Radiolabeled Antibodies

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Another targeting strategy for NHL has been the use of radioimmunoconjugates. Radiolabeled antibodies are capable of delivering a radiation dose to neighboring cells while minimizing doses to nonmalignant tissues. Low-dose-rate radiation continues to expose cells to radiation even after initial exposure, resulting in accumulation of cell damage leading to apoptosis in cells that may have been effectively repaired after more conventional high-dose-rate radiation.

Two radioimmunoconjugates targeting the CD20 epitope on B cells have been FDA approved for patients with B-cell NHL (Table 68.2). 131I tositumomab (Bexxar) and 90Y-ibritumomab tiuxetan differ in the characteristics of their radioisotope. 90Y-ibritumomab tiuxetan consists of the high-energy fi emitter 90Yttrium

Table 68.2 Radioimmunotherapy in non-Hodgkin's lymphoma

1311 tositumomab

Clinical trial and response rates

Response duration

Kaminski et al.

60 patients with LGL: 81% ORR, 20% CR

6.5 months

Zelenitz et al.

250 patients with LGL: 56% ORR, 30% CR

13.5 months

Kaminski et al.

76 patients with untreated LGL: 95% ORR, 74% CR

62% 5 year PFS6

Coleman et al.

55 patients with rituximab relapsed/refractory disease who had CR

Median not reached at 3.9 years

Y-90 Ibritumomab tiuxetan

Witzig et al.

34 patients Phase I/II study: 82% ORR, 26% CR

12.9 months

Witzig et al.

143 patients randomized to Y-90 Ibritumomab tiuxetan vs rituximab

ORR 80% for Y-90 Ibritumomab, 30% CR

11.2 months

Witzig et al.

57 patients rituximab refractory: 74% ORR, 15% CR

6.8 months

LGL: low-grade lymphoma; CR: complete response; ORR: overall response rate; PFS: progression-free survival.

LGL: low-grade lymphoma; CR: complete response; ORR: overall response rate; PFS: progression-free survival.

and has a half-life of 28 h. Beta particles deliver high energy (2.2 MeV) within a radius of approximately 5 mm, which corresponds to 100-200 cell diameters. 131I tositumomab emits both gamma and beta particles and has a decay half-life of 8 days.20-22

The pivotal trial for 131I tositumomab by Kaminski and colleagues in 2001 was a phase III nonrandomized, multicenter, single dosimetric, and therapeutic dose study in refractory/relapsed low-grade or transformed low-grade B-cell NHL.23 The purpose of this study was to compare the efficacy of 131I tositumomab to the last qualifying chemotherapy regimen. Sixty patients, virtually all with stage III or IV disease, were enrolled. Eighty-eight percent of patients had at least two risk factors by the International Prognostic Index.24 The median number of prior treatments was four, and 27% of patients had prior radiation therapy. The response rate was 65% with a median duration of 6.5 months. The highest responses were seen in patients with small tumor burden (81%), patients who had not received radiotherapy (77%), and those with nontransformed low-grade NHL (81%). The only variables significantly associated with higher rate of response in a multivariate analysis were tumor burden less than 500 g and nontransformed histology.

Adverse events included fatigue (43%), fever (30%), nausea (25%), infection (25%), chills (15%), vomiting (13%), pruritis (13%), anorexia (10%), and hypotension (10%). The hematologic nadir occurred on days 43, 46, and 34 for red cells, white cells, and platelets, and median recovery occurred at 74, 78, and 73 days, respectively. In this study, five patients developed myelodysplastic syndrome 1.2-7.5 years after treatment, but all had previously received alkylating agents.25 Two patients later developed bladder cancer, but both had previously received cyclophosphamide. An elevation of Thyroid stimulating humane (TSH) was noted in five patients, but was asymptomatic in all five.

Further analysis of a combined database from five trials using 131I tositumomab reported a median response duration of 20.2 months in patients with transformed low-grade lymphoma.26 The overall response rate was 56% with a median duration of response of 14.7 months. In previously untreated, advanced-stage follicular lymphoma (n = 76), 131I tositumomab induced a response in 95% of patients, with 74% achieving CR.27 Further analysis of several studies of 131I tositumomab demonstrated "remission inversion," a longer response to radiolabeled antibody than to the last cytotoxic therapy.28 In studies of rituximab-refractory patients, the overall response rate was 68% with 30% CR.29,30 Retreatment with 131I tositumomab has been reported with a 56% response rate to the second dose and a median response duration of 10.7 months. In this population, the annual incidence of myelodysplastic syndrome was 4.1%.31 Combination studies of 131I tositumomab with other agents such as fludarabine32 are underway.

90Y-ibritumomab tiuxetan was FDA approved in the United States at a dose of 0.4 mCi/kg, with a dose reduction to 0.3 mCi/kg in patients with low platelets (100,000-150,000/mL).22 Unlike 131I tositumomab, 90Y-ibritumomab tiuxetan does not require individualized dosimetry. Witzig et al. reported the superiority of 90Y-ibritumomab tiuxetan versus rituximab in 143 patients with CD20-positive relapsed or refractory low-grade, follicular, or transformed NHL who had received a median of two previous chemotherapies and half of whom were refractory to their last ther-apy.33 The response rates of 90Y-ibritumomab tiuxetan versus rituximab were 80% versus 56%, respectively (p = 0.002), and complete responses were seen in 30% versus 14% (p = 0.04), respectively. Overall response favored the follicular lymphoma subgroup with a response rate of 86%. The time to progression estimates were similar at 11.2 months in the 90Y-ibritumomab tiuxetan group and 10.1 months in the rituximab group.

Combined safety data from 349 patients treated on this and four other trials showed the incidence of thrombocytopenia and neutropenia to be 61% and 57%, respectively.33 In this group of patients, 13% received granulocyte colony-stimulating factor, 8% erythropoietin, and 22% and 20%, respectively, platelet and red blood cell transfusions. 90Y-ibritu-momab tiuxetan was approved in 2002 for use in relapsed or refractory low-grade, follicular, or transformed B-cell NHL. A long-term follow-up study has reported a time to progression of 12.6 months and response duration of 11.7 months.34

Other trials have further defined the use of 90Y-ibritumomab tiuxetan in subgroups of patients. A single arm phase II study in rituximab refractory patients reported an overall response rate of 74% and complete response rate of 15%.35 Patients with detectable levels of rituximab in their serum at the time of radiolabeled antibody administration had a lower response rate than those with nondetectable levels. Currently, multiple trials are evaluating the combination of 90Y-ibri-tumomab tiuxetan as an in vivo purge prior to autolo-gous stem cell transplantation. Thirty-one patients treated with 90Y-ibritumomab tiuxetan have subsequently been successfully mobilized for stem cell transplantation with no increased toxicity.36 A phase I study is evaluating sequential treatments of 90Y-ibritu-momab tiuxetan 3-6 months following initial treatment. With the use of prophylactic growth factors, retreatment with lower doses of 90Y-ibritumomab tiux-etan in 15 patients has been safe and well tolerated.20 Finally, investigators are still trying to determine the best time to give radioimmunotherapy. In a retrospective analysis, Emmanouilides et al. reported in a study of patients who received 90Y-ibritumomab tiuxetan as second-line therapy that the response rate and duration were greater than those reported in more heavily pretreated patient populations.37

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