Rapid clearance of rituximab may contribute to the continued high incidence of autoimmune hematologic complications of chemoimmunotherapy for chronic lymphocytic leukemia

Abstract

Rituximab is an effective treatment for autoimmune cytopenias associated with chronic lymphocytic leukemia. Despite the incorporation of rituximab into fludarabine-based chemotherapy regimens, the incidence of autoimmune cytopenias has remained high. Inadequate rituximab exposure due to rapid antibody clearance may be a contributing factor. To test this hypothesis, we measured serum rituximab levels in patients treated with fludarabine and rituximab (375 mg/m(2)). All patients had undetectable rituximab trough levels by the end of cycle 1, and one-third had undetectable levels already on Day 6 of cycle 1. Although rituximab trough levels increased progressively with each cycle, only by cycle 4 did the median trough level exceed 10 ug/mL. The median half-life of rituximab during cycle 1 was 27 hours, compared to 199 hours during cycle 4 (P<0.0001). There was a significant inverse correlation between the rituximab half-life in cycle 1 and the degree of tumor burden (P=0.02). Two patients who were identified as having subclinical autoimmune hemolysis prior to therapy were given additional doses of rituximab during the initial cycles of therapy and did not develop clinically significant hemolysis. One patient who developed clinically significant hemolysis during therapy was given additional rituximab doses during cycles 3-5 and was able to successfully complete his treatment. In conclusion, rituximab is cleared so rapidly during the initial cycles of therapy for chronic lymphocytic leukemia that most patients have only transient serum levels. More frequent dosing of rituximab may be required to prevent autoimmune complications in at-risk patients (clinicaltrials.gov identifier:00001586).

Trial registration: ClinicalTrials.gov NCT00001586.

Figures

Figure 1.

Rituximab pharmacokinetics in CLL. (A) Rituximab was administered every 4 weeks in combination with fludarabine. Rituximab trough levels during cycles 1–5 are depicted on Whisker plots (P<0.0001 by ANOVA). (B) Percentage of patients with detectable trough levels at the end of cycles 1–5 (P=0.0019 for time effect). (C) Minimum (open squares), median (solid line), and maximum (open circles) rituximab serum levels measured 24 and 120 hours after the first dose. Lines indicate an estimate of serum levels at time points in between actual measurements. (D) Median serum rituximab half-life during cycles 1–4. P values by t-test for comparison of the respective cycle to cycle 1 are *P<0.01 and ***P<0.0001.

Figure 2.

Tumor burden correlates inversely with rituximab serum concentration and half-life. (A) Median serum rituximab half-life in the first treatment cycle for patients with high (n=8) and low (n=9) tumor burden (P=0.02 by Student’s t-test). (B) ALC (solid lines) and rituximab trough levels (dotted lines) over time in 2 representative patients.