Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using 89Zr-ibritumomab tiuxetan and PET

Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands.
European Journal of Nuclear Medicine (Impact Factor: 4.53). 01/2012; 39(3):512-20. DOI: 10.1007/s00259-011-2008-5
Source: PubMed

ABSTRACT Positron emission tomography (PET) with (89)Zr-ibritumomab tiuxetan can be used to monitor biodistribution of (90)Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of (90)Y-ibritumomab tiuxetan in humans on the basis of (89)Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of (90)Y-ibritumomab tiuxetan influences biodistribution of (89)Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with (89)Zr-ibritumomab tiuxetan can be used to predict biodistribution of (90)Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.
Seven patients with relapsed B-cell non-Hodgkin's lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq (89)Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg (90)Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data.
The highest (90)Y absorbed dose was observed in liver (3.2 ± 1.8 mGy/MBq) and spleen (2.9 ± 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 ± 0.04 mGy/MBq, and the effective dose was 0.87 ± 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on (89)Zr-ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75).
Biodistribution of (89)Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with (90)Y-ibritumomab tiuxetan, and (89)Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using (111)In-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.

  • [Show abstract] [Hide abstract]
    ABSTRACT: PET/CT imaging allows for image based estimates of organ and red marrow (RM) residence times. The aim of this study was to derive PET/CT based radiation dosimetry for (89)Zr-cetuximab with special emphasis on determining RM absorbed dose. Seven patients with colorectal cancer received 36.9 ± 0.8 MBq (89)Zr-cetuximab within 2 hours after administration of a therapeutical dose of 500 mg•m(-2) cetuximab. Whole body PET/CT scans as well as blood samples were obtained 1, 24, 48, 94 and 144 hours post injection. RM activity concentrations were calculated from manual delineation of the lumbar vertebrae and blood samples assuming a fixed red marrow to plasma activity concentration ratio (RMPR) of 0.19 The cumulated activity was calculated as the area under the curve of the organ time-activity data (liver, lungs, kidneys, spleen and red marrow), assuming physical decay after the last scan. The residence time for each organ was derived by dividing the cumulated activity with the total injected activity. The residence time in the remainder of the body was calculated as the maximum possible residence time minus the sum of residence time of source organs, assuming no excretion during the time course of the scans. The (self and total) RM and organ absorbed doses as well as the effective whole body radiation dose were obtained using dose conversion factors from OLINDA/EXM 1.1. Several simplified three time-point dosimetry approaches were also evaluated. Approach a yielded self and total RM doses of 0.17 ± 0.04 and 0.54 ± 0.07 mGy•MBq(-1), respectively. Approach b deviated by -21% in self dose and -6% in total dose. RMPR increased over time in 5 out of 7 patients. The highest (89)Zr absorbed dose was observed in liver with 2.60 ± 0.78 mGy•MBq(-1), followed by kidneys, spleen and lungs, whilst the effective whole body dose was 0.61 ± 0.09 mSv•MBq(-1). The simplified three time-point (1, 48 and 144 hr) dosimetry approach deviated by at most 4% in both organ absorbed doses and effective dose. Although total RM dose estimates obtained with the two approaches only differed by at most 6%, image based approach is preferred, as it accounts for non-constant RMPR. The number of successive scans can be reduced to 3 without affecting effective dose estimates. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasing interest in immuno-positron emission tomography (PET) studies requires development of dosimetry methods which will provide accurate estimations of organ absorbed doses. The purpose of this study is to develop and validate simplified dosimetry approaches for (89)Zirconium-PET (Zr-PET)/computed tomography (CT) studies.
    Medical Physics 10/2014; 41(10):102503. DOI:10.1118/1.4895973 · 3.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antibody-drug conjugates (ADC) have shown promising effects in cancer therapy by combining the target-specificity of an antibody with the toxicity of a chemotherapeutic drug. As the number of therapeutic antibodies is significantly larger than those used as ADCs, there is unused potential for more effective therapies. However, the conjugation of an additional molecule to an antibody may affect the interaction with its target, altering association rate, dissociation rate, or both. Any changes of the binding kinetics can have subsequent effect on the efficacy of the ADCs, thus the kinetics are important to monitor during ADC development and production. This paper describes a method for the analysis of conjugation effects on antibody binding to its antigen, using the instrument LigandTracer and a fluorescent monovalent anti-IgG binder denoted FIBA, which did not affect the interaction. All measurements were done in real-time using living cells which naturally expressed the antigens. With this method the binding profiles of different conjugations of the therapeutic anti-EGFR antibody cetuximab and the anti-CD44v6 antibody fragment AbD15171 were evaluated and compared. Even comparatively small modifications of cetuximab altered the interaction with the epidermal growth factor receptor (EGFR). In contrast, no impact on the AbD15171 - CD44v6 interaction was observed upon conjugation. This illustrates the importance to study the binding profile for each ADC combination, as it is difficult to draw any general conclusion about conjugation effects. The modification of interaction kinetics through conjugation opens up new possibilities when optimizing an antibody or an ADC, since the conjugations can be used to create a binding profile more apt for a specific clinical need.
    Molecular Pharmaceutics 09/2014; 11(11). DOI:10.1021/mp500379d · 4.79 Impact Factor

Full-text (3 Sources)

Available from
May 23, 2014