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 Elmer Witzig, Bryan R. Leigh

Research output: Contribution to journalArticle

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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 - 2001

Fingerprint

Radioimmunotherapy
B-Cell Lymphoma
Non-Hodgkin's Lymphoma
Randomized Controlled Trials
Radiometry
Radiation
Bone Marrow
ibritumomab tiuxetan
Immunotherapy
Half-Life
Software
Population
Whole Body Imaging
Maximum Tolerated Dose
Rituximab

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

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

In: Critical Reviews in Oncology/Hematology, Vol. 39, No. 1-2, 2001, p. 181-194.

Research output: Contribution to journalArticle

Wiseman, Gregory A. ; White, Christine A. ; Sparks, Richard B. ; Erwin, William D. ; Podoloff, Donald A. ; Lamonica, Dominick ; Bartlett, Nancy L. ; Anthony Parker, J. ; Dunn, William L. ; Spies, Stewart M. ; Belanger, Richard ; Witzig, Thomas Elmer ; Leigh, Bryan R. / 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. In: Critical Reviews in Oncology/Hematology. 2001 ; Vol. 39, No. 1-2. pp. 181-194.
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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{\circledR}, MabThera{\circledR}) 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.",
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author = "Wiseman, {Gregory A.} and White, {Christine A.} and Sparks, {Richard B.} and Erwin, {William D.} and Podoloff, {Donald A.} and Dominick Lamonica and Bartlett, {Nancy L.} and {Anthony Parker}, J. and Dunn, {William L.} and Spies, {Stewart M.} and Richard Belanger and Witzig, {Thomas Elmer} and Leigh, {Bryan R.}",
year = "2001",
doi = "10.1016/S1040-8428(01)00107-X",
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TY - JOUR

T1 - 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

AU - Wiseman, Gregory A.

AU - White, Christine A.

AU - Sparks, Richard B.

AU - Erwin, William D.

AU - Podoloff, Donald A.

AU - Lamonica, Dominick

AU - Bartlett, Nancy L.

AU - Anthony Parker, J.

AU - Dunn, William L.

AU - Spies, Stewart M.

AU - Belanger, Richard

AU - Witzig, Thomas Elmer

AU - Leigh, Bryan R.

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Y Zevalin

KW - Dosimetry

KW - IDEC-Y2B8

KW - Non-Hodgkin's lymphoma

KW - Radioimmunotherapy

KW - Rituximab

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