Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup phase III trial E2997. J Clin Oncol 2007;25:799-804.

CLL is a highly heterogeneous disorder with markedly disparate clinical course and variable therapeutic response among patients. A number of phenotypic and molecular markers have been shown in retrospective studies to correlate with the pace of disease progression, time to first treatment, and treatment response. In this paper, Grever and colleagues prospectively analyzed CLL cells from patients in the U.S. Intergroup trial (ECOG/ CALGB/SWOG) of fludarabine (F) single agent vs. fludarabine plus cyclophosphamide (FC) as initial therapy for symptomatic patients who require treatment. Pre-treatment samples were analyzed for IgVH (immunoglobulin heavy chain variable gene) and p53 mutation status, expression of ZAP-70, CD38 and other phenotypic markers, and cytogenetics by FISH (fluorescent in situ hybridization). The study demonstrated significantly improved complete and overall response rates in patients receiving FC, as detailed in an accompanying report1 . Two hundred and thirty-five of the 278 study patients had the correlative marker analyses performed. None of the markers correlated with response to either treatment arm. However, patients with the del(17p13.1) or del(11q22.3) had a significantly shorter progression-free survival (PFS) with either F or FC therapy. Interestingly, mutations in the p53 gene located at the chromosome 17p locus did not correlate with outcome, suggesting another relevant gene or genes in the deleted segment.

The clinical and biologic heterogeneity of CLL, reflected in definable subsets of disease using molecular and phenotypic markers, has led to the hypothesis that a risk-adapted therapeutic approach may be feasible. This study by Grever et al. is among the first to prospectively apply these markers in a randomized multicenter trial. The results confirm a significantly shorter PFS for patients with del(17p) or del(11q) despite similar responses to induction therapy. Such high-risk patients would be logical candidates for alternative initial treatment or consolidation approaches. It will be important to validate these findings in ongoing and future CLL clinical trials, and to standardize methodologies and endpoints for positive vs. negative marker expression. The predictive value for any marker may well differ depending upon the therapeutic regimen applied, as shown by a recent study wherein CLL patients with the del(11q) responded as well to the PCR regimen (pentostatin, cyclophosphamide, rituximab) as did those with more favorable markers2 . The use of prognostic markers thus will be a moving target, but nonetheless one that helps us know where to aim.

1.
Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial EJ Clin Oncol 2007;25:793-
2.
Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007;109:405-11.

Competing Interests

Dr. Williams indicated no relevant conflicts of interest.