Cladribine (CdA) Gives Longer Response Duration Than Fludarabine (F) and High-Dose Intermittent Chlorambucil (Chl) as First-Line Treatment of Symptomatic Chronic Lymphocytic Leukemia (CLL). First Results from the International Randomized Phase III Trial.

Fludarabine and chlorambucil are standard therapies for CLL, whereas cladribine, although effective, is much less used. F was shown to improve response rate and duration but not survival when compared to low-dose Chl (Rai et al, 2000), whereas high-dose Chl was more effective (Jaksic et al, 1988, 2000). Single drug CdA has not previously been compared with F for CLL. Although there are major similarities in the mechanism of action, clinical activity, and toxicity between F and CdA, there are also important differences. We have therefore conducted a prospective randomized phase III trial comparing single-drug treatment with (A) high-dose intermittent Chl 10 mg/sqm/day for 10 days orally, (B) standard-dose F 25 mg/sqm/day for 5 days iv bolus, and (C) CdA 5 mg/sqm/day for 5 days iv/2h (or equivalent administrations). All study regimes were repeated every 4 weeks. After 3 courses reevaluation was performed, and patients with lymphocyte counts <50% of pretreatment values and without prohibiting toxicity continued with another 3 courses. From November 1997 through September 2004 229 previously untreated symptomatic patients mostly from Scandinavia and Australia were included. This is the first report on the outcome of the total study population of 221 patients; 8 were excluded due to incompatibility with inclusion criteria or lack of reporting. Mean age was 62.8 years (30–75), and mean lymphocyte count was 124, with well balanced treatment groups. The median follow-up of 141 surviving patients is 4.2 years, and the median survival of 80 deceased patients is 2.7 years. The median number of courses was 6 for all groups; however, 2 or less courses were given to 10% with F, 17% with Chl, and 27% with CdA (F vs CdA, p=0.019). Overall response rates were 62% for Chl (n=76), 70% for F (n=73), and 75% for CdA (n=72), (n.s.). Median time to progression was 9 months for Chl, 10 months for F, and 25 months for CdA (p=0.0003). Median time to second-line treatment was 21 months for Chl, 24 months for F, and 50 months for CdA (p=0.005). Similar differences between study arms were seen when older (70–75 years, n=50) and younger patients were analysed separately. Median overall survival from inclusion was 62 months for Chl, 68 months for F, and 82 months for CdA (n.s.). Hemolysis post randomization was seen after Chl in 1 patient, after F in 5, and after CdA in 4 patients (Chl vs F+CdA, p=0.08). The platelet grade III–IV toxicity was 31%, 24%, and 43% after Chl, F and CdA, respectively (F vs CdA, p=0.073). Similar data for neutrophils were 35%, 34%, and 57%, respectively (p=0.023). Correspondingly, grade III–V infections were seen in 17%, 24%, and 36%, respectively (p=0.02). There were 3 infectious deaths, all from sepsis; 1 after F and 2 after CdA. With this dose CdA seems to be more efficacious, especially as regards response duration, than F and Chl, but leads to more neutropenia and infections, although fatal toxicity was rare. The results from F and Chl were similar.