Prognostic Factors in the UK LRF CLL4 Trial.

The CLL4 trial randomised 777 previously untreated patients between Chlorambucil (Chlor), Fludarabine (Fluda) and Fludarabine with Cyclophosphamide (FC). The median follow-up is 21 months. V_H gene mutation status using a 98% cut off, CD38 expression using a 7% cut off, ZAP70 expression (Orchard et al Lancet 2004) and interphase FISH were measured on samples taken at randomisation. In an interim analysis 253/397 patients had unmutated V_H genes. 32 patients utilised the V_H3-21 gene, of whom 27 showed restricted HCDR3 usage. 343/535 were CD38 positive and 131/261 were ZAP70 positive. 10/24 V_H 3-21 cases were ZAP 70 positive, of whom 7 were unmutated. There was no significant association between V_H genes and age, sex or a positive DAT. There were significant correlations between V_H gene mutations and CD38, ZAP70 and FISH results.

Logistic regression including age, stage, gender, VH mutations and genetic factors shows that stage (p=0.002), VH genes (p=0.05), p53 loss (p=0.02) and del 11q (p=0.01) affect response. Response rates by V_H gene mutation status and treatment arm are given in table 2.

Analysis of variance shows that both V_H genes (p=0.01) and treatment (p<0.0001) have an effect on response with no significant interaction. Among 104 patients with unmutated V_H genes and both ZAP 70 expression and response data available, there was no significant difference in response rates between ZAP positive and negative cases. In univariate analysis p53 loss (p<0.00005), unmutated V_H genes (p=0.003), CD38 positivity (p=0.06) but not ZAP70 positivity correlate with poor overall survival. In multivariate Cox regression analyses, age (p<0.0001) stage (p=0.01) and p53 loss (p<0.0001) are significant for survival. When patients with p53 loss are excluded unmutated V_H genes (p=0.007) but not CD38 or ZAP70 positivity are significant. In conclusion p53 loss identifies a small group of patients with both poor response to treatment and short survival. In the remaining cases, unmutated V_H genes are associated with a relatively poor response independent of treatment arm, and with a shorter survival.