Currently, patients with early-stage chronic lymphocytic leukemia (CLL) without active disease are observed. However, those patients with elevated beta-2-microglobulin levels appear to have a shorter median survival (6 years vs 10+ years). Strategies designed to impact the eventual progression of disease include use of targeted therapies with minimal long-term risk. Single-agent rituximab(Drug information on rituximab) (Rituxan) has activity in previously treated CLL (J Clin Oncol 19:2165, 2001; 19:2153, 2001) and in untreated low-grade lymphomas (Semin Oncol 27:25, 2000). We designed this study to investigate the activity of rituximab in untreated high-risk, early-stage CLL.
Patients were eligible if they had untreated Rai stage 0 to II CLL with beta-2-microglobulin levels ³ 2.0 mg/dL, without indications for therapy according to the National Cancer Institute Working Group criteria. Rituximab was given at 375 mg/m² weekly for 8 weeks. Baseline cytokine profiles known to be prognostic in CLL, including interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha (Blood 97:256, 2001), were obtained with serial measurements when feasible. Thirty-one patients have been enrolled to date; characteristics are as follows: median age, 67 years (range: 50-82 years); Rai stage II in 32%; and median beta-2-microglobulin level, 3.6 mg/dL.
The overall response rate in 21 evaluable patients (eight under active therapy, two not reassessed) was 90% (19% complete response, 19% nodular partial response, 48% partial response). Significant reductions in fatigue were reported. Two patients did not respond. With a median follow-up of 8 months (range: 2-16 months), one patient with partial response progressed.
No unexpected toxicities were observed; most were grade 1/2 fever, chills, and/or hypotension related to the first infusion. Samples were collected for cytokine analysis in 10 patients to date. Although the numbers were small, preliminary observations suggested reductions in TNF-alpha levels correlated with response.
CONCLUSION: Rituximab has significant activity in early-stage CLL. Impact on survival and time to progression requires longer follow-up. Further investigation of the effect of rituximab on cytokine profiles and implementation of strategies to modulate CD20 expression is planned.