Phase I/II Study of Fractionated Radioimmunotherapy (RIT) in Relapsed Low Grade Non-Hodgkin’s Lymphoma (NHL).

RIT produces high rates of durable complete responses in “low grade” NHL. Clinical studies have thus far been limited to a single infusion of a radiolabeled anti-CD20 mAb (¹³¹I tositumomab or ⁹⁰Y ibritumomab tiuxetan) in patients with < 25% bone marrow involvement. In this study we have tested the safety and efficacy of 4 weekly infusions of Rituximab followed by 2 fractions of ¹³¹I labelled rituximab given 8 weeks apart in relapsed "low grade" NHL and have included patients with higher levels than 25% bone marrow infiltration with lymphoma. Whole body dose (WBD) calculations have been used to allow the total dose given in 2 fractions to be increased in cohorts of 30cGy, 60cGy, 90cGy and 120cGy. A unique anti-rituximab idiotype mAb has been generated enabling serial analysis of serum rituximab concentrations (Cragg et al Blood 2004 Jun 22 Epub). This tool has allowed us to accurately quantify the serum levels of rituximab during the entire treatment schedule. We have also analysed the impact made by induction rituximab, the pre-dose of cold antibody and effects of fractionated RIT on the clearance and biodistribution of the ¹³¹I labeled rituximab. Sequential pharmacokinetic analyses have identified wide variation in the effective half-life of ¹³¹I-rituximab not only between patients but also within the same patient over the course of the treatment protocol. We found that the mean effective half-life of ¹³¹I rituximab increased from 43 hours prior to induction rituximab to approximately 106 hours prior to the second fraction of ¹³¹I-rituximab. A strong inverse correlation was found between the patients’ disease burden and the clearance of rituximab, both in the same patient as the tumor burden decreased and between different patients. We have demonstrated that higher cumulative WBD doses can be safely delivered by RIT dose fractionation than can be given with a single dose of anti-CD20, with no grade 3–4 myelotoxicity at the 90 cGy dose level. All 12 patients in the first 3 dose cohorts experienced responses and response durations equal to, or in the majority of cases, superior to that seen with their previous chemotherapy regimen. Data on all 16 patients including 120 cGy dose level will be available at the time of presentation. In conclusion, this fractionated RIT protocol is feasible, efficacious and enables larger WBD doses to be safely delivered than has previously been achieved with non-myeloablative RIT.