Cladribine treatment of hairy cell leukemia (HCL) is complicated by neutropenic fever in 42% of patients despite documented infections being relatively uncommon. We performed a study of priming filgrastim followed by cladribine and then filgrastim again to determine if filgrastim would lead to a reduction of neutropenia and febrile episodes. Thirty-five patients received filgrastim and cladribine and were compared with 105 historic controls treated with cladribine alone. Cladribine was administered at 0.1 mg/kg/d by continuous infusion for 7 days. Filgrastim was administered at 5 micrograms/kg/d subcutaneously on days -3, -2, and -1 and then again after the completion of cladribine until the absolute neutrophil count (ANC) was >/=2 x 10(9)/L on 2 consecutive days (days +8, +9, etc). After filgrastim priming, the median ANC increased from 0.9 x 10(9)/L to 2.26 x 10(9)/L (2.5-fold increase), and after cladribine, the median nadir ANC in the filgrastim-treated group was 0.53 x 10(9)/L compared with 0.29 x 10(9)/L among historic controls (P =. 04). The median number of days to an ANC greater than 1.0 x 10(9)/L was 9 days in the filgrastim-treated group versus 22 days among historic controls (P < 10(-5)). The percentage of febrile patients, number of febrile days, and frequency of admissions for antibiotics were not statistically different in the two groups. Filgrastim regularly increases the ANC in patients with HCL and shortens the duration of severe neutropenia after cladribine. This phase II study, with comparison to historical controls, failed to detect any clinical advantage from the use of filgrastim and cladribine in the treatment of HCL. Accordingly, the routine adjunctive use of filgrastim with cladribine in the treatment of HCL cannot be recommended.