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

Gregory A. Wiseman, Christine A. White, Richard B. Sparks, William D. Erwin, Donald A. Podoloff, Dominick Lamonica, Nancy L. Bartlett, J. Anthony Parker, William L. Dunn, Stewart M. Spies, Richard Belanger, Thomas E. Witzig, Bryan R. Leigh

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162 Scopus citations

Abstract

Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90YZevalin™ (90yttrium 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 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan®, MabThera®) 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 90Y 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) 111In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m2 rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of 111In 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/m2 weekly×4). Results: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For 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: 234-1856 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 90Y in blood, or radiation absorbed dose to the red marrow or total body. Conclusion: 90Y 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 90Y Zevalin in this defined patient population without pre-treatment 111In-based radiation dosimetry.

Original languageEnglish (US)
Pages (from-to)181-194
Number of pages14
JournalCritical Reviews in Oncology/Hematology
Volume39
Issue number1-2
DOIs
StatePublished - Jul 4 2001

Keywords

  • Dosimetry
  • IDEC-Y2B8
  • Non-Hodgkin's lymphoma
  • Radioimmunotherapy
  • Rituximab
  • Y Zevalin

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Wiseman, G. A., White, C. A., Sparks, R. B., Erwin, W. D., Podoloff, D. A., Lamonica, D., Bartlett, N. L., Anthony Parker, J., Dunn, W. L., Spies, S. M., Belanger, R., Witzig, T. E., & Leigh, B. R. (2001). 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. Critical Reviews in Oncology/Hematology, 39(1-2), 181-194. https://doi.org/10.1016/S1040-8428(01)00107-X