Annals of Oncology Advance Access originally published online on March 31, 2005
Annals of Oncology 2005 16(5):786-792; doi:10.1093/annonc/mdi148
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© 2005 European Society for Medical Oncology
Report of a European consensus workshop to develop recommendations for the optimal use of 90Y-ibritumomab tiuxetan (Zevalin®) in lymphoma
1 Department of Haematology, University Medical Center Utrecht, The Netherlands; 2 Department of Nuclear Medicine and PET, Royal Marsden Hospital, Sutton, UK
* Correspondence to: Dr A. Hagenbeek, University Medical Center Utrecht, Department of Haematology (GO3.647), PO Box 85500, Heidelberglaan 100, Utrecht, 3508 GA, The Netherlands. Tel: +31-30-250-7769; Fax: +31-30-251-1893; Email: a.hagenbeek{at}azu.nl
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Abstract |
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Abstract
IntroductionBackground:: Non-Hodgkin's lymphoma (NHL) comprises a group of related haematological malignancies, predominantly of B-cell origin, which have been described as indolent or aggressive according to their clinical course. Standard treatment for indolent NHL consists of conventional chemotherapy, but, although long-term remissions may occur, most patients will die of their disease. Radioimmunotherapy (RIT) is a novel modality for treating indolent NHL, using monoclonal antibodies to target tumour cells with systemic, low-dose radiation. 90Y-Ibritumomab tiuxetan (Zevalin®; Schering AG, Berlin, Germany), the first RIT approved for use in relapsed/refractory indolent NHL, comprises the murine anti-CD20 monoclonal antibody ibritumomab, covalently linked to the high-energy beta-emitter, yttrium-90, by the chelator, tiuxetan.
Materials and methods:: A multidisciplinary consensus workshop of European clinicians who had taken part in clinical trials of 90Y-ibritumomab tiuxetan was convened to develop recommendations for the clinical preparation and administration of 90Y-ibritumomab tiuxetan in Europe. The workshop was held in anticipation of European Medicines Agency approval of this agent, which was gained in 2004 for adult patients with rituximab-relapsed or refractory CD20+ follicular B-cell NHL.
Results and conclusions:: This article summarises the consensus recommendations developed for haemato-oncologists.
Key words: guidelines, haematologist, lymphoma, oncologist, 90Y-ibritumomab tiuxetan
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Introduction |
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Non-Hodgkin's lymphoma (NHL) comprises a heterogeneous group of lymphoproliferative malignancies with differing patterns of behaviour and treatment responses. The majority of NHL cases (85%) are of B-cell origin [1
], with the most common B-cell histologies being follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Based on its clinical course and prognosis, NHL can be described as aggressive or indolent. Although up to 50% of patients with aggressive lymphomas, such as DLBCL, are curable using standard combination chemotherapy, the majority of patients with indolent lymphomas, such as FL, have a course characterised by multiple relapses and progressive chemoresistance, and eventually die of their disease. Despite advances in drug therapy and, more recently, immunotherapy, the median survival for patients with FL has not improved in more than 30 years [2]. The recent development of radioimmunotherapy (RIT) has provided an important advance in the treatment of advanced or refractory NHL, which is an inherently radiosensitive malignancy. In RIT, monoclonal antibodies are used to target tumour cells with systemic, low-dose radiotherapy. In a ‘crossfire’ effect (Figure 1), neighbouring malignant cells that do not bind the antibody are targeted with radiation emitted from antibody-binding cells. This effect may be of particular value in patients with bulky tumours, or tumours that are poorly vascularised.
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90Y-Ibritumomab tiuxetan (Zevalin®; Schering AG, Berlin, Germany) was the first RIT to be approved for use in malignant disease [3
]. It comprises ibritumomab (a murine IgG1 anti-CD20 mAb), covalently linked to the radioisotope yttrium-90 by stable chelation via the linker, tiuxetan. 90Y is a high-energy, pure beta-emitter, with a half-life of 64 h and a median path length of 
5 mm in soft tissue. In 2002, 90Y-ibritumomab tiuxetan was approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including rituximab-refractory follicular NHL. In 2004, European Medicines Agency (EMEA) approval was granted for the treatment of adult patients with rituximab-relapsed or refractory CD20+ follicular B-cell NHL.
In Europe, clinical experience with 90Y-ibritumomab tiuxetan has been obtained from the treatment of 300 patients with aggressive and follicular NHL, mainly in clinical trials, including the use of 90Y-ibritumomab tiuxetan as first-line consolidation treatment in a phase III trial in patients with follicular NHL in partial or complete remission following conventional first-line chemotherapy. 90Y-Ibritumomab tiuxetan treatment has also been investigated in a phase II study in patients with relapsed or refractory DLBCL.
To facilitate the formulation of recommendations for administering 90Y-ibritumomab tiuxetan in NHL, a questionnaire was sent to 100 clinicians who had taken part in the European clinical trials of 90Y-ibritumomab tiuxetan, enquiring about their clinical experience of 90Y-ibritumomab tiuxetan and asking them to identify potential difficulties and recommendations for the use of 90Y-ibritumomab tiuxetan in NHL. Forty-four respondents, equally divided between haemato-oncologists and nuclear medicine (NM) specialists, completed the survey, and this information provided the basis for a workshop held in October 2003 attended by 20 European clinicians from the European clinical trial programme.
The workshop aimed to develop European recommendations for the optimal use of 90Y-ibritumomab tiuxetan in the treatment of NHL outside the clinical trial setting, and to address specific issues concerning the use of radiopharmaceuticals. The group comprised similar numbers of haemato-oncologists and NM physicians, as well as a radiopharmacist, medical physicist and radiophysicist. This article reports the recommendations of the workshop.
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Patient selection criteria |
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Following EMEA approval in January 2004, 90Y-radiolabelled ibritumomab tiuxetan treatment is indicated in Europe for the treatment of adult patients with rituximab-relapsed or refractory CD20+ follicular B-cell NHL. Exclusion criteria for treatment with 90Y-ibritumomab tiuxetan, as indicated in the summary of product characteristics, are summarised in Table 1 [4
].
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The haemato-oncologist is responsible for measuring the full blood count prior to the decision to provide therapy. However, the workshop concluded that the NM physician should re-check the platelet count on the day of the planned 90Y-ibritumomab tiuxetan administration. Treatment should not be given to a patient with a platelet count <100 x 109/l.
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Recommended administered activity of 90Y-ibritumomab tiuxetan |
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For patients with platelets
150 x 109/l, the recommended administered activity of 90Y-ibritumomab tiuxetan is 15 MBq (0.4 mCi) 90Y-ibritumomab tiuxetan per kilogram of body weight, up to a maximum of 1200 MBq (32 mCi). Patients with platelet counts of 100–149 x 109/l should receive 11 MBq (0.3 mCi/kg) 90Y-ibritumomab tiuxetan per kilogram of body weight, up to a maximum of 1200 MBq (32 mCi). This reduced dose of 90Y-ibritumomab tiuxetan can be given to patients with mild thrombocytopenia without loss of efficacy [4, 5]. |
Patient information |
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Although most information will have been provided by the haemato-oncologist, the NM physician should provide patients with generic guidelines on radiation therapy and written information describing 90Y-ibritumomab tiuxetan treatment, anticipated adverse events, and contact telephone numbers (Table 2). Social interaction with relatives, friends and pets is without risk [6
], and there is no need for separate toilet facilities, or separate cutlery and dishes from the rest of the household. However, there are some precautions that should be taken for 1 week following treatment with 90Y-ibritumomab tiuxetan, as listed in Table 2. In accordance with other anticancer therapies, contraception should be used to avoid pregnancy for 1 year following treatment.
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Fertility was considered unlikely to be affected in females, but temporary infertility is possible in males, with a low risk of permanent sterility, as 90Y-ibritumomab tiuxetan treatment results in a radiation dose of 2.8 mGy/MBq to the testes (Schering AG; data on file [7
]). Male patients should therefore consider semen cryopreservation if prior therapies have not damaged sperm quality.
The patient should be advised of the risk of secondary malignancies, particularly myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). The incidence of MDS and AML is low (1.4%) following treatment with 90Y-ibritumomab tiuxetan [8]. This incidence is within the range (1 to 8%) previously reported with alkylator-based chemotherapy [9–11], and it is postulated that secondary malignancies after RIT may be attributable to exposure to alkylating agents during earlier treatments. To date, no secondary malignancies have been reported with the first-line use of RIT [12].
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Multidisciplinary teamwork and coordination between specialties |
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The delivery of 90Y-ibritumomab tiuxetan requires close cross-speciality cooperation, and the establishment of new multidisciplinary teams in many hospitals. Such teams are likely to include a haemato-oncologist, NM physician or radiation oncologist, nuclear pharmacist, haematology/oncology nurses, and NM nurses and technicians.
Selection of appropriate patients for treatment with 90Y-ibritumomab tiuxetan remains with the haemato-oncologist. However, it is strongly recommended that potential patients are seen by the NM physician prior to 90Y-ibritumomab tiuxetan treatment. The NM physician can provide the patient with additional information on treatment and confirm that the patient meets the relevant safety criteria.
To ensure the optimal delivery of 90Y-ibritumomab tiuxetan, regular communication between the different specialties involved is essential, and it is therefore recommended that a coordinator be appointed who is responsible for organising the logistics of treatment.
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Labelling procedure and 90Y-ibritumomab tiuxetan preparation |
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Labelling
Labelling and preparation of 90Y-ibritumomab tiuxetan should take place within the NM department, where appropriate facilities for shielding, calibration and quality control must be in place. Training on labelling and calibration is mandatory, and is supported by the manufacturer. Only trained personnel should undertake procedures.
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 will be published elsewhere.
The unlabelled, cold antibody, ibritumomab tiuxetan, is available as a commercial kit, which contains the non-radioactive components required to produce a single dose of 90Y-ibritumomab tiuxetan. The radioactive component, 90Y, must be obtained separately upon order from the manufacturer.
Preparation
It is essential to ensure that all the necessary local regulatory authorisations have been obtained prior to therapy with 90Y-ibritumomab tiuxetan. Before 90Y-ibritumomab tiuxetan is injected into the patient, the administered activity in the 10-ml syringe must be verified using a calibrator. 90Y-Ibritumomab should be administered either directly through a three-way valve line or using a remote infusion system shielded with Perspex®. A line filter is also required. After injection, tubing should be flushed to ensure all activity is administered to the patient, and residual activity in the syringe, filter and tubing should be measured to determine the exact dose that has been received by the patient.
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Treatment with 90Y-ibritumomab tiuxetan |
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Figure 2 provides an algorithm for the indication, administration and follow-up of treatment with 90Y-ibritumomab tiuxetan. Treatment may generally be given on an outpatient basis, in accordance with local regulations. The EMEA-approved treatment schedule consists of two stages (Figure 3).
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Day 1: rituximab infusion 250 mg/m2 intravenously to optimise distribution of 90Y-ibritumomab tiuxetan to tumour-bearing sites.
Day 8: Rituximab infusion, 250 mg/m2 intravenously, followed within 4 h by 90Y-ibritumomab tiuxetan.
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Imaging |
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Current evidence supports the reliability of pretreatment platelet levels and the percentage of bone marrow lymphoma involvement as predictors of treatment-related adverse events [13
, 14]. If the need for imaging arises (to predict 90Y-ibritumomab tiuxetan biodistribution), imaging should be performed using indium-111-labelled ibritumomab tiuxetan injected after the first rituximab infusion on day 1 of treatment. In the case of unusual biodistribution (e.g. in patients with massive splenomegaly), treatment with 90Y-ibritumomab tiuxetan may need to be reconsidered. The rituximab component of the treatment regimen may be administered in either the haematology or NM department, but should be given under the direct supervision of a haemato-oncologist with adequate experience in dealing with the adverse events associated with rituximab. The 250 mg/m2 rituximab dose shows the same toxicity profile as the therapeutic dose of 375 mg/m2 used in standard treatment regimens, and should be dealt with accordingly.
Responsibility for the administration of 90Y-ibritumomab tiuxetan is held by a physician licensed to administer radiation therapy. The 90Y-labelled ibritumomab tiuxetan should be administered on day 8, within 8 h of its preparation. If, however, for clinical or logistical reasons, administration on day 8 is not possible, 90Y-ibritumomab tiuxetan may be given on day 9 without an additional predose of rituximab. Data on further delay of 90Y-ibritumomab tiuxetan administration exist, but are limited [15].
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Efficacy of 90Y-labelled ibritumomab tiuxetan treatment |
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Clinical trials have demonstrated that treatment with 90Y-ibritumomab tiuxetan provides an effective and well tolerated therapy for NHL. In a phase III trial in 143 rituximab-naïve patients with relapsed or refractory low-grade follicular or transformed CD20+ NHL, the overall response rate (ORR) was 80% for 90Y-ibritumomab tiuxetan treatment [30% complete response (CR), 4% unconfirmed CR (CRu)] versus 56% for rituximab (16% CR, 4% CRu) (P=0.002) [16
]. The median duration for patients achieving CR was 23 months (26 months for patients with FL), with some patients achieving ongoing responses of longer than 6 years [17]. 90Y-Ibritumomab tiuxetan treatment was also effective in patients with rituximab-refractory NHL; in a phase II study, the ORR was 74% (15% CR) with RIT compared with 32% with prior rituximab [18]. |
Safety profile of 90Y-labelled ibritumomab tiuxetan treatment |
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To date, no acute adverse events have been described with 90Y-ibritumomab tiuxetan treatment, but steroids and antihistamines should be available for use in the event of an allergic reaction.
Extravasation of 90Y-ibritumomab tiuxetan has not been documented in either clinical trials or clinical use. Attention to proper procedures for the preparation and administration of 90Y-ibritumomab tiuxetan is the key to prevention of adverse events. In the unlikely event of extravasation occurring, the infusion should be halted immediately, the patient's arm should be elevated, and the patient should be directed to massage the arm to facilitate lymphatic drainage. Documentation of adverse reactions should be noted in the patient's file.
The main adverse events associated with 90Y-ibritumomab tiuxetan treatment are consequent to temporary myelosuppression, that is, primarily, granulocytopenia and thrombocytopenia. Haematological nadirs are usually reached 4–8 weeks after administration of 90Y-ibritumomab tiuxetan [8]. Weekly complete blood counts should be performed from 2 weeks after 90Y-ibritumomab tiuxetan administration until recovery from cytopenias. Particular attention should be given to the development of thrombocytopenia. If the platelet count falls to 30 x 109/l, the count should be checked at least three times per week until signs of recovery occur. If the platelet count continues to fall below 30 x 109/l, platelet transfusions should be given according to local guidelines. Anaemia is generally relatively mild; however, if required, red blood cell transfusions and/or recombinant erythropoietin may be administered, according to local guidelines. Antibiotic prophylaxis is not routinely required for patients with granulocytopenia, and support with haematopoietic growth factors should be left at the discretion of the treating physician, and in accordance with local guidelines.
In an analysis of 349 patients treated in five clinical studies of 90Y-ibritumomab tiuxetan treatment, non-haematological adverse events were reported in 80% of patients, and were generally grade 1 or 2 [8]. The most common events were asthenia (35%), nausea (25%) and chills (21%). Grade 3/4 infections occurred in 5% of patients. Hospitalisation due to infections was required in 7% of patients: febrile neutropenia occurred in 3%, and grade 3/4 bleeding events occurred in 2% [8].
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Patient follow-up after 90Y-ibritumomab tiuxetan treatment |
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In view of the supportive care that may be required, it is strongly recommended that a haemato-oncologist is responsible for the follow-up of patients given 90Y-ibritumomab tiuxetan. However, the NM physician must be kept informed of the patient's progress, and documentation of long-term follow-up should be available. Follow-up examinations should include weekly complete blood counts (including platelets), which should start from week 2 following 90Y-ibritumomab tiuxetan administration and continue until recovery occurs from thrombocytopenia and/or granulocytopenia. If indicated, physical examinations should also be conducted. Response to treatment should be assessed at 3 months after administration of 90Y-ibritumomab tiuxetan, using international guidelines on response criteria [19
]. Clinicians should be aware that the quality of response may improve beyond 3 months. |
Other treatments following administration of 90Y-ibritumomab tiuxetan |
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Treatment with 90Y-ibritumomab tiuxetan does not preclude treatment with further therapies. After relapse or progression following 90Y-ibritumomab tiuxetan therapy, a patient may receive further myelotoxic treatment as long as peripheral blood cell counts have recovered.
Research has been published on the feasibility of administering chemotherapy, harvesting autologous stem cells for reinfusion, myeloablative treatment and autologous stem cell transplantation, allogeneic stem cell transplantation, radiotherapy, and immunotherapy following administration of 90Y-ibritumomab tiuxetan [20–24]. Of 349 patients treated with 90Y-ibritumomab tiuxetan in the USA, 152 patients have received further therapy following disease progression, with response data available for 99 patients [22]. The ORR to all subsequent therapies was 62%, which is consistent with response rates for salvage therapy in advanced NHL [25]. A recent update on 725 patients involved in 90Y-ibritumomab tiuxetan clinical trials reviewed information on the first antilymphoma therapy subsequent to 90Y-ibritumomab tiuxetan in 254 patients [25]. Efficacy data available from 171 patients showed that 56% (95/171) responded to their subsequent treatment. In patients previously treated with 90Y-ibritumomab tiuxetan (n=41) and compared with matched historical controls previously treated with chemotherapy (n=40), subsequent chemotherapy was equally tolerated in both groups, with no significant differences in the incidence of serious haematological side-effects or hospitalisation rates [25].
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Additional information |
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Additional information required on any aspect of 90Y-ibritumomab tiuxetan treatment may be obtained from the manufacturer, Schering AG, Berlin, Germany.
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Acknowledgements |
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The European Consensus Workshop on Nuclear Oncology was supported by an unrestricted educational grant from Schering AG, Berlin.
Participants in European workshop (October 2003, Marbella, Spain) to develop recommendations for optimal use of 90Y-ibritumomab tiuxetan in lymphoma: Angelika Bischof-Delaloye (nuclear medicine physician), Centre Hospitalier Universitaire Vaudois, Switzerland; Marco Chinol (nuclear medicine physician), Istituto Europeo di Oncologia, Italy; Maggie Cooper (radiopharmacist), St Bartholomew's Hospital, UK; Francesco D'Amore (haematologist), Aarhus University Hospital, Denmark; John de Klerk (nuclear medicine physician), University Medical Centre Utrecht, The Netherlands; Anton Hagenbeek (haematologist), University Medical Centre Utrecht, The Netherlands; Tim Illidge (oncologist), Manchester University Hospital, UK; Elias Jabbour (haematologist), Institut Gustave Roussy, France; Michael Lassman (medical physicist), Klinik und Poliklinik für Nuklear-medizin der Universität Würzburg, Germany; Valerie Lewington (nuclear medicine physician), Royal Marsden Hospital, Sutton, UK; Jose Martin Comin (nuclear medicine physician), Hospital de Bellvitge, Spain; Giovanni Martinelli (oncologist), Istituto Europeo di Oncologia, Italy; Frank Morschhauser (haematologist), Ho^pital Claude Huriez CHRU Lille, France; Marie Mougin (radiophysicist), CHU Hotel Dieu, Nantes, France; Giovanni Paganelli (nuclear medicine physician), Istituto Europeo di Oncologia, Italy; Thierry Prangere (nuclear medicine physician), Ho^pital Claude Huriez CHRU Lille, France; Klemens Scheidhauer (nuclear medicine physician), Technische Universität München, Germany; Christoph von Schilling (haematologist), Technische Universität München, Germany; Josee Zijlstra (haematologist), Free University Medical Centre, Amsterdam, The Netherlands; Pier Luigi Zinzani (haematologist), Institute of Hematology and Medical Oncology ‘Seràgnoli’, University of Bologna, Italy.
Received for publication December 9, 2004. Accepted for publication December 20, 2004.
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