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.

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.

Full text

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ORIGINAL ARTICLE
Biodistribution, radiation dosimetry and scouting
of90Y-ibritumomab tiuxetan therapy in patients
with relapsed B-cell non-Hodgkin’s lymphoma
using89Zr-ibritumomab tiuxetan and PET
Saiyada N. F. Rizvi & Otto J. Visser &
Maria J. W. D. Vosjan & Arthur van Lingen &
Otto S. Hoekstra & Josée M. Zijlstra &
Peter C. Huijgens & Guus A. M. S. van Dongen &
Mark Lubberink
Received: 12 August 2011 /Accepted: 15 November 2011 /Published online: 5 January 2012
#The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
Purpose Positron emission tomography (PET) with
ibritumomab tiuxetan can be used to monitor biodistribution
of90Y-ibritumomab tiuxetan as shown in mice. The aim of
this study was to assess biodistribution and radiation dosim-
etry of90Y-ibritumomab tiuxetan in humans on the basis
of
whether co-injection of a therapeutic amount of90Y-ibritumo-
mab tiuxetan influences biodistribution of89Zr-ibritumomab
89Zr-
89Zr-ibritumomab tiuxetan imaging, to evaluate
tiuxetan and whether pre-therapy scout scans with89Zr-ibri-
tumomab tiuxetan can be used to predict biodistribution
of90Y-ibritumomab tiuxetan and the dose-limiting organ
during therapy.
Methods Seven patients with relapsed B-cell non-Hodgkin’s
lymphoma scheduled for autologous stem cell transplanta-
tion underwent PET scans at 1, 72 and 144 h after injection
of ~70 MBq89Zr-ibritumomab tiuxetan and again 2 weeks
later after co-injection of 15 MBq/kg or 30 MBq/kg90Y-
ibritumomab tiuxetan. Volumes of interest were drawn over
liver, kidneys, lungs, spleen and tumours. Ibritumomab tiux-
etan 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.
Results The highest
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 on89Zr-ibritumo-
mab tiuxetanimageswashigh(Pearsoncorrelationcoefficient
r00.97). No significant difference between pre-therapy and
therapytumourabsorbeddoseswasfound,butcorrelationwas
lower (r00.75).
Conclusion Biodistribution of89Zr-ibritumomab tiuxetan is
not influenced by simultaneous therapy with90Y-ibritumo-
mab tiuxetan, and89Zr-ibritumomab tiuxetan scout scans
can thus be used to predict biodistribution and dose-
limiting organ during therapy. Absorbed doses to spleen
90Y absorbed dose was observed in
Saiyada N.F. Rizvi and Otto J. Visser contributed equally to this work.
S. N. F. Rizvi (*):A. van Lingen:O. S. Hoekstra:
M. Lubberink
Department of Nuclear Medicine and PET Research,
VU University Medical Center,
PO Box 7057, De Boelelaan 1117,
1007 MB Amsterdam, The Netherlands
e-mail: snf.rizvi@vumc.nl
O. J. Visser:J. M. Zijlstra:P. C. Huijgens
Department of Haematology, VU University Medical Center,
De Boelelaan 1117,
1007 MB Amsterdam, The Netherlands
M. J. W. D. Vosjan:G. A. M. S. van Dongen
Department of Otolaryngology and Head and Neck Surgery,
VU University Medical Center,
De Boelelaan 1117,
1007 MB Amsterdam, The Netherlands
M. Lubberink
Department of Nuclear Medicine & PET, Uppsala University,
and Medical Physics, Uppsala University Hospital,
751 85 Uppsala, Sweden
Eur J Nucl Med Mol Imaging (2012) 39:512–520
DOI 10.1007/s00259-011-2008-5

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were lower than those previously estimated using
ibritumomab tiuxetan. The dose-limiting organ in patients
undergoing stem cell transplantation is the liver.
111In-
Keywords Immuno-PET.Molecularimaging.
Radioimmunotherapy.Ibritumomabtiuxetan.89Zr.90Y.
Dosimetry.Lymphoma
Introduction
Non-Hodgkin’s lymphomas (NHL) account for 3% of all
cancers worldwide [1]. Not all patients are cured with stan-
dard induction treatment [2]. For patients with aggressive,
relapsed or progressive disease after first-line (immuno-)
chemotherapy, a second-line regimen consisting of reinduc-
tion chemotherapy and consolidation with high-dose che-
motherapy (carmustine, etoposide, cytarabine, melphalan;
BEAM) followed by autologous stem cell transplantation
(auSCT) is standard therapy with curative intent. A signif-
icant number of these patients will not be able to meet
response criteria before transplantation or will relapse after
transplantation [3]. The addition of anti-CD20 monoclonal
antibodies (mAb) has substantially improved response rates
and overall survival [4–6]. The90Y-labelled anti-CD20 mAb
ibritumomab tiuxetan (Zevalin®) is approved for treatment
of patients with relapsed and refractory NHL. In recent
studies, radioimmunotherapy (RIT) was integrated into
upfront treatment in indolent NHL [7] or added to high-
dose chemotherapy followed by auSCT, showing significant
benefit [8, 9]. In standard treatment, the maximum amount
of90Y-ibritumomab tiuxetan given to patients is 15 MBq/kg
with a maximum of 1.2 GBq [10]. The dose-limiting toxic-
ity of RIT is myelosuppression. The effect of myelosuppres-
sion is prevented in auSCT with stem cell support. In
general, higher external radiation doses are associated with
improved clinical outcomes [11, 12]. To optimize therapeutic
amounts of activity in individual patients, one needs to know
the biodistribution of90Y-ibritumomab tiuxetan and the effec-
tive dose to dose-limiting organs.
Biodistribution studies with111In-ibritumomab tiuxetan
and131I-ibritumomab tiuxetan in humans have been pub-
lished [e.g. 13, 14]. These studies were performed using
gamma cameras, which complicates quantification. Label-
ling of ibritumomab tiuxetan with the positron-emitting
isotope
biodistribution of ibritumomab tiuxetan with positron emis-
sion tomography (PET). Perk et al. [15] used N-succinyl-
desferal for coupling of89Zr to ibritumomab tiuxetan and
showed that89Zr-ibritumomab tiuxetan has a nearly identical
biodistribution compared with90Y-ibritumomab tiuxetan in
mice, which allows for assessment of biodistribution of90Y-
ibritumomab tiuxetan using89Zr-ibritumomab tiuxetan and
89Zr allows for better quantitative assessment of
PET. Ascoutscanprocedure using89Zr-ibritumomabtiuxetan
to assess biodistribution of ibritumomab tiuxetan prior to
therapy can then aid in selection of patients that can benefit
from a potentially toxic therapeutic amount of90Y-ibritumo-
mab tiuxetan, as well as in optimizing the administered
amount of90Y-ibritumomab tiuxetan in the individual patient.
However, eventhough89Zr-ibritumomab tiuxetanis represen-
tative of90Y-ibritumomab tiuxetan, a scout scan procedure
with89Zr-ibritumomab tiuxetan for this purpose is only valid
when biodistribution during scout scan and therapy are
similar, that is not dependent on the administered amount of
labelled antibody.
The aim of this clinical, prospective study was to assess
biodistribution and radiation dosimetry of90Y-ibritumomab
tiuxetan in humans using89Zr-ibritumomab tiuxetan and to
investigate whether pre-therapy scout scans with89Zr-ibri-
tumomab tiuxetan can be used to predict biodistribution
during therapy, that is whether a co-injection of a therapeutic
amount of90Y-ibritumomab tiuxetan influences biodistribu-
tion of89Zr-ibritumomab tiuxetan. A secondary aim was to
determine the dose-limiting organ for therapy with
ibritumomab tiuxetan, in order to enable dose escalation
and/or optimization with
patients undergoing auSCT.
90Y-
90Y-ibritumomab tiuxetan in
Materials and methods
Patients
Seven patients with relapsed or refractory aggressive B-cell
(CD20-positive) NHL, who did not qualify for standard
auSCT and were younger than 66, were included. All
patients had previously been treated in first line with R-
CHOP (cyclophosphamide, doxorubicin hydrochloride, vin-
cristine and prednisolone, combined with rituximab).
Second-line chemotherapy consisted of R-DHAP (cisplatin,
cytarabine, dexamethasone combined with rituximab), R-
VIM (etoposide, ifosfamide, methotrexate, combined with
rituximab) and R-DHAP, which did not lead to at least
partial remission as monitored by18F-fluorodeoxyglucose
(FDG) PET.
All patients had a WHO performance status of 0–2.
Exclusion criteria were history of intolerance to exogenous
protein administration, severe cardiac dysfunction [New
York Heart Association (NYHA) functional classification
class II–IV], severe pulmonary dysfunction (vital capacity
or diffusion capacity<70%), unless clearly related to NHL
involvement, hepatic dysfunction, bilirubin or transami-
nase≥2.5 times the upper normal limit, renal dysfunction
(serum creatinine≥180 μmol/l or clearance≤40 ml/min),
prior treatment with radiation therapy, uncontrolled infec-
tions, human immunodeficiency virus (HIV) positive and
Eur J Nucl Med Mol Imaging (2012) 39:512–520 513

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NHL localization in the central nervous system. The study
was approved by the Medical Ethics Committee of the VU
University Medical Center and all patients signed a written
informed consent prior to inclusion.
Synthesis of89Zr-ibritumomab tiuxetan
and90Y-ibritumomab tiuxetan
Ibritumomab tiuxetan was obtained from Bayer Schering
AG (Berlin, Germany).
half-life T1/2064.1 h) was obtained from IBA (Louvain-la-
Neuve, Belgium) and90Y-ibritumomab tiuxetan was pre-
pared according to instructions of the supplier.
(≥0.15 GBq nmol−1, T1/2078.5 h) was produced in-house
by a (p,n) reaction on natural89Y and isolated with the use
of a hydroxamate column [16]. Methods for radiolabelling
were used as described previously [15].89Zr-ibritumomab
tiuxetan conjugates were analysed by instant thin-layer
chromatography (ITLC) for radiochemical purity, and by a
cell binding assay for immunoreactivity, as described before
[16]. Endotoxin levels were assessed by use of a limulus
amebocyte lysate (LAL) test system licensed by the US
Food and Drug Administration (FDA) according to the
instructions provided by the supplier (Endosafe®-PTS,
Charles River Laboratories, Wilmington, MA, USA).
These procedures resulted in a sterile final product with
endotoxin levels<5 EU/ml. The radiochemical purity
was always >97% (mean 97.4±1.5%). The immunore-
active fraction of89Zr-ibritumomab tiuxetan preparations
ranged from 72 to 81% (mean 75.0±3.2%).
90Y (18.5 GBq/ml, radioactive
89Zr
Scan protocol
Patients received standard treatment with 250 mg/m2Rituxan
1 week before and on the same day prior to both90Y- and/or
89Zr-ibritumomab tiuxetan administrations. They received ap-
proximately 68±11 MBq89Zr-ibritumomab tiuxetan 31 days
before stem cell transplantation (Table 1) followed by three
PET scans at 1, 72 and 144 h post-injection (p.i.) covering
skull base to femur. Blood samples were drawn at 5, 10,
30minand1,2,72and144hp.i.formeasurementofabsolute
radioactivity concentrations in whole blood and plasma. In
fourpatients,thiswasfollowed14dayslaterby15MBq/kgor
30MBq/kgof90Y-ibritumomabtiuxetan,eachintwopatients,
with a co-injection of 69±6 MBq89Zr-ibritumomab tiuxetan,
againfollowedbythesamePETandblood samplingprotocol.
The first two patients were treated in hospital; therefore, all
urine during the first 72 h after injection was collected and
radioactivity in urine was measured. Patients 3 to 7 were
treated in our outpatient department, until high-dose chemo-
therapy started 7 days before stem cell transplantation.
PET scans were made on a dedicated full ring ECAT
EXACT HR+ (CTI/Siemens, Knoxville, TN, USA) PET
camera in 3-D acquisition mode. Whole-body scans con-
sisted of 7-min emission and 3-min transmission scans per
bed position. Data were normalized and corrected for ran-
doms, scatter, attenuation and decay. Attenuation correction
was based on a transmission scan with rotating68Ge rod
sources. Images were reconstructed to 128×128 pixels with
dimensions 5.15×5.15×2.43 mm using an attenuation- and
normalization-weighted ordered subsets expectation maxi-
mization (NAW-OSEM) algorithm with 2 iterations with 16
subsets, followed by post-smoothing of the reconstructed
image using a 5-mm full-width at half-maximum Gaussian
filter. This resulted in images with a spatial resolution of
about 7 mm. Quantitative accuracy of89Zr PET scans was
previously confirmed using phantom studies and compari-
sons between PET-derived and sampled blood radioactivity
concentrations, as well as between PET-derived and biopsy
tumour radioactivity concentrations [17].
Volume of interest definition
The activity, percentage injected dose (%ID) and standard-
ized uptake value (SUV) normalized to body mass in all
organs that could be distinguished from background (lung,
liver, spleen and kidneys) were determined using the mean
activity concentration in volumes of interest (VOI) drawn
over the entire organs using software developed in-house
[18]. The activity in tumours was defined by drawing a 50%
Table 1 Patient characteristics
No.Sex AgeWeight (kg)
89Zr
89Zr+90Y
89Zr scan 1 (MBq)
89Zr scan 2 (MBq)
90Y (MBq)
1
2
3
4
5
6
7
F
F
M
M
M
M
F
50
50
43
61
46
64
37
84
90
71
78
82
76
82
1, 72, 144
1, 72, 144
1, 72, 144
1, 72, 144
1, 72, 144
72, 144
1, 72
1, 72, 144
1, 72, 144
1, 72, 144
72, 144
49.7
48.0
79.2
74.7
68.4
77.5
75.8
65.5
88.5
77.7
64.8
1,267.7
2,473.40
1,151.3
2,378.8
–
–
–
514 Eur J Nucl Med Mol Imaging (2012) 39:512–520

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isocontour VOI. VOIs were drawn separately on all PET
scans available for each patient. VOIs were drawn indepen-
dently over each acquired PET image.
Dosimetry
For calculation of90Y residence times and absorbed doses,
organ and tumour radioactivity were corrected for
decay, i.e. multiplied by exp(ln(2)t/78.4), with t the time
since injection and 78.4 the radioactive half-life of89Zr in
hours, and then uncorrected for decay applying the radioac-
tive half-life of
with the 64.1 h half-life of90Y. Residence times for89Zr-
and
under the curve of the organ time-activity data determined
by piecewise exponential fitting and assuming only physical
decay after the last measurement, divided by the amount of
injected activity. Residence time for the red marrow was
estimated by assuming a red marrow radioactivity concen-
tration of 30% of the whole blood activity concentration
[19]. The residence time of the remainder of the body was
calculated as the maximum possible residence time [the
radioactive half-life of the tracer divided by ln(2)] mi-
nus the sum of residence time of source organs includ-
ing red marrow, assuming no excretion during the time
course of the scans. Tumour absorbed doses were esti-
mated assuming local deposition of all radiation emitted
by
activity curves was estimated using a single exponential
fit to two measured data points at 72 and 144 h p.i. Absorbed
doses were calculated using the OLINDA/EXM 1.0 software
[20].
89Zr
90Y, i.e. multiplied by exp(−ln(2)t/64.1),
90Y-labelled antibodies were calculated as the area
90Y. The area under the curve of the tumour time-
Statistical analysis
Total
tumours during the scout procedure and during treatment
were compared using regression analysis.
89Zr-ibritumomab tiuxetan uptake in organs and
Results
Patient characteristics are shown in Table 1. All patients
tolerated89Zr-ibritumomab tiuxetan well, with no adverse
reactions noted. Three patients underwent all scans both
prior to and during therapy. Two patients (1 and 3) received
standard therapy activity of90Y-ibritumomab tiuxetan and
two patients (2 and 4) were treated with a higher
ibritumomab tiuxetan activity. Three patients (5–7) did not
receive the co-injection of89Zr- and90Y-ibritumomab tiux-
etan because of logistical problems. One patient (7) had to
be excluded from further analysis because he did not under-
go a third PETscan (144 h p.i.) because of scanner problems.
In total, data from six patients could be used to assess biodis-
tribution of89Zr-ibritumomab tiuxetan at 72 and 144 h p.i.
Calculation of residence times in the first three patients, both
with and without the 1-h p.i. scans, revealed no significant
differences due to exclusion of the first scan (Pearson corre-
lation coefficient r00.99, linear regression with and without
1-hp.i.datapoint).Therefore,dosimetrydataofpatients4and
6 were included in the analysis and data from four patients
could be used to compare biodistribution of89Zr-ibritu-
momab tiuxetan prior to and during therapy.
Images at 1 h p.i. showed mainly blood pool activity and
activity in heart, liver, spleen, bone marrow and kidneys. No
activity was seen at tumour sites. The images at 72 and
144 h p.i. showed increasing activity on tumour sites and
decreasing activity in source organs (Fig. 1). Negligible
amounts of activity (<1% of administered activity) were
found in urine.
Figure 2 shows SUV as a function of time for all source
organs. As shown in Fig. 3, a strong correlation between
estimated absorbed doses in different organs with89Zr-ibri-
tumomab tiuxetan without
89Zr-ibritumomab tiuxetan with90Y-ibritumomab tiuxetan
was found (r00.97). The highest mean90Y absorbed dose
as calculated from the89Zr-ibritumomab tiuxetan biodistri-
bution was seen in the liver with 3.2±1.8 mGy/MBq (range
1.8–6.6 mGy/MBq, Table 2). However, absorbed dose to the
spleen (2.9±0.7 mGy/MBq, range 1.8–3.8 mGy/MBq) was,
90Y-
90Y-ibritumomab tiuxetan and
Fig. 1 Typical coronal section
89Zr-ibritumomab tiuxetan
images at 1, 72 and 144 h p.i.
Arrows indicate tumour
localizations
Eur J Nucl Med Mol Imaging (2012) 39:512–520515

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although marginally, higher in five of six patients. The
effective dose was 0.87±0.14 mSv/MBq. Table 3 shows
effective half-lives of90Y-ibritumomab tiuxetan for the 1–
72 and 72–144 h intervals. As expected, no effect of the
higher treatment activity of90Y-ibritumomab tiuxetan on the
biodistribution in two of the four patients was seen, although
this could not be tested statistically due to the small patient
groups.
Tumour absorbed dose estimates were made for the 4
patients that underwent
both prior to and during therapy with
tiuxetan, with 13 tumour localizations in total. The average
size of the lesion VOIs was 3.3 cm3(range 0.8–11.3 cm3).
Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq
(mean 14.9 mGy/MBq). Figure 4 shows estimated tumour
89Zr-ibritumomab tiuxetan scans
90Y-ibritumomab
absorbed doses. Correlation between absorbed doses esti-
mated using a scout scan and during therapy was moderate
(r00.75), with no significant differences between baseline
and therapy absorbed dose estimates (p00.09, two-tailed
paired t test).
Figure 5 shows the correlation between SUV of89Zr-
ibritumomab tiuxetan and absorbed dose of90Y-ibritumo-
mab tiuxetan in the liver. Correlation was high for SUV at
72 h p.i. as well as 144 h p.i. (both r00.99), with a nearly
identical relationship between SUV and absorbed dose for
both time points (slope 0.50 and 0.49 mGy⋅MBq−1⋅SUV−1;
intercept 0.85 and 0.89 mGy/MBq, respectively).
Discussion
To our knowledge, this is the first study describing the
biodistribution and radiation dosimetry of90Y-ibritumomab
tiuxetan therapy as assessed by89Zr-ibritumomab tiuxetan
PET. All prior studies aiming to estimate90Y-ibritumomab
tiuxetan absorbed doses were performed using111In-ibritu-
momab tiuxetan and single photon imaging. The advantage
of using a positron-emitting isotope is that PET is inherently
quantitative, whereas quantification with, especially planar,
gamma camera imaging involves considerable uncertainties
that can often surpass estimated activity concentrations
themselves. Comparison of measured trues and random
count rates as measured during scout scans and during scans
with both89Zr and therapeutic amounts of90Y showed that
the presence of90Y had no effect on PET count rates and
hence did not influence quantitative accuracy.
Although the results of the present work are generally
consistent with previous studies using
tiuxetan, there are a few important differences. The highest
absorbed dose in the current work was found for the liver
(3.2±1.8 mGy/MBq, range 1.5–6.6 mGy/MBq) and the
spleen (2.9±0.7 mGy/MBq, range 1.8–3.6 mGy/MBq).
Wiseman et al. [13], using111In-ibritumomab tiuxetan in a
study population of follicular lymphomas and transformed
B-cell NHL, found the highest absorbed dose in the spleen
with a median absorbed dose of 7.30 mGy/MBq with a
range of 3.50–26.0 mGy/MBq followed by liver (4.60,
range 2.20–11.0 mGy/MBq), lungs (1.90 mGy/MBq, range
1.30–4.30 mGy/MBq), red marrow (0.65 mGy/MBq, range
0.26–1.10 mGy/MBq) and kidneys (0.20 mGy/MBq, range
(0.01–0.65 mGy/MBq). Although Fisher et al. [14], with a
study population of low- and intermediate-grade NHL,
found an absorbed dose to the spleen of 4.7±2.3 mGy/
MBq, closer to the results in the current study, the spleen
was the organ with the highest absorbed dose, followed by
liver (3.6±1.4 mGy/MBq), red marrow (2.7±0.9 mGy/
MBq), kidneys (2.4±0.6 mGy/MBq) and lungs (0.8±
0.8 mGy/MBq). Shen et al. [21], using111In-ibritumomab
111In-ibritumomab
Fig. 2
liver, spleen, lung, kidneys and blood (mean ± SD, n06)
89Zr-ibritumomab tiuxetan SUV versus time after injection in
Fig. 3 Absorbed organ doses estimated using a scout scan with89Zr-
ibritumomab tiuxetan prior to therapy versus those estimated using a
simultaneous administration of
ibritumomab tiuxetan. The solid line is the line of identity
89Zr-ibritumomab tiuxetan and
90Y-
516Eur J Nucl Med Mol Imaging (2012) 39:512–520

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tiuxetan as well, also found the spleen to be the organ
receiving the highest absorbed dose with a median absorbed
dose of 6.1 mGy/MBq (range 1.8–17.8 mGy/MBq).
Absorbed dose estimates from all publications referred to
above and from the Zevalin package insert are summarized
in Table 4. The doses from the Zevalin package insert were
estimated with111In-Zevalin. In this study, the spleen is the
organ with the highest absorbed dose as well, at 9.4 mGy/
MBq (range 1.8–20.0 mGy/MBq). Shen et al. (study popu-
lation of follicular or transformed CD20-positive B-cell
NHL) administered
without additional treatment with rituximab and found no
difference in absorbed radiation dose before and during
treatment except in the spleen where a significant decrease
of residence time was found. They also analysed the
tumour absorbed dose which was consistent with our
data with a median absorbed dose of 18.1 mGy/MBq
(range 4.7–98.9 mGy/MBq). Shen et al. showed a de-
crease in residence timeandvolumeofthespleenafterlong-
term rituximab treatment compared to a single dose of
rituximab before111In/90Y-ibritumomab tiuxetan. This could
also apply to our study population and explain the difference
from the four other studies where a single dose of rituximab
was given prior to ibritumomab tiuxetan therapy. This
111In-ibritumomab tiuxetan with and
observation is also in agreement with the study of Illidge et
al. [22].
Differences in biodistribution between111In-mAb and90Y-
mAbconjugateshavebeenobservedbeforeinvivointumour-
bearing mice and in cancer patients [23–25]. Perk et al. [26]
showed in their study that biodistribution of89Zr-Df-cetuxi-
mab and88Y-DOTA-cetuximab (88Yas a substitute for90Y) is
comparableforallobservedorgans,exceptdifferencesinbone
accumulation (sternum and thigh bone). What is more, the
same was shown for89Zr-ibritumomab tiuxetan and90Y-ibri-
tumomab tiuxetan in NHL-bearing mice [15]. Therefore, we
can state that89Zr-ibritumomab tiuxetan absorbed doses in
liver and spleen are representative for90Y-ibritumomab tiux-
etan. Furthermore, the discrepancy between111In-ibritumo-
mab tiuxetan and89Zr-ibritumomab tiuxetan uptake in liver
and especially spleen has been described before when com-
paring111In-DTPA-octreotide and86Y-DOTA-octreotide as
Table 2
89Zr-ibritumomab tiuxetan (n06)
89Zr-ibritumomab tiuxetan and90Y-ibritumomab tiuxetan organ residence times and absorbed doses as estimated using a scout scan with
89Zr-ibritumomab tiuxetan
90Y-ibritumomab tiuxetan
Residence time
Mean ± SD (h)
Absorbed dose
Mean ± SD (mGy/MBq)
Residence time
Mean ± SD (h)
Absorbed dose
Mean ± SD (range) (mGy/MBq)
Liver
Spleen
Kidney
Lung
Red marrow
Remaindera
Effective dose (mSv/MBq)
11.6±4.8
1.08±0.31
0.93±0.22
2.83±0.55
0.59±0.22
96±5
1.36±0.58
1.04±0.16
0.754±0.062
0.63±0.11
0.460±0.047
9.9±4.1
0.95±0.26
0.81±0.19
2.54±0.48
0.48±0.10
78±4
3.2±1.8 (1.5–6.6)
2.88±0.67 (1.83–3.83)
1.46±0.31 (0.99–1.88)
1.47±0.34 (1.07–1.82)
0.520±0.041 (0.485–0.581)
0.55±0.07 0.87±0.14
aBased on maximum residence time minus sum of source organ residence times
Table 3 Mean (± SD) effective half-life of90Y-ibritumomab tiuxetan
as estimated using a scout scan with89Zr-ibritumomab tiuxetan (1–
72 h: n05; 72–144 h: n06)
Effective half-life (h)
1–72 h p.i.72–144 h p.i.
Liver
Spleen
Kidney
Lung
Blood
185±124
43±15
57±22
32±6
42±9
74±8
54±6
51±15
42±9
66±20
Fig. 4 Absorbed tumour doses estimated using a scout scan with89Zr-
ibritumomab tiuxetan prior to therapy versus those estimated using a
simultaneous administration of
ibritumomab tiuxetan. The solid line is the line of identity
89Zr-ibritumomab tiuxetan and
90Y-
Eur J Nucl Med Mol Imaging (2012) 39:512–520517

Page 7

analogues of90Y-DOTA-octreotide [27]. In this study111In-
DTPA-octreotidewasshowntooverestimateabsorbeddosein
kidneysandspleen,whereasabsorbeddosetoliverwasunder-
estimated in comparison to86Y-DOTA-octreotide.
The effective dose found in the present study was gener-
ally higher than found in previous studies using111In-ibri-
tumomab tiuxetan (0.87±0.14 mSv/MBq compared to~
0.5 mSv/MBq). The remainder of the body residence times
were based on the assumption of no excretion of radioactiv-
ity, which is likely to lead to conservative effective dose
estimates in the current study. Using whole-body VOIs
instead, which in the present work would not include the
legs, would have resulted in somewhat lower effective doses
(mean 0.72 mSv/MBq). However, because the energy of the
radiation emitted by90Y is deposited within the same organ
only, this does not affect90Y-ibritumomab tiuxetan organ
absorbed doses.
Red marrow and liver absorbed doses were 26 and 9% of
the threshold for nonstochastic effects (2 and 35 Gy, respec-
tively) [28]. Since the liver is the dose-limiting organ in
patients undergoing auSCT, this implies that a considerably
higher amount than 30 MBq/kg can be given to these
patients without resulting in deterministic effects. Clinically,
no significant abnormalities were seen and no significant
decreases of liver function or liver function abnormalities
were seen in this particular group of patients. Use of blood
data to estimate marrow absorbed doses may underestimate
dosimetry results if there is any interaction of the targeting
agent with the bone marrow. However, this is not relevant
for the patient group discussed in the present work, since
patients will undergo auSCT following therapy.
Relative to organ dosimetry, tumour dosimetry shows a
moderate correlation between baseline and therapy scans.
This is most probably due to the small volumes of the
tumours comparing the organ volumes, resulting in in-
creased uncertainty in measurement of radioactivity concen-
trations. Tumour VOIs were drawn as 50% isocontours
independently on each image, as recommended in the Eu-
ropean Association of Nuclear Medicine procedure guide-
lines for tumour imaging with18F-FDG [29]. The size of
these isocontour VOIs is dependent on the statistically un-
certain values for the maximum pixel, and variations in
tumour VOI sizes over time result in variations in partial
volume errors, which further affect the accuracy of absorbed
dose estimates. To minimize these effects, tumour VOIs
could be based on anatomical information (e.g. coregistered
CT or MRI scans, preferably acquired using PET/CT or
PET/MRI scanners), and partial volume corrections could
be applied based on the anatomical information. Since the
data in the present study were acquired on a stand-alone
PET scanner, VOIs could not be drawn on coregistered CT
images and no attempts to further improve the quantitative
accuracy of tumour measurements were made. In addition,
the limited number of data points and resulting uncertainty
in tumour uptake, especially during the first 24–48 h after
injection, may contribute to the low tumour dose correlation.
As Fig. 5 shows, SUV of89Zr-ibritumomab tiuxetan at
either 72 or 144 h p.i. may be a good predictor of the
absorbed radiation dose to the liver during90Y-ibritumomab
tiuxetan therapy, although this should be confirmed in a
larger study. Therefore, a single PET scan of the liver at 3
or 6 days after injection of89Zr-ibritumomab tiuxetan could
be sufficient to estimate the maximum amount of90Y-ibri-
tumomab tiuxetan that can be administered to an individual
patient who will also undergo auSCT. This strategy will lead
Fig. 5 Absorbed90Y dose to the liver, based on scout scans with89Zr-
ibritumomab tiuxetan, versus SUVof89Zr-ibritumomab tiuxetan at 72
and 144 h p.i. The solid lines represent linear fits to the data
Table 4 Comparison of median absorbed doses of90Y-ibritumomab tiuxetan for selected organs in mGy/MBq in different studies
Liver SpleenKidneyLung Red marrow Whole body
(mSv/MBq)
Current study
Wiseman et al. [13]
Fisher et al. [14]
Shen et al. [21]
90Y-Zevalin®
3.2 (1.5–6.6)
4.60 (2.20–11.0)
3.1 (2.3–6.6)
3.66 (2.11–11.62)
4.8 (2.9–8.1)
2.9 (1.8–3.6)
7.30 (3.50–26.0)
4.3 (0.98–9.0)
6.14 (1.82–17.76)
9.4 (1.8–20.0)
1.46 (0.99–1.88)
0.20 (<0.01–0.65)
2.4 (1.4–3.9)
3.31 (1.95–4.65)
0.1 (0.0–0.3)
1.47 (1.07–1.82)
1.90 (1.30–4.30)
0.60 (0.31–1.6)
1.10 (0.41–2.31)
2.0 (1.2–3.4)
0.52 (0.49–0.58)
0.65 (0.26–1.10)
2.4 (1.7–4.5)
0.79 (0.32–1.22)
1.3 (0.6–1.8)
0.87 (0.70–1.06)
0.54 (0.46–0.78)
0.55 (0.44–0.81)
0.48 (0.24–0.86)
0.5 (0.4–.07)
518 Eur J Nucl Med Mol Imaging (2012) 39:512–520

Page 8

to a therapy increasingly tailored to the individual patient.
Although the present protocol requires administration of
Rituxan prior to the pretreatment scan as well, this has
limited influence on clinical feasibility since this is part of
the routine treatment of the present patient group. Poor
uptake in the tumour at the pre-therapy scan cannot be a
reason to exclude patients from receiving this therapy. In
tumour, not only the effect of RIT is important, but also the
effect of Rituxan. Additional studies are needed for im-
proved assessment of tumour dosimetry.
Conclusion
Biodistributionof89Zr-ibritumomabtiuxetanisnotinfluenced
by simultaneous therapy with90Y-ibritumomab tiuxetan.
Therefore, a pre-therapy scan with89Zr-ibritumomab tiuxetan
can be used to accurately predict radiation dosimetry during
treatment with90Y-ibritumomab tiuxetan. Absorbed doses to
the spleen were lower than those previously estimated
using
gan in patients undergoing stem cell transplantation is
the liver. In the future, a single89Zr-ibritumomab tiuxetan
PET scan may be sufficient to optimize the administered
amount of90Y-ibritumomab tiuxetan RIT in the individual
patient when combined with auSCT.
111In-ibritumomab tiuxetan. The dose-limiting or-
Acknowledgement
Nuclear Medicine & PET Research for their assistance in performing
the PET scans.
The authors thank the staff at the Department of
Conflicts of interest
None.
Open Access
tive Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
This article is distributed under the terms of the Crea-
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