Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine

Fludarabine, the 5'-monophosphate of 9-β-D-arabinofuranosyl-2-fluoroadenine (FaraAMP), is effective in the treatment of chronic lymphocytic leukemia (CLL) and has been demonstrated to increase natural killer (NK) cell lytic activity (NK(a)) in humans and mice. To determine the effect of FaraAMP on NK cells in CLL, we analyzed NKa toward K562 targets after in vitro incubation with FaraAMP and after in vivo exposure to fludarabine. Pretreatment analysis of peripheral blood from 12 CLL patients (9 untreated) revealed: median number of NK cells 500/μl (range 290-1160); median NKa lytic unit₃₀/10⁶ cells (range 5-80). These results were similar to those from healthy adult donors. After exposure to 3, 30, or 300 μM FaraAMP, the median maximum stimulation index (NK(a) FaraAMP/NK(a)) was 1.2 (range 0.9-1.5), within the range observed in normal adults. FaraA also stimulated NK(a) in vitro toward autologous CLL cells in two of five patients as measured by a dye-exclusion assay. In three patients following three or more treatment courses of fludarabine (30 mg/m² per day for 5 days) the NK cell number and NK(a) were maintained near pretreatment values. Phenotypic analysis of the peripheral mononuclear cells in 34 consecutive CLL patients revealed a marked reduction in CD5/CD20 and CD4 cell numbers after three courses of fludarabine with less effect on CD8 and CD56 cells. These results indicate that fludarabine spares NK cells and may stimulate NK(a) in some CLL patients.