Single-Agent Rituximab in Early-Stage Chronic Lymphocytic Leukemia

Currently, patients with early-stage chronic lymphocytic leukemia (CLL)without active disease are observed. However, those patients with elevatedbeta-2-microglobulin levels appear to have a shorter median survival (6 years vs10+ years). Strategies designed to impact the eventual progression of diseaseinclude use of targeted therapies with minimal long-term risk. Single-agentrituximab (Rituxan) has activity in previously treated CLL (J Clin Oncol 19:2165, 2001; 19:2153, 2001) and in untreated low-grade lymphomas (Semin Oncol27:25, 2000). We designed this study to investigate the activity of rituximab inuntreated high-risk, early-stage CLL.

Patients were eligible if they had untreated Rai stage 0 to II CLL withbeta-2-microglobulin levels ³ 2.0 mg/dL, without indications for therapy according to the National CancerInstitute Working Group criteria. Rituximab was given at 375 mg/m² weekly for 8weeks. Baseline cytokine profiles known to be prognostic in CLL, includinginterleukin (IL)-6,IL-10, and tumor necrosis factor (TNF)-alpha (Blood 97:256, 2001), were obtainedwith serial measurements when feasible. Thirty-one patients have been enrolledto date; characteristics are as follows: median age, 67 years (range: 50-82years); 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 activetherapy, two not reassessed) was 90% (19% complete response, 19% nodular partialresponse, 48% partial response). Significant reductions in fatigue werereported. 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 forcytokine analysis in 10 patients to date. Although the numbers were small,preliminary observations suggested reductions in TNF-alpha levels correlatedwith response.

CONCLUSION: Rituximab has significant activity in early-stage CLL. Impact onsurvival and time to progression requires longer follow-up. Furtherinvestigation of the effect of rituximab on cytokine profiles and implementationof strategies to modulate CD20 expression is planned.