Chlorambucil has been used for many years for the treatment of low-grade B-cell lymphoproliferative disorders, including chronic lymphocytic leukaemia and low-grade non-Hodgkin's lymphoma. There is evidence in the literature that increasing the dose of chlorambucil produces better results than 'standard' doses in terms of response rates and overall survival. There is also evidence that this approach may be at least as effective as the use of fludarabine, as well as being very much less expensive. We describe a high-dose chlorambucil (HDC) regimen, which involves a sustained but intermittent dose of chlorambucil. i.e. 30 mg/d for 4 d per week for 4 weeks, followed by a further four courses at fortnightly intervals for 8 weeks (a total of eight 4-d courses) given as a single drug over an initial 12-week period. The outcome of treatment in previously treated and untreated patients was excellent, with a median time to treatment failure of 33 months for the patient cohort overall and for previously treated and chemotherapy-naive patients of 13 and 104 months respectively. In patients previously treated with fludarabine, 78% had a response. Autoimmune haemolytic anaemia was reversed in one patient. Toxicity, both haematological and other, was minimal. We propose that escalated-dose chlorambucil regimens should be compared with fludarabine in randomized controlled trials, rather than 'standard' lower dose protocols.

Tumour necrosis factor (TNF) alpha is involved in the pathogenesis of established lymphoproliferative disease. Serum levels of TNFalpha and its soluble receptors are above normal values in B-cell chronic lymphocytic leukaemia (B-CLL) and they are valuable prognostic markers in lymphoma patients. The production of TNFalpha is genetically controlled. Altered synthesis of TNFalpha has been associated with polymorphisms at the TNF gene cluster (i.e. TNFA, TNFB and LTB). In the present study, we evaluated the prevalence of the known high TNFalpha- and TNFbeta- producing alleles TNF1, TNF2 of the TNFA gene, TNFB1, TNFB2 alleles of the TNFB gene and of the polymorphic alleles TNFd1, d2, d3, d4 and d5 of the microsatellite TNFd in patients with B-CLL, non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). This study demonstrates that there is no difference in the frequency of the tested TNF alleles between normal controls and cohorts of patients with lymphoproliferative disease. These results indicate that TNF alleles are not genetic predisposing factors in the development of these diseases.