT, two achieved a CR (one to rituximab/fludarabine/cytoxan_ZAP-70 positive patient, and one to R-CHOP combination_ZAP-70 negative), and another a PR (to R-EPOCH combination_ZAP-70 negative patient). Of the previously untreated PLT patients, two ZAP-70 positive patients achieved a CR (one to rituximab/fludarabine/cyclophosphamide, and one to R-CHOP). One ZAP-70 negative patient was refractory to fludarabine/rituximab combination.

Conclusion: ZAP-70 positive CLL is more likely to be refractory to treatment, while ZAP-70 negative pts achieved a higher ORR (p=0.01). Although pts who were ZAP-70 positive were more likely to have advanced stage, 30% of these pts had early stage disease. As such, ZAP-70 did not closely correlate with stage, and may be an independent prognostic factor in these pts. Response to treatment could also not be predicted by ZAP-70 expression.