ZAP-70 and CD38: Markers of Importance in CLL
ZAP-70 and CD38: Markers of Importance in CLL
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: In 156 patients with B-cell chronic lymphocytic leukemia, the presence of ZAP-70 and/or CD38 on the leukemic cell surface, as determined by flow cytometry, was shown to correlate with less favorable outcomes, including reduced event-free survival. These markers are thus useful clinical predictors of CLL aggressiveness and may ultimately be used to indicate which stage 0 patients should be treated at the time of diagnosis and which patients may have their treatment safely delayed.
Source: Hus I, et al. The clinical significance of ZAP-70 and CD38 expression in B-cell chronic lymphocytic leukaemia. Ann Oncol. 2006;17:683-690.
B-cell chronic lymphocytic leukemia (B-CLL) is a disease with a highly variable clinical course. Some patients have very indolent disease, never requiring specific therapy while in others the course is very aggressive and management may be very difficult. Although staging systems have proven very useful,1,2 it remains difficult to predict the clinical course for those who present in the earliest stages. Thus, efforts are underway to determine other features that will help identify stable or progressive forms of CLL that might facilitate risk-adapted treatment strategies.
In the current study, lymphocytes from 156 B-CLL patients were evaluated for the expression of ZAP-70 (zeta-associated protein) and CD38 by flow cytometry. Of these, 57 (37%) were ZAP-70 positive and 52 (33%) were CD38 positive. Of the entire group, 118 patients (76%) were both ZAP-70 and CD38 concordant. Both markers had predictive value but ZAP-70 proved superior. For example, although event-free survival (EFS) was significantly longer for both ZAP-70 negative and CD38 negative patient groups, when examining those individuals who, by clinical parameters had less favorable prognosis (stage of disease, high white blood count, low platelet count, and increased LDH) the presence or absence of ZAP-70 conferred more significant prognostic information than CD38 expression. Furthermore, in patients who required chemotherapy, ZAP-70 expression was significantly higher than in still-untreated patients (P = 0.032), and in all patients responding to first-line chemotherapy with purine analogues, ZAP-70 expression was significantly lower than in non-responding patients (P < 0.008). For this group there was no significant difference in CD38 expression.
Thus, both ZAP-70 and CD38 expression were shown to predict the clinical course of B-cell CLL. However, ZAP-70 expression appeared to be more predictive, particularly with regard to defining those cases that are likely to respond or not respond to first-line chemotherapy.
Commentary
ZAP-70 is a marker for IgVH mutation and has been associated with more aggressive CLL.3,4 CD38 is also considered an indication of IgVH mutation, and its presence on the surface of CLL cells was earlier demonstrated to be a negative prognostic indicator.5 Both measures are conveniently determined by flow cytometry and are becoming increasingly available in clinical laboratories. The data from this report would suggest that obtaining both markers would be useful for both precise prognostic classification and confirmation if one or the other markers is borderline positive. For clinicians who are presented with stage 0 CLL patients, would the presence of these markers be sufficient to initiate treatment? For this question, the answer is not yet available. Certainly this would be a question worth rigorous clinical trial. Prior to that, one would have to make the assumption that earlier treatment in patients with CLL would offer survival advantage, and this has not been clearly demonstrated. Yet, it would seem that if early treatment were to make a difference, it would be for those with aggressive disease (such as might be predicted by the presence of both ZAP-70 and CD38 on the cell surface). Hopefully, a clinical trial will soon address this question.
References
1. Rai K, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-234.
2. Binet JL, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198-206.
3. Durig J, et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia. 2003;17:2426-2434.
4. Crespo M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775.
5. Damle RN, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847.
B-cell chronic lymphocytic leukemia (b-cll) is a disease with a highly variable clinical course.Subscribe Now for Access
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