Summary Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long‐term outlook. Median follow‐up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse‐free survival was 16 years. After relapse (n = 79) or non‐response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse‐free survival was 11 years. After third‐line therapy (n = 23), 50% achieved CR and median relapse‐free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third‐line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 109/l before treatment had the longest relapse‐free survival (P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL‐related causes. Patients achieving a CR can expect a normal lifespan.

SummaryTo explore the mechanism(s) by which the Syk protein tyrosine kinase participates in B cell antigen receptor (BCR) signaling, we have studied the function of various Syk mutants in B cells made Syk deficient by homologous recombination knockout . Both Syk SH2 domains were required for BCR-mediated Syk and phospholipase C (PLC)-y2 phosphorylation, inositol 1,4,5-triphosphate release, and Ca" mobilization. A possible explanation for this requirement was provided by findings that recruitment of Syk to tyrosine-phosphorylated immunoglobulin (Ig) o and Igo requires both Syk SH2 domains . A Syk mutant in which the putative autophosphorylation site (Y518/Y519) of Syk was changed to phenylalanine was also defective in signal transduction ; however, this mutation did not affect recruitment to the phosphorylated immunoreceptor family tyrosine-based activation motifs (ITAMs) . These findings not only confirm that both SH2 domains are necessary for Syk binding to tyrosine-phosphorylated Iga and Ig[3 but indicate that this binding is necessary for Syk (Y518/519) phosphorylation after BCR ligation. This sequence of events is apparently required for coupling the BCR to most cellular protein tyrosine phosphorylation, to the phosphorylation and activation of PLC-y2, and to Ca 21 mobilization .

In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.