Predicting Aggressive CLL
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Three CLL cellular markers have been shown to be of prognostic value in determining those patients likely to have aggressive disease. Of the three, ZAP-70 was shown, in this current report from the CLL Research Consortium, to be the greatest discriminator of need for early treatment. The current value of these markers remains investigational.
Source: Rassenti LZ, et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood. 2008; 112:1923-1930.
In patients with chronic lymphocytic leukemia (CLL), the expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) by the leukemia cells are each associated with aggressive disease. To assess the relative strength of each marker, Rassenti et al in the Chronic Lymphocytic Leukemia Research Consortium examined cells from two separate cohorts of CLL patients. In the first (n = 307) they defined thresholds for designating a case as positive for CD38 or ZAP-70. They determined the optimal cutoff for designating a CLL sample as CD38+ to be 34% cells demonstrating fluorescence above background. Using this threshold, patients who had CLL cells classified as CD38+ had a median time from diagnosis to first treatment of 3.4 years, compared to those who were CD38-, for whom the time to treatment was 7.8 years (p < .001).
Using this defined criteria from the first cohort, Rassenti et al examined cells from a second independent group (n = 705) of CLL patients to stratify into high or low risk for progressive disease. Three specific criteria were used; CD38, ZAP-70, and mutation status of the immunoglobulin gene heavy chain variable region (IGHV). Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve the ability to predict the time to first treatment except for ZAP-70-negative cases, which could be segregated into two groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within one year of diagnosis.
Commentary
The current report is an example of the added value of coordinated research within a consortium of experts on a specific disease. Through the NCI-sponsored CLL Research Consortium, extensive clinical data is available from a number of CLL referral centers, and blood samples are subjected to identical protocol for investigation. This is particularly relevant with regard to these biomarkers of disease progression because, particularly for ZAP-70, there have been conflicting results.1-3 ZAP-(zeta chain associated protein) 70 is a 70kDa intracellular tyrosine kinase involved in T-cell receptor signaling.4 By gene expression analyses, it was discovered that CLL cells with unmutated IGHV differed from CLL cells with mutated IGHV in the expression levels of a small subset of genes, one of which encodes ZAP-70. It has been established that patients with CLL cells that have unmutated IGHV have more aggressive disease, and that measurement of ZAP-70 may be used as a surrogate marker for the expression of unmutated IGHV.5 Rassenti et al speculate that the conflicting results, with regard to ZAP-70, may be due to methodological issues inherent in using an antibody to detect small intracellular proteins. In this regard, the current study employed standardized reagents and protocols, and the results were consistent in large part with measures of IGHV mutational status.
Clinicians have become accustomed to the concept of indolent CLL and the notion of not treating until symptoms occur or evidence for organ system impairment develops. In fact, updated guidelines for when to initiate treatment have been recently published.6 Patients without symptoms, lymphadenopathy, splenomegaly, or cytopenias can safely delay treatment, as it has not been established that early intervention improves survival in this group. Markers of impending need for treatment, in addition to a careful inventory of signs and symptoms, include a rising beta2 microglobulin, calculated lymphocyte doubling time, or developing cytopenia. Yet, it would be valuable to know which patients are likely to have disease progression early, as these patients may require special attention. However, even with the added information, such as that provided by knowing the ZAP-70 or CD38 profile, it is too early to use this information to decide about treatment. As Rassenti et al clearly point out, only by clinical trial will it become established that early intervention in this group translates to better outcome. It is also clear that some patients in both cohorts studied exhibited CLL cells that have markers for aggressive disease and yet, the clinical course remains indolent, whereas others lacking the markers have experienced rapid progression.
References
1. D'Arena G, et al. Prognostic significance of combined analysis of ZAP-70 and CD38 in chronic lymphocytic leukemia. Am J Hematol. 2007;82:787-791.
2. 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.
3. Deaglio S, et al. CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. Blood. 2007;110:4012-4021.
4. Weiss A, et al. Molecular and genetic insights into T cell antigen receptor signal transduction. Adv Exp Med Biol. 1994;365:53-62.
5. 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.
6. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456.
Three CLL cellular markers have been shown to be of prognostic value in determining those patients likely to have aggressive disease. Of the three, ZAP-70 was shown, in this current report from the CLL Research Consortium, to be the greatest discriminator of need for early treatment. The current value of these markers remains investigational.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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