Radioimmunotherapy RIT

Two radioimmunoconjugates are currently commercially available; Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar). The clinical trials thus far conducted with radioimmunoconjugates have demonstrated greater activity than their cold antibody, and are useful in patients who have relapsed after or who are refractory to rituximab.

Y-90 ibritumomab tiuexetan Y-90 ibritumomab tiuxe-tan has a murine rituximab conjugated to the iso-tope.80 The Y-90 ibritumomab tiuxetan regimen takes about 8 days to administer. On the first day, a dose of cold rituximab at 250 mg/m2 is administered to bind nontumor CD20 sites and to facilitate better biodistribution. Because Y-90 is a beta emitter, it cannot be used for imaging; thus, indium-111 -labeled ibritu-momab is substituted for biodistribution studies performed at days 2-3, and if needed, 6-7 to ensure appropriate localization of the isotope. On days 7-8, another low dose of cold antibody is delivered followed by 0.4 mCi/kg of Y-90 ibritumomab tiuxetan (not to exceed 32 mCi) for patients with platelet counts of at least 150,000/mm3. The dose is reduced to 0.3 mCi in patients with a platelet count of 100-149,000/mm3.81

In the initial phase I/II trial,82 the overall response rate in 32 patients with follicular/low-grade NHL was 82%, including 26% complete remissions. Response could be predicted by tumor grade, tumor burden, whether or not the bone marrow was involved with lymphoma, and the extent of that bone marrow involvement. The median time to progression was 12.9+ months with a median response duration of 11.7+ months. The major toxicity was myelosuppression, with median granulocyte and platelet nadirs of 1100/mm3 and 49,500/mm3, respectively.

The additive benefit of the radioisotope is supported by the activity of radioimmunotherapy in rit-uximab failures. Y-90 ibritumomab tiuxetan induces responses in 74% of these patients with 15% complete remissions.83 How radioimmunotherapy compares with unconjugated antibody therapy has been addressed in a randomized trial in which 143 patients, with relapsed CD20-positive NHL without previous rituximab exposure, received either ritux-imab or Y-90 ibritumomab tiuxetan.84 Whereas the response rates were higher with Y-90 ibritumomab tiuxetan (80%) than with rituximab (56%), there was no difference between the arms in time to disease progression. Responses to this agent may be quite durable with 24% of responders having a time to progression longer than 3 years and some responses in excess of 5 years.85

I-131 tositumomab I-131 tositumomab is a conjugate of the murine anti-CD20 antibody tositumomab and I-131. It is approved for use in patients with relapsed/refractory follicular or transformed NHL. As with Y-90 ibritumomab tiuxetan, treatment occurs over about a week. Thyroid protection is required with I-131 tositumomab because of the radioactive iodine. I-131 is a gamma emitter, and dosimetry is required to provide patient-specific dosing. In a multicenter pivotal trial,86 65% of the 60 heavily pretreated patients with NHL responded including 20% CR. The response rate in the subset with follicular histologies was 81%. Response rates and response duration were significantly higher than from the last chemotherapy. The response rate has been 63% with 29% complete responses in rituximab-refractory patients.

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