Comparison of Dosimetry and Gamma Camera Methods for Evaluation of Biodistribution Prior to Administration of the Therapeutic Dose of Tositumomab and Iodine I 131 Tositumomab (Bexxar Therapeutic Regimen)

The Bexxar® Therapeutic Regimen for relapsed/refractory follicular lymphoma (FL) is administered in 2 steps: a dosimetric dose and a therapeutic dose. Radioactive counts, obtained from sequential gamma camera scans of the whole body at several time points after the dosimetric dose, determine the patient (pt)-specific clearance (total body residence time, TBRT) and, along with pt body size, allow determination of the prescribed activity (PA) of the therapeutic dose. Pts do not receive the therapeutic dose if TBRT is outside 50 to 150 hrs and/or gamma camera images show altered biodistribution. TBRT is used to calculate the mCi of I-131 (PA) required to deliver the appropriate therapeutic dose of 65 or 75 cGy to the total body, depending on platelet count. Our aims were 1) to evaluate an alternative, inexpensive sodium iodide probe (probe) detector-based method of measuring radioactive counts for determination of TBRT and 2) to evaluate the clinical benefit of visually assessing gamma camera images for altered biodistribution.

We retrospectively compared probe and gamma camera methods from a phase II study (RIT-II-001) and evaluated altered biodistribution assessed by gamma camera images from a post-marketing observational study. Forty-one of 47 FL pts enrolled in RIT-II-001 from December 1995 to November 1996 were included in the retrospective analysis of TBRT and PA. Pts received a median of 5 prior chemotherapies (range 2–13). Thirty of 41 (73%) pts had low-grade B-NHL, 90% had stage III or IV disease, 51% had bone marrow involvement, 88% had an International Prognostic Index score ≥ 2, and 16 of 34 (47%) pts had bulky disease >500 g. Dosimetry analysis was performed at 3 time points (Day 0; Day 2, 3, or 4; and Day 6 or 7) after dosimetric dose, as currently required for determining PA. The PAs of the therapeutic dose using TBRTs derived from probe and gamma camera counts were compared. Also, we retrospectively evaluated cases of altered biodistribution in an observational post-marketing study (BEX114606) of 2,649 pts who received a dosimetric dose from June 2003 to February 2010. Dosimetry and gamma camera images were independently reviewed from reported cases of altered biodistribution to evaluate the clinical benefit of visually assessing gamma camera images.

The mean TBRTs from the clinical study were 94.5 and 95.0 hrs from the probe and gamma camera methods, respectively, and individual TBRTs were highly correlated (r = 0.98). The mean PAs of the therapeutic dose, derived from probe and gamma camera TBRTs, were 85.8 mCi and 85.3 mCi, respectively. The point estimate for the ratio of the PA was 0.995 and the 90% CI (0.984, 1.006) was well within the typical range of 0.80 to 1.25 for demonstrating bioequivalence. The observational study found that only 5 of 2,649 (0.2%) pts did not receive the therapeutic dose due to suspected altered biodistribution. Dosimetry data and gamma camera images were available for 3 pts. Independent review confirmed that all 3 pts had accurately determined TBRTs, but only 1 pt had confirmed altered biodistribution by visual assessment of gamma camera images and TBRTs.

TBRTs derived from probe and gamma camera counts were highly comparable. Thus, the probe and gamma camera methods to determine TBRT and calculate the PA of the therapeutic dose of Bexxar appear equivalent. Altered biodistribution prevented only 5 of 2,649 (0.2%) pts from receiving the therapeutic dose of Bexxar. Only 1 pt (0.04%) was independently confirmed to have altered biodistribution by visual assessment of gamma camera images, consistent with the TBRT. Therefore, visual assessment of gamma camera images added no benefit beyond TBRT in determining whether to administer the therapeutic dose of Bexxar. These data indicate that either sequential probe or gamma camera-based dosimetry is sufficient for determining whether to administer the therapeutic dose, and that visual assessment of gamma camera images does not appear to be necessary to detect the rare instance of an altered biodistribution.

Horner: GlaxoSmithKline: Employment. Off Label Use: The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma. Siegel: GlaxoSmithKline: Consultancy. Jewell: GlaxoSmithKline: Employment. Lunger: GE Healthcare: Employment. Young: GlaxoSmithKline: Employment. Wynne: GlaxoSmithKline: Employment. Williams: GlaxoSmithKline: Employment. Lin: GlaxoSmithKline: Employment. Kaminski: GlaxoSmithKline: Patents & Royalties, Research Funding. Wahl: GlaxoSmithKline: Consultancy, Patents & Royalties; Nihon Medi Physics: Consultancy; Spectrum Pharmaceuticals: Consultancy; Naviscan PET systems: Consultancy; Threshold Pharmaceuticals: Equity Ownership. Vleisides: GlaxoSmithKline: Employment.