High Dose of Rituximab in B-Cell Malignancies.

Background: Rituximab is currently used as a standard agent in many B cell malignancies. High doses of rituximab may be more efficacious in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma, because CD20 antigenic sites occur in low density per cell, and soluble CD20 in the plasma binds with infused rituximab. We describe our results with escalated high doses of single agent rituximab given as weekly induction doses followed by monthly maintenance doses.

Methods: 18 patients (10 males, 8 females) with median age 58 years (range 42 – 80); 4 patients with MCL and 14 patients with CLL were enrolled. Rai stages were: Stage 0–1, Stage I–2, Stage II–5, Stage III–8, Stage IV–2. 9 patients had at least one prior treatment (range, 1–8 treatments): fludarabine-7 patients, chlorambucil-6 patients, chlorambucil and fludarabine-4 patients. Median duration of disease prior to rituximab administration was 23 months (1–143 months). 9 patients had bulky disease (mass largest diameter > 5 cm). All patients received the standard single agent rituximab dose 375 mg/m2 with weekly escalation up to 2,250 mg/m2, followed by the highest escalated dose of rituximab as a monthly maintenance dose. The median monthly dose 1000 mg/m2 (range 500 – 2,250 mg/m2), and the median number of monthly doses was 18 (4–76 doses).

Results: The overall response rate (CR + PR) was 88% (CR 50%, PR 38%). CR median duration is 17 + months (6 – 46 + months). CD20 intensity of staining (range of mean fluorescense intensity ratio 162–4766) and CD38 expression (range 5–99%) did not correlate with responses. The median time to progression was not reached. 8 patients progressed and their median time to progression is 25 months (14–48). None of the patients with bulky disease reached CR. 2 CR and 4 PR were observed in previous fludarabine failures. 3 of 4 patients with MCL reached CR and one continues in CR 46+ months off treatment. Rituximab was very well tolerated and only 2 episodes of grade 3 infusion related toxicity were observed. Both patients completed infusion with appropriate supportive care.

Conclusion: Single agent rituximab in high doses can induce durable clinical response in non-bulky early stage CLL/MCL. Higher than standard doses improve responses possibly by saturating CD20 binding sites and overcoming the obstacle of circulating CD 20 antigen.