[90Y]Yttriumibritumomab tiuxetan

Radiopharmaceutical: [⁹⁰Y]Yttriumibritumomab tiuxetan (Zevalin^®)

Radionuclide: Yttrium-90 is a β emitter with a half-life of 64.1 h. The median radiation dose 1 meter away from the patient immediately after the administration of [⁹⁰Y]Yttriumibritumomab tiuxetan is 2.95 µSv/h (2.4-3.9 µSv/h).

Activity: Usually 11 MBq or 14 MBq are administered per kg of body weight, depending on platelet count. For standard treatments, the administered activity is usually capped at 1200 MBq.

Administration: slow i.v., 1 mL per min over 10 min

9.2.1 Mechanism of uptake / drug biology

Monoclonal antibodies (the CD20-directed mouse antibody ibritumomab tiuxetan) are labelled with yttrium-90 and carry it highly selectively to the malignant cells. The β radiation emitted by the radionuclide destroys the malignant cell the antibody has bound to as well as malignant cells in the vicinity. In the latter situation, a non-radiolabelled antibody cannot be sufficiently effective due to poor circulation in the tumour or due to the tumour size.

One of the reasons why radioimmunotherapy is a good option for the treatment of follicular non-Hodgkin lymphoma is that lymphoma cells are sensitive to radiation. The disease is often in an advanced stage (III/IV), in which total body irradiation is not an option.

9.2.2 Patient selection

Adult patients with relapsed or refractory CD20+ follicular B-cell non-Hodgkin lymphoma after treatment with rituximab.

9.2.3 Exclusion criteria

[⁹⁰Y]Yttriumibritumomab tiuxetan should not be administered to:

• patients with a risk of life-threatening haematological toxicity;
• patients with more than 25% bone marrow involvement;
• patients with a history of external radiotherapy to more than 25% of the active bone marrow;
• patients with <100x10⁹/L thrombocytes or <1.5x10⁹/mL neutrophil granulocytes;
• patients with a history of bone marrow transplantation or stem cell support (relative contraindication, see [190,191];

children and adolescents younger than 18 years (relative contraindication, see [192].

Contraindications:

• Hypersensitivity to ibritumomab tiuxetan, to yttrium chloride, to other mouse proteins, or to one of the excipients;
• Pregnancy and breast-feeding (pregnancy should be ruled out prior to administration, because ibritumomab is an IgG monoclonal antibody, and human IgG is known to cross the placenta and to be excreted in human milk).

9.2.4 Procedure

Two rituximab pre-treatments with Rituximab (Mabthera^®) 250 mg/m² (on days 1 and 8) eliminate circulating B-lymphocytes (B cells) and enable the optimization of [⁹⁰Y]-yttriumibritumomab tiuxetan biodistribution. [⁹⁰Y]Yttriumibritumomab tiuxetan is administered intravenously over 10 min on Day 8, within 4 h of the second rituximab administration. After a physical exam, the patient may return home. The [⁹⁰Y]Yttriumibritumomab tiuxetan solution should be slowly administered intravenously.

After administration, the line should be flushed with saline. The treatment, therefore, comprises 2 i.v. administrations of rituximab (under the supervision of the haematologist) and 1 administration of [⁹⁰Y]Yttriumibritumomab tiuxetan (by the specialist in nuclear medicine) in this order:

• Day 1, i.v. infusion of rituximab, 250 mg/m²;
• Day 8 (Day 7 or 9 are also acceptable), i.v. infusion of rituximab 250 mg/m² shortly followed by administration of [⁹⁰Y]Yttriumibritumomab tiuxetan.

Patients who have received therapeutic [⁹⁰Y]Yttriumibritumomab tiuxetan mouse proteins, should be tested for human anti-mouse antibodies (HAMA). Patients who have developed HAMA may have allergic or hypersensitivity reactions during their treatment with [⁹⁰Y]Yttriumibritumomab tiuxetan or other mouse proteins [193].

9.2.5 Dosimetry

The radioactivity to be administered takes into account patient body weight and platelet blood count only; no optimization based on pre-therapeutic dosimetry is routinely prescribed. [50].

Clearance of ⁹⁰Y-ibritumomab-tiuxetan from the blood is usually low. The main route of excretion is the urinary system. However, during the first 7 days after administration, only about 10% of the administered activity is excreted in the urine [51].

Normal organ dosimetry for [⁹⁰Y]Yttriumibritumomab tiuxetan has been the subject of a MIRD dose estimate report [51]. Median absorbed dose values calculated (in mGy/MBq) included Red Marrow 2.73 (±0.90), Liver 3.64 (±1.38), Kidneys 2.44 (±0.61), Spleen 4.65 (±2.32), Lungs 0.76 (±0.48) and Whole body 0.58 (±0.10). This report showed that the dosimetry approach, assumptions, and choice of parameters can substantially affect the calculated absorbed doses. Using a full SPECT/CT protocol instead of planar imaging, systematically lower absorbed doses have been found for the liver and spleen [194]. A separate study determined that image-based bone marrow dosimetry models are better predictors of myelotoxicity than methods based on blood samplings [195].

According to the experience of external beam radiotherapy, a total absorbed dose of 30-36 Gy is needed to eradicate lymphoma lesions. However, reduced-intensity protocols of 2x2 Gy are successfully used in selected cases of indolent lymphomas. When explored, the tumour absorbed dose range delivered by radioimmunotherapy was wide (range: 5.8-67 Gy), but no clear dose-response correlation was shown [196]. Initial studies used a two-dimensional approach, so that no refined radiobiological models could be taken into account. When this has been done in similar types of treatments, as in the case of radioimmunotherapy with the anti CD20 [¹³¹I]iodotositumomab (Bexxar^®), an improved dose-response correlation was demonstrated [197]. A three dimensional, voxel-based approach to radioimmunotherapy with [⁹⁰Y]Yttriumibritumomab tiuxetan still needs to be optimized [198].

The strongest rationale for pre-therapeutic dosimetry is the prevention of unexpected toxicities in the disease course of fragile patients or when a deviation from the standard administration protocol is foreseen, as in the frame of myeloablative protocols. The pre-therapeutic imaging with [¹¹¹In]indiumibritumomab tiuxetan can be used for treatment planning, which can also take into account the planned delivered absorbed dose to lesions. Studies on fractionated therapies have determined that median organ absorbed doses were equivalent between fractions except for the spleen [195]. Clinical studies employing myeloablative activities would always require an adequate planning as the risk of non-haematological toxicities may not be negligible. In this case, the liver becomes the limiting organ [199]. Up to 55.5 MBq/kg have been safely administered with autologous stem cell transplantation. Dosimetry proved to be useful in the setting of autologous stem cell transplantation by determining the most convenient timing of reinfusion in order to minimize the irradiation of the reinfused stem cells, thus facilitating the engraftment [200].

9.2.6 Effectiveness

A randomized study in patients with non-Hodgkin lymphoma showed [⁹⁰Y]Yttriumibritumomab tiuxetan to be more effective than non-radiolabelled rituximab, specifically 80% versus 56% (p=0.002) in overall response and 30% versus 16% (p=0.04) in complete response [199]. The overall response in a sub-analysis of the patients with follicular non-Hodgkin lymphoma was 86% versus 55% (p<0.001). The time to disease progression in patients with follicular non-Hodgkin lymphoma was 15.0 months in the [⁹⁰Y]Yttriumibritumomab tiuxetan group and 10.2 months in the rituximab group. The subgroup of patients achieving a complete response or complete response unconfirmed showed a time to disease progression of 24.7 months versus 13.2 months in favour of [⁹⁰Y]Yttriumibritumomab tiuxetan . The quality of life also significantly improved in patients to whom [⁹⁰Y]Yttriumibritumomab tiuxetan was administered (week 12 compared to baseline; p=0.001). This was not the case in the rituximab group. A study in patients with rituximab-refractory follicular non-Hodgkin lymphoma showed that 74% of the patients still achieved a good response to [⁹⁰Y]Yttriumibritumomab tiuxetan treatment (even complete response in 15% of the patients).

In follicular lymphoma, a single radioimmunotherapy infusion as first line treatment shows overall response rate of 87% and median progression-free survival of 26 months [201]. Radioimmunotherapy with [⁹⁰Y]Yttriumibritumomab tiuxetan has been fractionated in two administrations showing an overall response rate of 94.4% with 58.3% complete response. At a median follow-up of 3.1 years, estimated 3-year progression-free survival is 58%, and overall survival 95% [202].

9.2.7 Side Effects

Transient and generally manageable myelotoxicity is the most common side effect of radioimmunotherapy. Pilot studies have shown that, when given as standard, only in exceptional circumstances would administration of [⁹⁰Y]Yttriumibritumomab tiuxetan be contraindicated because of excessive absorbed doses to organs at risk [196]. However, concerns regarding the absorbed dose delivered to organs at risk may arise in case of severely ill and heavily pre-treated patients as well as if additional external beam radiotherapy is planned in the treatment course.

[⁹⁰Y]Yttriumibritumomab tiuxetan treatment regimen consists of the administration of rituximab and [⁹⁰Y]Yttriumibritumomab tiuxetan; the side-effects of both should therefore be considered. In the SmPC (“Summary of Product Characteristics” of Zevalin^®, the scientific package leaflet), the side-effects and their frequency during clinical studies are listed as very common (≥10%), common (≥1-10%), uncommon (≥1/1.000 to <1/100) and rare (≥1/10.000 to <1/1.000). The causality was not considered. The tables do not distinguish between the side-effects caused by [⁹⁰Y]Yttriumibritumomab tiuxetan and the side-effects caused by rituximab.

An integrated analysis of the side-effects in 349 patients treated with [⁹⁰Y]Yttriumibritumomab tiuxetan provides an overview of the side-effects that can be attributed mainly to rituximab and those that can be attributed to [⁹⁰Y]Yttriumibritumomab tiuxetan [203]:

• Infusion-related side-effects (fever, chills, etc.), mainly mild to moderate in severity (grade 1 and 2), are common and relate mainly to rituximab (250 mg/m²) administrations on Day 1 and Day 8. Side-effects may require the speed of the rituximab infusion to be adjusted resulting in the infusion time exceeding 5 h. The infusion-related side-effects of rituximab are generally much less severe during the infusion on Day 8. The rituximab infusion on Day 8 therefore generally takes less time (2-3 h). Infusion-related side-effects during the 10 min [⁹⁰Y]Yttriumibritumomab tiuxetan administration are rare but not impossible and less severe due to the lower ibritumomab dose (<2 mg) compared to rituximab (250 mg/m²).
• Anaphylactic and other hypersensitivity reactions have been reported in fewer than 1% of patients who received i.v. protein administration. Medicines for the treatment of hypersensitivity reactions, e.g. adrenaline, antihistamines and corticosteroids should be available for immediate use in the event of an allergic reaction during [⁹⁰Y]Yttriumibritumomab tiuxetan administration.
• Mild to severe thrombocytopenia and neutropenia are very common, in particular during the first 12 weeks after [⁹⁰Y]Yttriumibritumomab tiuxetan administration (nadir 4-6 weeks after injection) and are almost always reversible. Grade 3 (53% of patients) or 4 (10%) thrombocytopenia was reported with a median recovery time of 23 days; grade 3 (30%) or 4 (30%) neutropenia with a median recovery time of 28 days. Anaemia is also very common (>10% of patients). The decrease in haemoglobin recovers more quickly than the low thrombocyte and neutrophil granulocyte counts.
• Hospitalization due to an infection is fairly uncommon (7% of patients).
• Five patients (1%) in the integrated toxicity study were reported to have myelodysplastic syndrome (n=2), acute myeloid leukaemia (n=2) or acute myeloid leukaemia after myelodysplastic syndrome (n=1). All patients had had prior (alkylating) chemotherapy. More data (in particular long-term data) are needed for a definitive conclusion.
• Mucocutaneous reactions, including Stevens-Johnson syndrome with a fatal outcome, have rarely been reported (frequency: >1/10,000 and <1/1000). The mucocutaneous reactions reported occurred after the [⁹⁰Y]Yttriumibritumomab tiuxetan infusion. It could not be ascertained whether the rare mucocutaneous reactions were attributed specifically to rituximab or to [⁹⁰Y]Yttriumibritumomab tiuxetan.
• [⁹⁰Y]Yttriumibritumomab tiuxetan can influence the ability to drive or use machines, as dizziness is a very common side-effect (8%).

9.2.8 Status

[⁹⁰Y]Yttriumibritumomab tiuxetan was authorized in January 2004 for the treatment of adult patients with relapsed or refractory CD20+ follicular B-cell non-Hodgkin lymphoma after treatment with rituximab.