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Expert Opinion on Biological Therapy Aug 2010Follicular lymphoma (FL) is a subgroup of B-cell Non-Hodgkin's lymphomas (NHL) that account for 15 - 30% of all lymphomas. I-131 tositumomab is a radiommunoconjugate of... (Review)
Review
IMPORTANCE OF THE FIELD
Follicular lymphoma (FL) is a subgroup of B-cell Non-Hodgkin's lymphomas (NHL) that account for 15 - 30% of all lymphomas. I-131 tositumomab is a radiommunoconjugate of (131)I and the anti-CD20 monoclonal antibody tositumomab. It is one of two available radioimmunoconjugates for the treatment of recurrent, refractory, or transformed FL.
AREAS COVERED IN THIS REVIEW
This review describes the clinical pharmacology of I-131 tositumomab, dosing and administration guidelines, and the key clinical trials providing evidence of its efficacy and safety in patients with FL, transformed, or other aggressive B-NHL, in combination with chemotherapy, or its incorporation in transplant conditioning regimens. This review also covers safety and regulatory concerns regarding the use of I-131 tositumomab.
WHAT THE READER WILL GAIN
This review critically appraises the clinical trials behind approval of I-131 tositumomab as a second-line agent for FL and also outlines the data supporting its use in the upfront setting.
TAKE HOME MESSAGE
I-131 tositumomab is a safe and effective option for patients with recurrent, refractory, or transformed FL and carries promise in the upfront treatment of FL, aggressive B-NHL, and as a transplant conditioning regimen.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Humans; Lymphoma, Follicular; Radioimmunotherapy; Radiopharmaceuticals; Treatment Outcome
PubMed: 20590521
DOI: 10.1517/14712598.2010.504707 -
Journal of Nuclear Medicine : Official... Jan 2005Tositumomab and (131)I-tositumomab constitute a relatively new radioimmunotherapeutic regimen for patients with CD20+ follicular non-Hodgkin's lymphoma (NHL). Currently,... (Review)
Review
UNLABELLED
Tositumomab and (131)I-tositumomab constitute a relatively new radioimmunotherapeutic regimen for patients with CD20+ follicular non-Hodgkin's lymphoma (NHL). Currently, it is approved for use in patients whose disease has relapsed after chemotherapy and is refactory to rituximab, including patients whose tumors have transformed to a higher histologic grade. This review outlines the current and evolving status of this therapeutic regimen at nonmyeloablative doses.
METHODS
Clinical data from multiple published studies and preliminary communications encompassing more than 1,000 patients were reviewed to describe the current status of tositumomab and (131)I-tositumomab therapy. The therapy is delivered in 2 parts, a dosimetric dose and a therapeutic dose. The therapeutic radioactivity millicurie dose is calculated on a patient-individualized ("tailored") basis. A series of 3 total-body gamma-camera scans are used to determine the patient-specific pharmacokinetics (total-body residence time) of the radiolabeled antibody conjugate required to deliver the desired total-body radiation dose, typically 75 cGy.
RESULTS
In clinical trials, objective response rates in patients who had been extensively pretreated with chemotherapy ranged from 47% to 68%. Tositumomab and (131)I-tositumomab therapy also was effective in patients who had failed to respond to or who had relapsed after rituximab therapy, with a 68% overall response rate. Thirty percent of such patients achieved complete responses that were generally of several years duration. Single-center trials using tositumomab and (131)I-tositumomab therapy alone or after chemotherapy in previously untreated patients have shown response rates in excess of 90%, with most responses complete. Retreatment with tositumomab and (131)I-tositumomab and use of lower total-body radiation doses of tositumomab and (131)I-tositumomab to treat patients who have relapsed after stem cell transplantation have been shown feasible in limited clinical studies. Toxicity is predominately hematologic; however, human antimouse antibodies, hypothyroidism, and myelodysplastic syndrome have been reported in a small fraction of patients.
CONCLUSION
Tositumomab and (131)I-tositumomab therapy at patient-specific, nonmyeloablative doses is safe and effective in treatment of relapsed and refractory follicular NHL. Toxicity is mainly hematologic and reversible. Tositumomab and (131)I-tositumomab therapy is assuming a growing role in this common malignancy.
Topics: Animals; Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Immunotherapy; Lymphoma, Non-Hodgkin; Practice Guidelines as Topic; Practice Patterns, Physicians'; Radioimmunotherapy; Treatment Outcome
PubMed: 15653661
DOI: No ID Found -
BioDrugs : Clinical Immunotherapeutics,... Sep 2000black triangle (131)I tositumomab is a radiolabelled murine anti-CD20 monoclonal antibody that binds specifically to the CD20 antigen on normal and malignant B...
black triangle (131)I tositumomab is a radiolabelled murine anti-CD20 monoclonal antibody that binds specifically to the CD20 antigen on normal and malignant B lymphocytes. It has antitumour activity as a result of emission of beta particles, and activation of antibody-dependent cellular and complement-mediated cytotoxicity. black triangle (131)I tositumomab monotherapy consistently produced objective response rates of >or=60% in patients with relapsed or refractory, low grade or transformed low grade non-Hodgkin's lymphoma (NHL) in clinical trials. 62% of patients responded to retreatment in 1 small trial. black triangle In 2 studies, objective and complete response rates were higher and overall durations of response were significantly longer in patients treated with (131)I tositumomab compared with their last chemotherapy regimen. black triangle High dose (131)I tositumomab combined with autologous stem cell transplant produced an objective response rate of 86% in relapsed or refractory patients. black triangle (131)I tositumomab alone or in combination with fludarabine achieved an objective response rate of 100% in 2 preliminary reports in patients with previously untreated NHL. black triangle The dose-limiting toxicity of (131)I tositumomab is reversible myelosuppression, with approximately 18% of patients requiring haematological support in combined trial data. Other nonhaematological toxicities occur in approximately 20 to 40% of patients and include mild to moderate flu-like symptoms.
PubMed: 18034570
DOI: 10.2165/00063030-200014030-00005 -
Expert Review of Anticancer Therapy Feb 2004Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked... (Review)
Review
Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked covalently with iodine-131 to produce the radioimmunoconjugate iodine-131 tositumomab (Bexxar). The iodine-131 tositumomab regimen was approved by the US Food and Drug Administration in June 2003 for the treatment of patients with CD20-positive, follicular non-Hodgkin's lymphoma, both with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy. The dose-limiting toxicity of iodine-131 tositumomab is bone marrow suppression and resulting cytopenias. Unlike chemotherapy, the majority of nonhematologic adverse events associated with iodine-131 tositumomab are mild to moderate in nature and usually self limited. Iodine-131 tositumomab represents one of the most active single agents for the treatment of recurrent indolent and transformed B-cell non-Hodgkin's lymphoma, as demonstrated by several clinical trials summarized in this review. At the present time, the use of radioimmunoconjugate therapy is largely limited to patients with disease refractory to rituximab therapy and transformed disease not amenable to high-dose therapy and autologous stem cell support. Longer follow-up of ongoing clinical trials should provide reassurance as to safety and insights as to the additive stem cell toxicity from iodine-131 tositumomab administration. Studies are also addressing the role of iodine-131 tositumomab as a component of initial therapy for indolent non-Hodgkin's lymphoma and in additional histologies of non-Hodgkin's lymphoma.
Topics: Antibodies, Monoclonal; Antigens, CD20; Antineoplastic Agents; Clinical Trials as Topic; Humans; Immunoconjugates; Iodine Radioisotopes; Lymphoma, B-Cell; Neoplasm Recurrence, Local; Radioimmunotherapy
PubMed: 14748653
DOI: 10.1586/14737140.4.1.18 -
Seminars in Oncology Apr 2003The majority of patients with non-Hodgkin's lymphoma (NHL) who respond to conventional chemotherapy will relapse and eventually become refractory to chemotherapy. Each... (Review)
Review
The majority of patients with non-Hodgkin's lymphoma (NHL) who respond to conventional chemotherapy will relapse and eventually become refractory to chemotherapy. Each subsequent remission is typically of similar or shorter duration than the last. Recent developments in radioimmunotherapy using monoclonal antibodies to specifically target malignant B cells have yielded promising results in relapsed and refractory NHL patients. The radiolabeled anti-CD20 antibody tositumomab and iodine 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA and GlaxoSmithKline, Philadelphia, PA) has been shown to be safe and effective in the treatment of patients with relapsed low-grade (indolent) NHL. Objective responses were achieved in 57% to 71% of patients in phase I to phase III trials, and remission durations were significantly longer in the phase III trial compared with the last remission induced by chemotherapy. In addition, tositumomab and iodine I 131 tositumomab was shown to be effective in the subset analysis of patients with transformed low-grade NHL, which is particularly resistant to conventional therapies. The incidence of transient, nonhematologic adverse events was low and mainly mild to moderate in severity. Hematologic toxicity is the major dose-limiting toxicity associated with radioimmunotherapy; however, patient-specific dosimetry maintained hematologic toxicity within predictable, transient, and manageable limits in the phase II and phase III trials of tositumomab and iodine I 131 tositumomab. Although approximately 10% of patients treated with tositumomab and iodine I 131 tositumomab developed human-antimouse antibodies, treatment with tositumomab does not preclude the administration of subsequent chimeric antibody therapies. In conclusion, these studies show that tositumomab and iodine I 131 tositumomab treatment is safe and induces high response rates and durable remissions in heavily pretreated patients with low-grade or transformed low-grade NHL.
Topics: Antibodies, Monoclonal; Antigens, CD20; Antineoplastic Agents; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Lymphoma, Non-Hodgkin; Radioimmunotherapy
PubMed: 12728404
DOI: 10.1053/sonc.2003.23803 -
Future Oncology (London, England) Jun 2007Iodine 131 (I131) tositumomab is composed of murine anti-CD20 antibody linked to the radioisotope I131. I131 tositumomab exploits the specificity of monoclonal antibody... (Review)
Review
Iodine 131 (I131) tositumomab is composed of murine anti-CD20 antibody linked to the radioisotope I131. I131 tositumomab exploits the specificity of monoclonal antibody therapy and the radiosensitivity of non-Hodgkin's lymphoma to exact a combined antitumor effect. It is currently approved in the USA for treatment of relapsed or refractory low-grade (and transformed) non-Hodgkin's lymphoma. High response rates in this setting, with some patients achieving a remission of longer duration than that of their prior treatment, provided the basis for approval of the drug. Studies using I131 tositumomab as initial treatment for low-grade non-Hodgkin's lymphoma (with or without chemotherapy), and in conditioning regimens for autologous transplantation, have yielded promising results. Randomized, comparative trials are needed to define its optimal clinical use.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Lymphoma, Non-Hodgkin; Radioimmunotherapy
PubMed: 17547519
DOI: 10.2217/14796694.3.3.255 -
Seminars in Oncology Feb 2005The median survival for patients with advanced indolent non-Hodgkin's lymphoma (NHL) has remained at 7 to 8 years since the 1960s. Targeted treatment using...
The median survival for patients with advanced indolent non-Hodgkin's lymphoma (NHL) has remained at 7 to 8 years since the 1960s. Targeted treatment using radioimmunotherapy (RIT), radiolabeled monoclonal antibodies directed against tumor-specific antigens, is an attractive option for this patient population, combining the advantages of an active biologic therapy with low dose-rate irradiation of an inherently radiosensitive tumor. Two anti-CD20 RIT agents have now been approved for the treatment of refractory NHL: 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) is approved in both the United States and Europe, and 131I-tositumomab (Bexxar; Corixa Corp, Seattle, WA) is approved only in the United States. This article discusses the development of 131I-tositumomab. Because 131I-labeled antibody clearance varies significantly among patients, prescription of 131I-tositumomab activity must be based on a calculated total-body dose derived from quantitative whole-body imaging. The maximum tolerated total-body dose has been established at 75 cGy in patients with adequate bone marrow reserves and less than 25% bone marrow involvement by lymphoma (65 cGy in patients with mild thrombocytopenia; 45 cGy in patients who have received stem cell transplantation). In a phase III trial, overall response rate (ORR) and complete response (CR) rate were significantly higher following 131I-tositumomab than following the patient's last qualifying chemotherapy (ORR, 65% v 28%; P <.001; CR, 20% v 3%; P <.001). 131I-tositumomab has also been shown to be effective in patients who are refractory to rituximab (ORR, 70%; CR, 32%) and as first-line therapy in patients with NHL (ORR, 97%; CR, 63%). The major side effects of 131I-tositumomab are hematologic. In the phase III study, 20% of patients experienced grade 4 neutropenia and 22% experienced grade 4 thrombocytopenia. Myelodysplastic syndromes or secondary acute myeloid leukemia have been reported in 8.4% of patients with chemotherapy-refractory disease treated with 131I-tositumomab, but have not been observed to date in patients receiving 131I-tositumomab as first-line therapy. Future progress in NHL management is likely to include RIT as part of a multi-modality approach; trials are planned or currently underway to investigate the combination of RIT with chemotherapy regimens.
Topics: Antibodies, Monoclonal; Antigens, CD20; Humans; Iodine Radioisotopes; Lymphoma, Non-Hodgkin; Radioimmunotherapy; Radiopharmaceuticals
PubMed: 15786026
DOI: 10.1053/j.seminoncol.2005.01.014