Co-Expression of CD38 with Zap-70 Is Predictive of Treatment Intervention in Patients (pts) with Early Stage Chronic Lymphocytic Leukemia (CLL).

Introduction: CLL is a heterogeneous disease where advanced stage pts have compromised survival despite treatment, while early stage pts may not require any intervention. Based on current NCI-WG guidelines, most early stage (Rai stage 0 and 1) CLL pts do not require treatment until the development of progressive or symptomatic disease, though eventually over 70% of CLL pts will receive therapy. Currently, there are no markers to predict this subset of pts. Several markers of adverse prognosis, including ZAP-70⁺, CD38⁺, un-mutated IgV_H gene and cytogenetic aberrations (17p-, 11q-, +12) have been identified. These markers are primarily studied in context of aggressive clinical course and survival outcome. The value of these markers to predict the necessity of treatment intervention in early stage CLL pts has not yet been completely evaluated. We investigated the expression pattern of Zap-70 and CD38 to examine their predictive value in identifying early stage CLL pts who will require therapeutic intervention.

Methods & Results: 93 CLL pts were evaluated since 2002 at our institution. Flow cytometry was used to determine Zap-70 and CD38 expression on CD19⁺ CLL cells obtained from peripheral blood. Pts were considered to be positive for Zap-70 and CD38 expression if ≥ 20% and ≥ 30% of the cell stained for these proteins, respectively. For the Zap-70 analysis we used similar methodology as described by Crespo et al.¹ Thirty-six (19M, 17F) pts had limited stage CLL, based on Rai staging criterion. Median age was 65 years (range 43–86) with stage 0 or 1 observed in 14 and 22 pts, respectively. Median time from diagnosis is 2 years (range <1–17). Increased expression of either Zap-70 or CD38 was seen in 22 and 7 pts, respectively. Five (14%) pts were positive for both. All (100%) pts with concurrent increased expression of Zap-70 and CD38 required treatment (p=0.003), as compared to 30% of patients requiring treatment that were negative for both proteins or positive for only protein. Among the pts that required treatment 4 had 13q- and one had trisomy 12 on cytogenetic analysis.

Conclusion: Our study, demonstrates for the first time, the clinical utility of CD38 and Zap-70 co-expression in determining the probability of treatment intervention in early stage CLL pts. Although the number of pts studied is small, our findings highlight a potentially important use of these markers in the management of early-stage CLL pts. These observations warrant validation in a larger cohort of pts early stage CLL pts as well as correlation with other prognostic markers such as cytogenetic and IgV_H gene mutational status.