Prognostic factors in chronic lymphocytic leukemia

There has been a revolution in prognostic markers in chronic lymphocytic leukemia (CLL). In 1999, two papers published alongside each other in the journal Blood [1,2] suggested that the mutational status of the immunoglobulin variable region genes (IgVH) cleanly separated the disease into a relatively benign and a relatively malignant version, and one of them suggested that the much more easily measured expression of CD38 on the CLL cells was a useful surrogate [2]. Unfortunately, it soon became clear that there was a considerable discordance between CD38 expression and IgVH mutations and that, in any case, CD38 expression does, in certain circumstances, change during the course of the disease [3]. This paper went on to show that CD38 and IgVH mutations were independent prognostic factors and could be used together to recognize three types of CLL prognosis: benign, malignant and intermediate. Despite disputes about what level of CD38 expression should be regarded as positive (30%, 20%, 7% or 5%); about the importance of a biphasic distribution of positivity; and about how many mutations might one allow and still be regarded as unmutated (2% or 3%); and despite the difficulty routine laboratories have in gene sequencing; these two assays have been increasingly used over the past 6 years. In 2003, ZAP-70 was proposed as a surrogate assay for IgVH mutations [4] and three different flow cytometry assays for this protein have been described [5 – 7]. Again, different laboratories have produced different results; two assays give greater than 90% concordance with IgVH mutations, the third 23% discordance. Even more important, the third assay, which is much the easiest of the three to perform, appears to give extra prognostic information; patients who had unmutated IgVH genes but were ZAP-70 negative, had a significantly better prognosis than those who had mutated IgVH genes but were ZAP70 positive [7], and this finding has recently been confirmed [8]. In this issue of Leukemia and Lymphoma, Hayat et al. [9] produce yet another conundrum. In their hands, ZAP-70 measured by the Crespo assay shows more concordance with CD38 expression than with IgVH mutations and, in a multivariate analysis, it does not have independent prognostic value. They also confirm the value of including patients who show biphasic CD38 expression among the group with a poor prognosis. Where do prognostic factors currently stand? Although originally evaluated in retrospective surveys, the prognostic value of both IgVH mutations and CD38 expression have been conformed in prospective clinical trials in Germany and the UK, and will be used to stratify the disease in future therapeutic studies. The genetic hierarchy originally described by Dohner et al. [10] using flourescence in situ hybridization (FISH) has also been confirmed in prospective studies in Britain and Germany, although only the presence of del 17p will contribute to future stratification. It defines a small group of patients (approximately 5%) whose disease is refractory to most types of chemotherapy. ZAP-70 is still something of a puzzle. Disparity between the different assays needs to be resolved by sample swapping and collaborative agreement. Reasons for the discordance with IgVH mutations need to be sought. The suggestion that it is caused by the use of the VH3-21 gene or the presence of del 11q or del 17p by FISH [11] does not hold water when applied to our large series of patients. Although ZAP-70 is widely thought to be stable throughout the