The FDA has updated the labeling for fludarabine phosphate injection, expanding its approved use in treating B-cell chronic lymphocytic leukemia (CLL). This update, part of Project Renewal, now includes the use of fludarabine phosphate in combination regimens for adult patients with B-cell CLL, and for those who have experienced disease progression on alkylating agents. The revised labeling provides updated dosage recommendations, particularly when used in combination with cyclophosphamide and rituximab.
Updated Indications and Dosage
Fludarabine phosphate is now indicated for adult patients with B-cell CLL, both as part of a combination regimen and for those who have not responded to or have progressed on treatment with one or more alkylating agent-containing regimens. When administered with cyclophosphamide and rituximab, the recommended dose of fludarabine phosphate is 25 mg/m2 intravenously over 30 minutes daily for days 1 to 3 of six 28-day cycles. This is combined with cyclophosphamide at 250 mg/m2 intravenously daily on days 1 to 3, and rituximab at 375 mg/m2 intravenously on day 1 of cycle 1, followed by 500 mg/m2 on day 1 of each subsequent cycle. As a single-agent therapy, the recommended dose remains 25 mg/m2 intravenously for 5 consecutive days of each 28-day cycle.
Safety Profile and Warnings
The prescribing information for fludarabine phosphate includes warnings and precautions for neurological toxicities, myelosuppression, autoimmune cytopenias, transfusion-related graft-vs-host disease, and tumor lysis syndrome. It also warns of pulmonary toxicity in CLL patients when fludarabine phosphate is administered with pentostatin. Common adverse effects associated with fludarabine phosphate include myelosuppression, fever, infection, nausea, vomiting, weakness, and pain.
Efficacy Data from Prior Studies
Efficacy data supporting the use of single-agent fludarabine phosphate comes from two single-arm, open-label studies in patients with CLL and refractory disease after one or more prior lines of alkylating agent-containing regimens. In the MD Anderson Cancer Center study, the overall response rate (ORR) was 48%, with a complete response rate of 13%. The SWOG Cancer Research Network trial reported an ORR of 32% and a complete response rate of 13%. Median time to response was 7 weeks (range, 1-68) in the MD Anderson study and 21 weeks (range, 1-53) in the SWOG trial. Median duration of disease control was 91 weeks and 65 weeks, respectively. Median survival was 43 weeks and 52 weeks, respectively.
In the MD Anderson trial, 48 patients received fludarabine phosphate at doses ranging from 22 mg/m2 to 40 mg/m2 for 5 days every 28 days. In the SWOG trial, 31 patients received the agent at doses ranging from 15 mg/m2 to 25 mg/m2 for 5 days in each 28-day cycle. Among patients with Rai stage III or IV disease at baseline, disease improved to stage II or better in 58% (n = 7/12) of responders in the MD Anderson trial and 71% (n = 5/7) of responders in the SWOG trial. Across both studies, mean hemoglobin concentration increased from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in anemic patients, and average platelet count increased from 63,500/mm3 at baseline to 103,300/mm3 at the time of response in thrombocytopenic patients.
