Fractionated radioimmunotherapy of non-Hodgkin's lymphoma

Abstract

Impressive durable responses from clinical studies using higher myeloablative dose RIT followed by peripheral blood stem cell transplant (PBSCT) suggest that there may be a radiation dose response for RIT. With the development of rituximab, a chimeric mAb, multiple or fractionated treatments are possible. This may enable higher cumulative doses of RIT to be delivered without the need for PBSCT and may offer the potential for improving the biodistribution of the radioactive antibody. Here the fractionation of RIT has been investigated both in murine model and in the context of a clinical trial. Using a dose escalation protocol the clinical tests the safety and efficacy of fractionated RIT in relapsed CD20 positive NHL using 2 fractions of ¹³¹I-rituximab given with an 8-week interval. The feasibility of producing a clinical grade ¹³¹I-rituximab and delivering the treatment has been demonstrated with high response rates and acceptable toxicity seen in the first 3 dose cohorts. Pharmacokinetic analysis has involved measurement of the clearance of the radioimmunoconjugate as well as the development of an assay to measure serum rituximab concentrations. Wide inter-patient variability in pharmacokinetics and a strong association between the availability of CD20 antigen and clearance of both the radioimmunoconjugate and the unlabelled mAb has been seen. The results support individualism of the dose and scheduling of RIT. The anti-rituximab idiotype mAb developed in order to assay serum rituximab concentrations by enzyme linked immunosorbent assay has also provided a tool for studying the binding of rituximab to CD20.

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