Administration Guidelines for Radioimmunotherapy of Non-Hodgkin’s Lymphoma with ⁹⁰Y-Labeled Anti-CD20 Monoclonal Antibody

Physical Characteristics of ⁹⁰Y

⁹⁰Y is a pure β-emitter with a half-life of 64 h (2.7 d) that decays to ⁹⁰Zr. It has high β-energy and an effective pathlength of 5.3 mm, meaning that 90% of its energy is absorbed within a sphere with a 5.3-mm radius (5). This pathlength corresponds to 100–200 cell diameters, giving ⁹⁰Y a broad crossfire effect when it is conjugated to a monoclonal antibody such as ibritumomab (Table 1) (6,7). This crossfire effect is postulated to increase tumor killing beyond that of nonradiolabeled antibodies, by irradiating tumor cells that are not bound to the antibody. This effect may be particularly beneficial in patients with bulky tumors or tumors that are poorly vascularized.

Dosimetry and Dosing

The therapeutic index of a radionuclide is the ratio of the radiation absorbed dose delivered to cancerous cells and the dose delivered to normal tissues. Dosimetry was performed in the clinical trials of ⁹⁰Y-ibritumomab tiuxetan to determine its therapeutic index and ensure that the radiation exposure to healthy organs and the red marrow was well within acceptable limits (8).

Dosimetry was initially an important component of therapy with ⁹⁰Y-ibritumomab tiuxetan in patients with low-grade NHL. The researchers sought to determine whether it was necessary or helpful to measure the organ-specific accumulation of a radiotherapeutic surrogate in each patient before treatment with ⁹⁰Y-ibritumomab tiuxetan. A tracer dose of ibritumomab labeled with ¹¹¹In, which emits γ-radiation, was used as an imaging agent to predict the distribution within the body of the subsequent therapeutic dose of ⁹⁰Y-ibritumomab tiuxetan. Preclinical studies had shown that the biodistribution of ⁹⁰Y-ibritumomab tiuxetan, assessed by direct determination of the presence of ⁹⁰Y, is in fact predicted by the biodistribution of the ¹¹¹In-labeled antibody (9).

Wiseman et al. (10) have evaluated the estimated dose to solid organs and the marrow after the administration of a tracer dose of ¹¹¹In-ibritumomab tiuxetan in a phase 1–2 clinical trial. Patients with histologically confirmed relapsed or refractory low-grade, intermediate-grade, or mantle cell NHL in whom chemotherapy had failed and in whom there was no more than 25% involvement of the bone marrow space (as determined by bone biopsy) were eligible for the trial. Quantitative gamma camera imaging, serial blood sampling, and MIRDOSE3 software (Radiation Internal Dose Information Center, Oak Ridge, TN) were used to estimate the radiation absorbed doses before treatment with ⁹⁰Y-ibritumomab tiuxetan. The radiation absorbed doses to normal organ and the marrow were within the specified upper limits of 20 Gy for solid organs and 3 Gy for red marrow in all 56 patients in the study. The median estimated radiation absorbed dose to tumor was 17 Gy (range, 5.8–67 Gy). The tumor–to–normal organ (i.e., the normal organ with the highest radiation absorbed dose) ratio was 7:1. Because of the acceptable radiation absorbed doses to normal solid organs and the marrow, it was possible to give the therapeutic ⁹⁰Y-ibritumomab tiuxetan dose in all patients. Furthermore, the estimated radiation absorbed dose to the red marrow did not correlate with hematotoxicity manifested as transient thrombocytopenia, neutropenia, or anemia. These findings indicate that, although the primary toxicity of therapy with ⁹⁰Y-ibritumomab tiuxetan is hematologic, such toxicity in this population of heavily pretreated patients with NHL could be predicted not by dosimetry but by the patients’ bone marrow reserves.

Additional dosimetry results in 72 patients who were treated with ⁹⁰Y-ibritumomab tiuxetan in a phase 3 clinical trial confirmed the initial results in the phase 1–2 study (Fig. 1) (11). Further analyses of these data found no significant correlations between the grade of hematologic toxicity and pharmacokinetic or dosimetric parameters, including whole-blood half-life, whole-blood residence time, red marrow radiation dose (blood- and image-derived), and total body dose (Table 2) (11).

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FIGURE 1.

Mean radiation absorbed doses to tumor and organs for patients treated with ⁹⁰Y-ibritumomab tiuxetan (n = 72) in a multicenter phase 3 randomized trial (11).

On the basis of the dosimetry results and the results in dosing based on patient body weight and platelet count, investigators have concluded that ⁹⁰Y-ibritumomab tiuxetan can be safely used in doses based on patient body weight and pretreatment platelet counts (14.8 MBq/kg [0.4 mCi/kg] in patients with platelet counts of 150 × 10⁹/L or higher, and 11.1 MBq/kg [0.3 mCi/kg] in patients with counts of 100 × 10⁹/L to 149 × 10⁹/L). Dosimetry was not necessary in the cohort of patients in the clinical trials who met the criteria for pretreatment platelet count and percentage of marrow involvement with lymphoma (<25% as determined by bone marrow biopsy), and clinical trials without dosimetry in such patients are ongoing. Dosimetry should be performed, however, when ⁹⁰Y-ibritumomab tiuxetan is used as an investigational treatment in indications (e.g., in the myeloablative setting) different from the one defined in the registration trials in patients with low-grade NHL. Imaging with ¹¹¹In-ibritumomab tiuxetan is performed to confirm the expected biodistribution as an additional safety measure before administering the therapeutic dose of ⁹⁰Y-ibritumomab tiuxetan.

It should also be noted that pharmacokinetic studies have shown that almost the entire radioactivity in the therapeutic dose of ⁹⁰Y-ibritumomab tiuxetan is retained within the body. Urinary excretion is the primary clearance mechanism, and it accounts for the elimination of only 7.3% ± 3.2% of the administered dose over 7 d (12).

Radioimmunoconjugate Preparation and Administration

Radiolabeling to produce ⁹⁰Y-ibritumomab tiuxetan begins with 1,480 MBq (40 mCi) ⁹⁰Y. A typical patient dose range is 777–1,110 MBq (21–30 mCi), with a maximum administered activity of 1,184 MBq (32 mCi). Ibritumomab tiuxetan is provided as a solution containing 3.2 mg of the immunoconjugate (the linker-chelator tiuxetan covalently attached to the murine antibody ibritumomab) in 2 mL of saline solution. Only 1.3 mL of this solution is required to incorporate the 1,480-MBq (40 mCi) dose of ⁹⁰Y, resulting in a relatively small final murine antibody dose for the patient.

Because of the relatively short physical half-life of ⁹⁰Y, centralized radiolabeling before drug shipment is neither practical nor cost-effective (13). The radiolabeling is performed by regional commercial radiopharmacies and the ¹¹¹In- and ⁹⁰Y-labeled ibritumomab tiuxetan is delivered for on-site dose preparation and administration.

Materials with a low atomic number, such as plastic or acrylics, make ideal shields for preparing the drug. The β-particles are completely absorbed in approximately 1 cm of these materials. In addition, bremsstrahlung production is proportional to the atomic number (or the effective atomic number for compounds), which is low for these materials (14,15). For comparison, the effective Z of polyethylene is 5.9; of acrylic, 7.5; and of water, 7.9. In the case of ⁹⁰Y, the percentage of the total β-energy that is converted to bremsstrahlung when it passes through a material with a Z of 7.9 is only 0.6%. Geiger–Müller survey counters are extremely efficient for detecting these low-energy photons but could give erroneously high readings unless they have been calibrated for ⁹⁰Y bremsstrahlung. Syringe shields made of materials such as acrylic are preferred over conventional shields made with lead or leaded glass for use during radiolabeling and preparation. If lead is used, the higher-energy bremsstrahlung produced will necessitate thicker shielding than is commonly used.

Before ⁹⁰Y-ibritumomab tiuxetan is released from the nuclear pharmacy, it must be tested for radiochemical purity, to assess the percentage of ⁹⁰Y that has been chelated by the antibody–tiuxetan complex. A commercial kit for instant thin-layer chromatography can be used. The test is performed in triplicate and the results are averaged. The radioimmunoconjugate can be released for patient administration if its radiochemical purity is ≥95%.

When the drug is administered, it should also be shielded as described above. In addition to the 1 cm of plastic surrounding the syringe, lead (or more plastic) can be used for shielding the low-energy bremsstrahlung.

⁹⁰Y-ibritumomab tiuxetan is administered as a slow intravenous push over approximately 10 min. The drug should not be given as a rapid intravenous bolus. As shown in Table 1, therapy with ⁹⁰Y-ibritumomab tiuxetan is preceded by a dose of rituximab, which is administered to enhance the biodistribution of the subsequent radiolabeled antibody by blocking readily accessible CD20 sites in the peripheral blood and preventing indiscriminate uptake of the radiolabeled antibody in the reticuloendothelial system (7). As such, rituximab is given at a dose of 250 mg/m² by slow intravenous infusion. Ideally, ⁹⁰Y-ibritumomab tiuxetan should be administered within 4 h of completion of the rituximab dose (16).

The most common nonhematologic adverse events reported during clinical trials of ⁹⁰Y-ibritumomab tiuxetan included, but were not limited to, asthenia, nausea, infection, chills, fever, and abdominal pain. Because of the potential for anaphylactic and other hypersensitivity reactions related to the administration of proteins to patients, medications for the treatment of such reactions, such as epinephrine, antihistamines, and corticosteroids, should be readily available during the administration of both rituximab and ⁹⁰Y-ibritumomab tiuxetan.

Precautions After ⁹⁰Y Administration

⁹⁰Y-ibritumomab tiuxetan can be routinely administered on an outpatient basis. Treatment with ⁹⁰Y-labeled antibodies results in the emission of β-radiation and low-level bremsstrahlung radiation, but there is no emission of penetrating γ-radiation, as there is with radiopharmaceuticals that contain ¹³¹I, for example. Because no penetrating γ-waves are produced during treatment with ⁹⁰Y, there is minimal risk of radiation exposure to health care workers or to patients’ family members and others with whom they have contact. Patients can be released immediately after treatment, in accordance with the guidelines in Nuclear Regulatory Commission (NRC) Regulatory Guide 8.39, corresponding to Title 10 Code of Federal Regulations, parts 20 and 35 (17,18). Because of the minimal risk of exposure to other persons, there is no need to determine activity limits or dose rate limits before patients who have been treated with ⁹⁰Y radioimmunotherapy are released, as is necessary with patients who have been treated with radiopharmaceuticals that contain ¹³¹I.

The radiation exposure to persons with whom a patient treated with ⁹⁰Y radioimmunotherapy has contact can be calculated. The specific bremsstrahlung constant for ⁹⁰Y in soft tissue in a 70-kg patient is 1.52 μGy · cm²/MBq · h (19). The NRC guidelines require inpatient stays for patients from whom radiation exposure to others is likely to exceed 5 mSv (500 mrem). Assuming some absorption of the bremsstrahlung by the patient, an inpatient stay for a patient treated with ⁹⁰Y-ibritumomab tiuxetan would be required only if activities > 4,180 GBq (113,000 mCi) were administered. Even with radiation absorption by the patient’s body disregarded, the administered dose would have to be at least 1,425 GBq (38,500 mCi) for the outpatient exposure limit of 5 mSv (500 mrem) to be exceeded. Because the typical patient dose of ⁹⁰Y-ibritumomab tiuxetan is at least a thousandfold less than this (777–1,110 MBq [21–30 mCi]), the NRC requirements for outpatient treatment will always be met.

Furthermore, in a study to quantify the radiation risks to family members with unrestricted contact with patients who had been treated with ⁹⁰Y-ibritumomab tiuxetan, it was determined that radiation exposure in the first week after treatment is very low, in the range of background radiation (20). The patients in this study were not isolated from their family members, nor was any type of patient shielding used. The only recommendations to the family were to avoid contamination from body fluids (saliva, blood, urine, stool). The family member with closest contact to the patient wore a DoseGUARD Plus personal electronic dosimeter (AEA Technology QSA, Inc., Burlington, MA) for the first 7 d after treatment with ⁹⁰Y-ibritumomab tiuxetan. The median deep dose equivalent radiation exposure was a total accumulation of 0.035 mSv over the 7-d period (range, 0.014–0.079 mSv), which is within the range of what might be expected from normal background radiation. The standardtriad of precautions against radiation exposure—minimizing the duration of exposure, maximizing distance from the source, and using shielding—are therefore not necessary with patients who have been treated with ⁹⁰Y radioimmunotherapy. Standard universal precautions to avoid contact with body fluids are all that are required.

Another consideration in radiation safety precautions for patients treated with ⁹⁰Y-ibritumomab tiuxetan is the pharmacokinetic profile. The median effective half-life of ⁹⁰Y-ibritumomab tiuxetan in the blood in clinical trials was 27 h (range, 14–44 h) (9). As was noted above, urinary excretion is the main route of elimination, as determined by the correlation of urinary-excretion and whole-body-retention data (12). Urinary excretion has been reported as 7.3% ± 3.2% over 7 d (12). Assuming a urinary excretion of 7.3% over a week and a maximum dose of 1,184 MBq (32 mCi), the total urinary excretion in that period would be 85 MBq (2.3 mCi). The activity per urination would be in kilobecquerels (microcuries), making this an unlikely source of exposure. Even if the radioactive compound were swallowed (e.g., in food that had been contaminated by contaminated hands), it would be transported through the gastrointestinal tract and not be absorbed (21). Ordinary amounts of blood, such as through menstruation, a severe laceration, or hemorrhoids, will not contain appreciable radioactivity. The recommended release instructions for patients who have been treated with ⁹⁰Y-ibritumomab tiuxetan are given in Table 3.

Some patients may be treated with ⁹⁰Y-ibritumomab tiuxetan as inpatients, not because of any radiation risk to others, but because it is medically required. Medical personnel handling blood or urine routinely wear gloves that would absorb the small amount of radiation that might be present and take other measures to avoid contact with these body fluids. In addition, the bags, vials, and tubes that are normally used to contain these fluids in the hospital would also absorb any radiation that might be present, making contamination of personnel highly unlikely. No additional special precautions beyond the standard universal precautions already in place are therefore necessary for hospital caregivers of inpatients treated with ⁹⁰Y-ibritumomab tiuxetan.