High dose chlorambucil has been shown to be an effective single-agent treatment in chronic lymphocytic leukemia (CLL), and to be useful as part of combination chemotherapy in low-grade non-Hodgkin's (NHL) and Hodgkin's disease (HD). In general, it is well tolerated and can be used in an outpatient setting. The optimum dose of chlorambucil has not been defined and there are numerous different dosing schedules available. Pharmacokinetic studies suggest decreased bioavailability with successive cycles, probably due to accelerated metabolism. There is good evidence that regimens which use higher doses of chlorambucil have a better outcome than standard dose therapy. Most of the trials which have compared chlorambucil with fludarabine have not used a higher dose regimen of chlorambucil and cannot truly be described as comparative. There is an increase in the incidence of grade 3 and 4 neutropenia and also of sepsis with fludarabine treatment, compared to chlorambucil. Fludarabine produces a higher initial response rate in CLL but no statistical difference has been shown in long term survival between fludarabine and high dose chlorambucil. In the treatment of lymphoma, single agent chlorambucil does not confer a durable remission. There have been good results with combination chemotherapy regimens such as CID and PECC. The oral route of administration of these combinations makes them particularly useful as part of palliative chemotherapy. A further point to consider is that chlorambucil is very much cheaper than fludarabine and other newer agents. Chlorambucil should not automatically be overlooked in favor of more recently developed drugs such as fludarabine. There is good evidence that the drug is an effective treatment at a suitable dose, and there is a need for randomized trials to compare it fully with other current treatments.

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CD31 is the physiological ligand for CD38. CD38 expression in a high percentage of malignant cells is a risk factor for patients with B-cell chronic lymphocytic leukaemia (B-CLL). A previous investigation demonstrated that quantification of CD38 improves upon the prognostic value of the percentage expression. A recent study states that the percentage of CD31 expression is not predictive in B-CLL. We reassessed the predictive power of CD31 in a cohort of 120 patients with B-CLL. Peripheral blood cells were stained with PCP-labelled anti (α)-CD19, FITC-α-CD5 and PE-α-CD31 antibodies. CD31 expression was quantified using beads of specific antibody binding capacity and the density was correlated with clinical outcome. End points were disease-specific survival and time to treatment (TTT). We report that CD31 density was significantly lower in the group of patients with Binet stage B and C of disease progression (P=0.0003). There was an inverse, significant correlation between CD31 and CD38 densities (R=-0.281, P=0.002). All CLL-related deaths occurred in patients with low CD31 density. Low CD31 predicted for poor disease outcome (survival, P=0.0087; TTT, P=0.0064) and identified Binet stage A patients (survival, P=0.0350; TTT, P=0.0716) and those with low CD38 (survival: all patients, P<0.0001; stage A, P=0.003) who followed a more aggressive clinical course. Disease-specific survival of patients with low CD31 and high CD38 densities was significantly shorter than all other groups. In addition, low CD31 density was a poor risk factor irrespective of patient age (survival: all patients, P=0.045; stage A, P=0.021) and identified patients with Binet stage B/C as the highest risk group (P<0.0001). In conclusion, low CD31 density is an adverse prognostic indicator in B-CLL. Also, low CD31 density enhances the prognostic power of CD38 density. The interaction between CD31 and CD38 and its clinical significance in B-CLL requires further investigation.

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The CD31 antigen is expressed by a variety of cells including B lymphocytes from patients with B-CLL. The CD31 gene is polymorphic and CD31 gene polymorphisms involving single nucleotide substitutions (SNPs) such as C+373G (Leu125Val) and G+1688A (Ser563Asn) have been implicated in the pathogenesis of a number of diseases. CD31 is the physiological ligand for the CD38, a powerfull and independent prognostic marker for patients with B-CLL. A recent published study reports that the percentage of CD31 expression does not predict for poor prognosis in B-CLL (Ibrahim S, et al. Cancer.2003;97:1914–1918). A previous study showed that quantification of CD38 expression by flow cytometry significantly improves its prognostic value (Mainou-Fowler T, et al. Br J Haematol.2002;118:755–761). To re-assess the predictive power of CD31 in B-CLL, we quantified its expression and correlated its intensity with clinical outcome in a cohort of 120 patients (70M, 50F, age 47–91). The role in B-CLL of CD31 SNPs was also examined. We report that Binet stage A patients had a significantly higher density of CD31 compared with stage B/C patients. A low CD31 predicted for poor disease outcome and identified those Binet stage A patients, and patients with low CD38, who followed a more aggressive clinical course. Disease-specific survival of patients with both low CD31 and high CD38 was significantly shorter than all other groups. Low CD31 expression significantly related with the homozygous GG and AA genotypes of the Leu125Val and Ser563Asn polymorphisms, respectively. The alleles found to be in strong disequilibrium but this was not 100%. There was no significant difference between observed and expected allele frequencies and no significant association was observed between patient genotype and clinical outcome. Statistical comparisons are as follows: All patients:survival:high CD31 vs low CD31: P=0.0087,high CD31, low CD38 vs low CD31, low CD38: P=0.0425,low CD31, low CD38 vs low CD31, high CD38: P=0.0013,time to treatment: high CD31 vs low CD31: P=0.0064. In stage A patients:P=0.0353,P=0.0721,P=0.0214,P=0.0716. Distribution of CD31 expression within the genotypes: Leu/Leu vs Leu/Val, P=0.1442; Leu/Leu vs Val/Val, P=0.0466; Leu/Val vs Val/Val, P=0.0466; Asn/Asn vs Asn/Ser, P=0.1850; Asn/Asn vs Ser/Ser, P=0.0251; Asn/Ser vs Ser/Ser, P=0.0439. In conclusion, low level of CD31 expression is an adverse prognostic indicator in B-CLL. The role of CD31 SNPs in B-CLL requires further investigation.