Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin™ radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma

Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with Y-90 Zevalin (TM) ((90)yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of Y-90 Zevalin radioimmunotherapy compared to rituximab (Rituxan (R), MabThera (R)) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to Y-90 Zevalin administration is required for safe treatment in this patient population. Methods: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) In-111 Zevalin ((111)indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) Y-90 Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of In-111 Zevalin, serial anterior and posterior whole-body scans. were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). Results: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. Wr all patients with Zevalin dosimetry data (N = 72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1586 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24 274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of Y-90 in blood, or radiation absorbed dose to the red marrow or total body. Conclusions Y-90 Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of, correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer Y-90 Zevalin in this defined patient population without pre-treatment In-111-based radiation dosimetry. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.