EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with 90Y-radiolabelled ibritumomab tiuxetan (Zevalin).
ABSTRACT BACKGROUND: In January 2004, EMEA approved 90Y-radiolabelled ibritumomab tiuxetan, Zevalin, in Europe for the treatment of adult patients with rituximab-relapsed or -refractory CD20+ follicular B-cell non-Hodgkin's lymphoma. The number of European nuclear medicine departments using Zevalin is continuously increasing, since the therapy is often considered successful. The Therapy, Oncology and Dosimetry Committees have worked together in order to define some EANM guidelines on the use of Zevalin, paying particular attention to the problems related to nuclear medicine. PURPOSE: The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients who may be candidates for radio-immunotherapy. The guideline also stresses the need for close collaboration with the physician(s) treating the patient for the underlying disease.
- SourceAvailable from: Gregory A Wiseman[show abstract] [hide abstract]
ABSTRACT: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data. Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow. Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC. Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.Journal of Nuclear Medicine 03/2003; 44(3):465-74. · 5.77 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkin's lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.Journal of Clinical Oncology 05/1999; 17(4):1244. · 18.04 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Radioimmunotherapy combines biologic and radiolytic mechanisms to target and destroy tumor cells, thus offering a needed therapeutic alternative for refractory non-Hodgkin's lymphoma (NHL) patients. This phase III randomized study compares the novel radioimmunotherapy yttrium-90 ((90)Y) ibritumomab tiuxetan with a control immunotherapy, rituximab, in 143 patients with relapsed or refractory low-grade, follicular, or transformed CD20(+) transformed NHL. Patients received either a single intravenous (IV) dose of (90)Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m(2) IV weekly for four doses (n = 70). The radioimmunotherapy group was pretreated with two rituximab doses (250 mg/m(2)) to improve biodistribution and one dose of indium-111 ibritumomab tiuxetan for imaging and dosimetry. The primary end point, overall response rate (ORR), was assessed by an independent, blinded, lymphoma expert panel. ORR was 80% for the (90)Y ibritumomab tiuxetan group versus 56% for the rituximab group (P =.002). Complete response (CR) rates were 30% and 16% in the (90)Y ibritumomab tiuxetan and rituximab groups, respectively (P =.04). An additional 4% achieved an unconfirmed CR in each group. Kaplan-Meier estimated median duration of response was 14.2 months in the (90)Y ibritumomab tiuxetan group versus 12.1 months in the control group (P =.6), and time to progression was 11.2 versus 10.1 months (P =.173) in all patients. Durable responses of > or = 6 months were 64% versus 47% (P =.030). Reversible myelosuppression was the primary toxicity noted with (90)Y ibritumomab tiuxetan. Radioimmunotherapy with (90)Y ibritumomab tiuxetan is well tolerated and produces statistically and clinically significant higher ORR and CR compared with rituximab alone.Journal of Clinical Oncology 05/2002; 20(10):2453-63. · 18.04 Impact Factor
EANM procedure guideline of radio-immunotherapy for B-cell lymphoma
with 90Y-radiolabeled ibritumomab tiuxetan (Zevalin®)
Jan Tennvall1, Manfred Fischer2, Angelika Bischof Delaloye3, Emilio Bombardieri4, Lisa
Bodei5, Francesco Giammarile6, Michael Lassmann7, Wim Oyen8, Boudewijn Brans9.
1 Department of Oncology, Lund University Hospital, Lund, Sweden
2 Im Bodden 60; 34 125 Kassel, Germany
3 Service Médecine Nucléaire, Centre Hospitalier Universitaire Vaudois, Lausanne,
4 Istituto Nazionale per la Cura e lo Studio dei Tumori, Direzione Medicina Nucleare-Centro
PET, Milano, Italy
5 European Institute of Oncology, Division of Nuclear Medicine, Milano, Italy
6 Service Médecine Nucléaire, Centre Leon Berard, Lyon, France
7 Klinik und Poliklinik fuer Nuklearmedizin, Universitaet Wuerzburg, Germany
8 Department of Nuclear Medicine, Radboud University, Nijmegen Medical Centre, The
9Department of Nuclear Medicine, University Medical Centre, Maastricht, The Netherlands
Department of Oncology,
Lund University Hospital
SE-221 85 Lund, Sweden
Fax +46 46 17 60 80
Abstract. EMEA has approved 90Y-radiolabelled ibritumomab tiuxetan, Zevalin®, in Europe
for the treatment of adult patients with rituximab-relapsed or -refractory CD20+ follicular B-
cell non-Hodgkin´s lymphoma (NHL) in January 2004. The number of European nuclear
medicine departments using Zevalin® is continuously increasing, since the therapy is often
The Therapy-, the Oncology- and the Dosimetry Committees have worked together in order to
define some EANM Guidelines on the use of Zevalin®, paying particular attention to the
problems related to Nuclear Medicine. The purpose of this guideline is to assist the nuclear
medicine physician in treating and managing patients who may be candidates for radio-
immunotherapy. These guidelines also stress a close collaboration with the physician(s)
treating the patient for the underlying disease.
Key Words: guidelines, nuclear medicine, 90Y- ibritumomab tiuxetan, non-Hodgkin’s
The purpose of this guideline is to assist the nuclear medicine physician in treating and
managing patients who may be candidates for radio-immunotherapy because of relapsed or
refractory CD20+ follicular B-cell non-Hodgkin´s lymphoma (NHL).
II. Background Information and Definitions
1. Radio-immunotherapy (RIT) for relapsed or refractory CD20-positive B-cell NHL
means intravenous administration of 90yttrium [90Y]-labelled ibritumomab tiuxetan
90strontium [90Sr]. The decay of 90Y is accompanied by the release of beta radiation
with a maximum energy of 2.281 MeV (99.98%) into stable 90zirconium [90Zr], with a
half life of 64 h (2.7 d). Ibritumomab tiuxetan is a conjugated murine anti-CD20
antibody genetically engineered from Chinese hamster ovary (CHO) line using the
MX-DTPA chelating agent.
3. The ibritumomab tiuxetan antibody targets the CD20 antigen, which is expressed on
the surface of normal (except for pre-B cells and secretory B cells) and malignant B
90Y is a virtually pure β--emitter, with a high β--energy and an effective pathlength of 5.3 mm,
meaning that 90% of its energy is absorbed within a sphere with 5.3-mm radius. This
pathlength corresponds to 100-200 cell diameters, giving 90Y a broad crossfire effect when it
is conjugated to monoclonal antibody such as ibritumomab.
Ibritumomab tiuxetan consists of ibritumomab, the parent murine monoclonal antibody from
which the widely used chimeric monoclonal antibody rituximab (Mabthera®) was derived,
and tiuxetan which is the chelate for the radionuclide. Development of human antimouse or
human antichimeric antibodies (HAMA or HACHA, respectively) is reported to be in the
range of 1%-2% of patients treated with Zevalin®. The low incidence of HAMA might partly
be due to the immunocompromised status of lymphoma patients due to the disease itself as
well as to previous therapies. The fact that rituximab is used for pre-targeting also reduces the
incidence of HAMA.
Pharmacokinetic studies have shown that almost the entire radioactivity of Zevalin® is
retained within the body after injection. The mean effective half life for Zevalin® in blood is
27 h (range 14-44 h), provided that pre-treatment with rituximab is performed and that there
are no detectable HAMA. Urinary excretion is the primary clearance mechanism, and it
accounts for the elimination of only 7.3% +/- 3.2% of the administered activity over 7 day.
Pre-targeting with unlabelled chimeric Mab (= preload) as part of a treatment with Zevalin®
leads to a more favourable biodistribution of the subsequently injected radiolabelled antibody
by clearing peripheral B-cells from the circulation. Not only does the unlabelled Mab prevent
the radiolabelled antibody to bind non-tumour sites (normal B-cells, spleen), but it is also said
to facilitate deeper penetration into the tumour, translating into a more homogenous
distribution. Furthermore, rituximab itself induces several mechanisms of tumour cell killing
such as antibody dependent cellular cytotoxicity (ADCC) and complement dependent
cytotoxicity (CDC), but also direct induction of apoptosis and possibly cell cycling blockade.
In radio-immunotherapy the biological effects of the monoclonal antibody and of radiation are
thought to be synergistic.
90Y(III)chloride is produced through decay of the radioactive precursor nuclide
EMEA has approved 90Y-radiolabelled ibritumomab tiuxetan, Zevalin®, in Europe for the
treatment of adult patients with rituximab-relapsed or -refractory CD20+ follicular B-cell
NHL in January 2004.
Exclusion criteria for treatment with 90Y-ibritumomab tiuxetan are indicated in the summary
of product characteristics (table 1).
Table 1. Exclusion criteria for treatment
pregnancy and continuing breast feeding
known hypersensitivity to 90Y-ibritumomab tiuxetan, yttrium chloride, other murine proteins, or any of
children and adolescents under 18 years of age
marked bone marrow suppression (< 1.5 x 109/L leukocytes; < 100 x 109/L thrombocytes)
greater than 25% of bone marrow infiltration by lymphoma cells, as judged by bone marrow biopsy.
previous external beam radiation involving >25% of the active bone marrow
prior bone marrow or stem cell transplantation
detectable HAMA, depending on titer
The peripheral blood cell count should not be lower than the limits stated above. However,
lower blood counts do not constitute an absolute contraindication, but they do increase the
risk of severe and prolonged bone marrow suppression and subsequently infection and/or
bleeding. The indication in such a case should be determined after weighing the benefits and
disadvantages of all available alternatives in term of local and systemic interventions.
A. Facility and personnel
1. Therapy with 90Y-ibritumomab tiuxetan should only be performed in facilities
capable of meeting the standards for treatment with unsealed radioactive
sources and licensed according to the national regulations.
2. The personnel engaged in the procedures must have the required qualification
and the appropriate government authorisation for the use and manipulation of
3. A representative of the nuclear medicine service is responsible synchronizing
and organizing the coordination of all pre-treatment and treatment steps along
with the referring haematology-oncology service, the services preparing the
radiopharmaceutical agent and other participants.
4. Proof of training in radiochemical labelling procedures, including quality
control, is required.
5. This radiopharmaceutical agent may be received, used and administered only
by authorized persons in designated settings. Its receipt, storage, use, transfer
and disposal are subject to national regulations.
B. Patient Preparation and Data required
1. Patient information: age, sex, height, weight, diagnosis.
2. Indication for the therapy.
3. Information on the previous therapies (including data on previously completed
radiotherapy and/or autologous/allogenic stem cell transplantation). Previous
chemotherapy – especially if recent – or external beam radiation therapy involving
active bone marrow can worsen radionuclide-induced leukocytopenia and/or
4. A representative (>2 cm long cylinder) bone marrow biopsy from the iliac crest
must not show a > 25% tumour infiltration (number of lymphoma cells as a
percentage of nucleated cells). The biopsy must have been performed no earlier
i. the last time at which disease progression was detected;
ii. or in any case a maximum of 3 months before the scheduled therapy
In addition, the density of cells under normal haematopoiesis must be judged
adequate to ensure satisfactory haematopoietic recovery after myelosuppressive
5. Pregnancy must be excluded prior to radionuclide therapy, while breast feeding
must be stopped.
6. Current medications, especially those that can affect coagulation or blood cell
counts must be recorded.
7. Blood profile, prothrombin time (INR), and serum creatinine and bilirubin tests
within 1 week prior to therapy. There is no adequate experience with the use of
Zevalin® in patients with increased creatinine or bilirubin levels. Usually it is
advised that therapy should not be performed if these values are above 2.5 times
the upper normal limit of the local laboratory.
8. Estimation of life expectancy (life expectancy > 3 months, Karnofsky index >
70%). A patient with a life expectancy of less than 3-4 weeks is unlikely to benefit
from treatment. Similarly, patients showing rapidly progressing disease are not
candidates for RIT because of delayed efficacy of the treatment.
9. Probably due to methodological problems, the dosimetry performed during the
registration trials showed a poor absorbed dose-response relationship, meaning
that the pre-therapeutic dosimetry did neither predict therapeutic efficacy nor
toxicity of the treatment. Thus, there is no evidence that currently available dose
calculations can predict either therapeutic efficacy nor toxicity of the treatment.
For this reason, EMEA has accepted that no such dosimetry studies are required in
the EU. The injected activity is determined according to body weight and platelet
Pre-therapeutic imaging with
Switzerland and the US. The imaging is performed not for dosimetric purposes but
to confirm the expected biodistribution, as an additional safety measure before
administering the Zevalin® therapy.
Dosimetry should be performed, however, when Zevalin® is used as an
investigational treatment at activities or indications different from the one defined
in the registration trials in patients with indolent B-cell lymphomas.
Presently, there are several clinical trials underway with a special focus on pre-
therapeutic dosimetry using 111In and applying more sophisticated dosimetry
protocols as compared to the registration trials.
111In-ibritumomab tiuxetan is mandatory in
C. Patient Information and Instruction
The treatment must be performed in close collaboration with the physician(s) treating the
patient for the underlying disease.
Prior to planning the treatment, the nuclear medicine physician, directly responsible for the
treatment and subsequent follow-up, must personally verify the safety-related suitability
criteria of the patient and discuss all technical and clinical aspects of the radio-
immunotherapy with the patient.
The patients should be provided with written guidelines on the radiation therapy, anticipated
adverse events and contact telephone numbers. The precautions that should be followed
during the first week are listed in table 2.
Table 2. Items to be included in patient education and counselling
(Modified from Hagenbeek and Lewington, Ann Oncol 2005)
-Generic guidelines describing administration and information relevant to radioimmunotherapy regimens
-Specific information describing the 90Y-ibritumomab tiuxetan treatment, including possible adverse events and
safety precautions required during actual treatment
-Risk of radiation exposure to others
-As there is minimal risk of radiation exposure to people in contact with the patient, social interaction with
friends, family and pets is without risk
-During treatment, the patients need not change their routine activities, and no special precautions are required,
such as separate toilet or separate cutlery, and dishes to the rest of the family
Following treatment for 1 week:
-Patients should use condoms if they engage in sexual activity
-When urinating, males should urinate sitting down; any spilt urine should be cleaned and cleaning cloths should
be disposed of in waste disposal or by flushing them down the toilet
-All patients should wash their hands after urination
-As with other anticancer treatments, contraception to avoid pregnancy is recommended for 1 year following
-Possible long-term effects
-Male patients may experience a temporary loss of fertility and may have a low risk of permanent sterility
-Although there are no studies validating this risk, Zevalin® treatment results in a radiation dose to the testes.
Thus, if prior therapies have not damaged sperm quality, male patients may be advised to consider semen
-It is unlikely that fertility is affected in female patients
-Prior treatment with chemotherapy may contribute to the low incidence of secondary malignancies (1.4%)
observed after Zevalin® treatment, which is in the range reported following alkylator-based chemotherapy alone
[1% to 8%]. No secondary malignancies have been reported to date with first–line use of radioimmunotherapy
After informing the patient both verbally and in writing, the patient must give consent to the
treatment, either verbally or in writing, depending on national legislation. Legal provisions
must be observed, including obtaining written informed consent where appropriate.
It is not necessary for the patient to be fasting before therapy. Care must be taken to ensure
Prior to therapy with
administered. These rituximab infusions must be performed under the responsibility of an
experienced haematologist-oncologist who is familiar with rituximab:
Day 1: Infusion of 250mg/m² rituximab. The volume of normal saline solution, which
contains the rituximab stock solution, and the infusion must comply with the
recommendations contained in the package insert of the preparation. In Switserland and the
U.S. this infusion is followed by IV infusion of 111In-ibritumomab tiuxetan (180 MBq) over
10 minutes. At least one anterior and posterior whole body scan has to be recorded within 24
hours and 7-9 days after injection.
Day 7 or 8 or 9: Infusion of 250 mg/m² rituximab, followed by administration of 90Y-
ibritumomab tiuxetan as slow IV infusion over 10 minutes. Zevalin® should not be
administered as an intravenous bolus.
For patients with platelets > 150 x 109/L, the recommended administered activity of 90Y-
ibritumomab tiuxetan is 15 MBq (0.4 mCi) per body weight (kg) up to a maximum limit of
1200 MBq (32 mCi). Patients with platelet counts of 100-149 x 109/L should receive 11
MBq/kg (0.3mCi/ kg).
There are insufficient data on the effects of re-treatment of patients with Zevalin® . The MTD
for haematological toxicity at repeated treatment may be lower.
90Y-ibritumomab tiuxetan, two infusions with rituximab are
If the average radiochemical purity is less than 95%, the preparation must not be
administered. After labelling, Zevalin® must be stored at 2-8 ˚C, protected from light and
administered within 8 hours. The Zevalin® infusion should be performed within 4 hours after
the second rituximab infusion, but it can be postponed up to 48 hours without another pre-
load of rituximab.
The infusion of the radiopharmaceutical agent must take place via a venous catheter or an
indwelling infusion device to ensure safe intravenous administration and prevent paravascular
infiltration. The simplest method to check for proper venous access, even during the
administration, is to run a free rapid infusion of normal saline during the injection into the
same venous access. If a slowdown in drop speed occurs, check the position of the venous
access. Zevalin® should either be administered directly through a three way valve line or
using a remote infusion system shielded with Perspex®. A line filter is required. After infusion
of Zevalin® flush the line with at least 10 ml of sodium chloride (0.9%) solution, to ensure
administration of the full dose of radiopharmaceutical agent. The residual activity in the
needle and/or the infusion kit and catheter can be measured to calculate the precise activity
In the event of extravasation, the infusion must be immediately halted. Extravasation can lead
to radionecrosis. There is no specific therapy for paravenous infiltration. If extravasation
should occur, local hyperthermia, elevation of the extremity, and gentle massage might
somewhat favour lymphatic drainage and thereby reduce the local radiation dose. The event
must be recorded in the procedure report.
Anaphylactic and other hypersensitivity reactions have been reported in less than 1% of
patients following the intravenous administration of proteins to patients. Blood pressure and
pulse should be monitored just as with any administration of monoclonal antibodies. An
emergency kit including glucocorticoids and antihistamines should be kept on hand.
Depending on national/regional regulations, hospitalization may not be required for Zevalin®
administration. The patient is discharged after completion of the infusion and an adequate
period of observation for side effects (20-30 minutes). The nursing staff attending hospitalized
patients and relatives dealing with patient excretions should wear rubber gloves to prevent
skin contamination from contact with patient excretion. Social contacts with relatives or other
patients, as well as pets, do not carry any risk.
E. Precautions, follow-up and side-effects
The nuclear medicine specialist must participate in the ongoing and follow-up care of the
patient as a part of the patient management team.
It should be noted that a reduction of 30-70% in leukocyte and platelet counts from their
baseline levels is possible, sometimes very rapidly. The nadir usually occurs about 7-9 weeks
after therapy (median: day 60), i.e. later than after chemotherapy. Weekly blood tests from the
second post-therapy week on are recommended until baseline levels have been reached. If
levels drop faster than expected, shorter-term controls should be instituted. If the platelets fall
below 30 x 109/L, levels should be checked at least three times per week. Platelet transfusions
and growth factors should be administered if indicated. The patient should also be informed of
the increased risk of infection and bleeding.
Response to treatment should be assessed three months after therapy of Zevalin® using the
international guidelines on response criteria. It should be emphasized that quality of response
may still be improved beyond three months.
For side effects (WHO grades 1-2) observed during therapy see table 3.
Table 3. Zevalin® therapy: non-haematological adverse events
(Modified from Witzig et al, J Clin Oncol 2003)
Treatment period is the time from the first rituximab infusion to 12 weeks after the 90Y-ibritumomab tiuxetan
Neutropenia, leukopenia, thrombocytopenia not included.
Approved name: 90Y- ibritumomab tiuxetan or Zevalin®
Table 4. Zevalin®: physical characteristics
Nuclide Radiopharmaceutical Half
Radius of a unit
density sphere inside
of which 90% of the
energy is emitted
Y-90 Ibritumomab tiuxetan 2.67
Ibritumomab tiuxetan is supplied as a kit containing the non-radioactive components required
for generating a single dose of 90Y-labelled ibritumomab tiuxetan. The kit must be stored at
2°-8° C and should not be frozen. Likewise, the preparation of 90Y-ibritumomab tiuxetan is
performed at room temperature. After radiolabelling it may be stored at 2°-8° C (in a
refrigerator) and protected from light for a maximum of 8 hours.
A bottle with piercable seal contains 3.2 mg (1.6 mg/ml) ibritumomab tiuxetan. The kit also
contains: 2 ml sodium acetate solution in a bottle with piercable seal; 10 ml formulated buffer
solution in a bottle with piercable seal; and an empty 10 ml reaction vial. The final
formulation after radiolabelling contains 2.08 mg ibritumomab tiuxetan in a total volume of
The radioactive component,
manufacturer. Use only carrier-free
labelling. Metal contamination has a detrimental effect on the labelling efficiency.
Labelling and preparation of Zevalin® should be performed where appropriate facilities for
shielding, calibration and quality control are in place. Training on labelling and calibration is
a prerequisite. Labelling must be performed only by qualified personnel with appropriate
authorisation for the use and manipulation of radionuclides.
Providing the procedure is strictly adhered to, labelling is straightforward and failures are
rare. It is crucial that radiopharmaceutical-grade 90Y is used for antibody labelling, and aseptic
technique must be maintained at all stages of preparation. Detailed guidelines on labelling and
preparation can be found in the summary of product characteristics.
Before Zevalin® is injected, the administered activity in the 10 mL syringe must be measured
using a calibrator.
Use protective shields for needles and containers. Observe local regulations for procedures
involving unsealed radioactive sources. Use at least 1 cm-thick perspex or lead-loaded
perspex shields during labelling. Use forceps and tongs as gripping tools. Plastic gloves,
disposable waterproof gowns, and plexiglass eye protection should be used.
90Y, must be obtained separately upon order from the
90Y of pharmaceutical grade quality for antibody
Table 5. Organ radiation absorbed dose factors (mGy/MBq) for 90Y, based upon pre-
therapeutic 111In imaging
(Modified from Wiseman et al, Crit Rev Oncol Hematol 2001)
Number of Patients
Red Marrow (blood derived) 179
Red Marrow (sacrum
Bone surfaces3 179
Urinary bladder wall 179
Other organs45 179
Total body 179
1. Rescaled according to the ratio of the absorbed doses given by Wiseman (J Nucl Med 2003)
2. The doses to the kidneys were calculated without any correction of the individual patient kidney mass.
3. Dose to the bone surfaces includes contributions from both red marrow and whole-body remainder
4. Includes adrenals, brain, breasts, gall bladder wall, heart wall, lower intestine wall, muscles, pancreas,
skin, small intestine, stomach, thymus, thyroid, upper large intestine wall, ovaries and uterus (female
patients) or testes (male patients).
5. In some publications the dose to the testes has been reported to be higher. Caution is advised for young
These organ radiation absorbed doses were assessed using the data of registration trials. They
should not be used prospectively to predict the toxicity in an individual patient. Particularly
the red marrow absorbed doses are strongly dependent on the quantification method. Should
additional data become available these dose estimates will be updated accordingly.
Should a pre-treatment absorbed dose estimate be needed, than the highest absorbed dose
values should be used as a conservative estimate.
• A quality control procedure is mandatory before administration of Zevalin®. Thin
layer chromatography is recommended for this purpose. A gamma counter is adequate
• A labelling efficiency of 95% or more is required.
• Common sources of error in quality control are: drop size, dead-time error during
measurement of the thin layer chromatography strips.
• Dose calibrators must have been calibrated using a source of 90Y of known activity
and volume before preparing the first patient dose of Zevalin®.
• The same measurement equipment used for the baseline measurement must also be
used for subsequent activity measurements; otherwise, recalibration will be necessary.
• Activity measurement must be performed under the appropriate geometric- and
volume- and material-specific (plastic needles, glass vials) conditions.
V. Issues requiring further clarification
• The use of Zevalin® in a broader indication area
• Myeloablative strategies
• The role of patient dosimetry.
VI. Concise bibliography
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monoclonal antibody for treatment of non-Hodgkin´s lymphoma. Int J Oncol 1999; 15:1017-
Goldenberg DM. Advancing role of radiolabeled antibodies in the therapy of cancer. Cancer
Immunol Immunother 2003; 52: 281-9
Fischer M, Behr Th, Grünwald et al. Guideline for radioimmunotherapy of rituximab relapsed
or refractory CD20+ follicular B-cell non-Hodgkin´s lymphoma. Nuklearmedizin 2004; 43:
Griesinger F, Trümper L, Becker W. Radioimmunkonjugate: Therapie von Non-Hodgkin-
Lymphomen und kolorektalen Karzinomen. Der Internist 2001; 42:860-73
Juweid ME. Radioimmunotherapy of B-cell Non-Hodgkin´s lymphoma: from clinical trials to
clinical practice. J Nucl Med 2002; 43:1507-29
Hagenbeek A, Lewington V. Report of a European consensus workshop to develop
recommendations for the optimal use of 90Yttrium-ibritumomab tiuxetan (Zevalin®) in
lymphoma. Ann Oncol 2005: 16: 786-792
Press OW, Leonard JE, Coiffier B et al. Immunotherapy of Non-Hodgkin´s
Lymphoma.Hematology 2001; 221-40
Wagner HN, Wiseman GA, Marcus CS et al. Administration guidelines for
radioimmunotherapy of Non-Hodgkin´s Lymphoma with 90Y-labeled anti-CD20 monoclonal
antibody. J Nucl Med 2002; 43: 267-72
Wiseman GA, Gordon LI, Multani PS et al. Ibritumomab tiuxetan radioimmunotherapy for
patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a
phase II multicenter trial. Blood 2002; 99: 4336-42
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The European Association of Nuclear Medicine has written and approved guidelines to
promote the cost-effective use of high quality nuclear medicine procedures. These generic
recommendations cannot be rigidly applied to all patients in all practice settings. The
guidelines should not be deemed inclusive of all proper procedures or exclusive of other
procedures reasonably directed to obtaining the same results. Advances in medicine occur at
a rapid rate. The date of a guideline should always be considered in determining its current
Last amended: October 2006