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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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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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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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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Recommended administered activity of 90Y-ibritumomab tiuxetan |
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Patient information |
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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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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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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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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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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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Safety profile of 90Y-labelled ibritumomab tiuxetan treatment |
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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 48 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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Other treatments following administration of 90Y-ibritumomab tiuxetan |
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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 [2024
]. 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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Acknowledgements |
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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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