A phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia: results from CALGB Study 9211

Cladribine has been reported to have little activity in fludarabine-refractory chronic lymphocytic leukemia (CLL). We sought to determine whether resistance to therapy with cladribine in fludarabine-refractory CLL patients represented primary drug resistance or the inability to tolerate the myelosuppression associated with this therapy. Patients with fludarabine refractory CLL patients without severe thrombocytopenia (platelets greater than or equal to50 x 10(9)/I) or granulocytopenia (neutrophils >1.5 x 10(9)/l) were enrolled. All patients received cladribine (0.14 mg/kg) as a 2-h intravenous infusion daily for 5 days, repeated every 4 weeks. Patients received up to six cycles of therapy. Twenty-eight patients enrolled; 13 had intermediate (Rai stage I or II) and 15 high (Rai stage III and IV) risk stages. No patient had a complete remission, but nine (32%; 95% confidence interval, 15-49%) attained a partial remission when assessed using the modified NCl criteria (1996). The median time to relapse for responders was 12 months, while median progression-free survival for the entire group was 9 months (95% confidence interval, 4-14 months). The median overall survival was 2.2 years (95% confidence interval, 0.8-3.1 years). Response was predicted by pre-treatment Rai status with seven of 13 (54%) intermediate risk vs two of 15 (13%) high-risk patients responding (P=0.04). Toxicity was myelosuppression and infections (grade 3-5: neutropenia 75%, thrombocytopenia 68%, and infections 43%). Cladribine has modest clinical activity and considerable toxicity in a very selected group of patients with fludarabine-refractory CLL lacking pre-treatment neutropenia and thrombocytopenia.