Prognostic Factors in the UK LRF CLL4 Trial.

The LRF CLL4 trial randomised 777 previously untreated patients with Binet stage progressive A, B or C disease between January 1999 and October 2004 to receive either Chlorambucil, Fludarabine or Fludarabine and Cyclophosphamide. Interphase FISH for deletions of chromosome 6q, 11q, 13q, 17p and trisomy 12, IgV_H gene mutational status (98% cut off), CD38 (7% cut off) and ZAP70 (10% cut off) expression were measured at randomisation on 579, 523, 535 and 478 patients respectively. Leukemic cells from 39 patients utilised the V_H3-21 gene of whom 33 had homologous CDR3’s. Among the biological markers, log rank analysis showed that >20% p53 loss, del 11q, unmutated VH genes, high CD38 and high ZAP 70 correlated with disease progression or death (Table 1) but not deletion of chromosome 6q, 13q and trisomy 12 (p=0.7, 0.3 and 0.2 respectively). There was no difference in PFS or response duration between the 52 patients with 5–20% p53 loss and the 494 patients with no p53 loss. Multivariate Cox regression analysis showed that >20% p53 loss (p<0.0001), unmutated IgV_H genes (p=0.0001), deletion of 11q (p=0.02) and male gender (p=0.03) were independent risk factors for short PFS. The effects of stage and age were overridden by FISH abnormalities. High ZAP70 expression was only significant when V_H gene mutation status was not included in the model. CD38 expression was only significant in univariate analysis.

Among the 320 unmutated cases there was no significant difference in PFS between those with 100% homology (227 cases) and those with 99% or 98% homology to the germline sequence (93 cases). Mutated V_H3-21 cases were more likely to express ZAP70 than other mutated cases, p=0.004. Excluding patients with >20% p53 loss, patients using the V_H3-21 gene had similar progression free survival (PFS) to those remaining patients with unmutated V_H genes and an inferior PFS to those with mutated V_H genes (2p=0.0001). The adverse prognostic significance of 11q deletions was not clearly evident in an interim analysis presented at ASH ‘05. Patients can now be divided into 3 risk groups (Table 2). This risk stratification provides the basis of evaluating differing treatment modalities for each risk group in subsequent clinical trials.