UNIPROT:Q06643 - FACTA Search

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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
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This review summarizes the current clinical status of radioimmunotherapy (RAIT) in the treatment of patients with non-Hodgkin's lymphoma (NHL), as a prototype of the advances of RAIT in the management of cancer. Four radiolabeled antibody products are progressing towards commercialization for the RAIT of NHL: 131I-tositumomab (Bexxar), 90Y-ibritumomab tiuxetan, 90Y-epratuzumab (hLL2), and 131I-Lym-1. All except epratuzumab are murine monoclonal antibodies (Mabs) labeled with an isotope, except that ibritumomab (Zevalin) adds chimeric rituximab to the product, whereas epratuzumab is solely a humanized Mab. Bexxar and Zevalin target CD20, epratuzumab binds to CD22, and Lym-1 reacts with HLA-DR. Clinical studies have shown that all four antibody products can be safe and efficacious. Bexxar has been shown to induce responses that are relatively better than the prior chemotherapy, and has also been shown to be effective in combination with chemotherapy as a frontline therapy of low-grade and transformed NHL. However, since it is a fully murine Mab, it did show a approximately 60% HAMA rate in untreated patients. Zevalin has been found to be more effective than rituximab, its naked chimeric Mab counterpart, as well as in chemotherapy-relapsed low-grade NHL patients. Both radiolabeled epratuzumab and Lym-1 have shown efficacy in patients who have failed chemotherapy, either with low-grade or aggressive forms of NHL. It appears that Bexxar and Zevalin will be the first two radiolabeled antibodies that may be available for widespread use in the U.S., and will mark the final introduction of RAIT as an approved cancer treatment modality. Future studies will help define the role of these RAIT products in the management of NHL, especially as part of a multimodal therapy of this disease.
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PMID:The role of radiolabeled antibodies in the treatment of non-Hodgkin's lymphoma: the coming of age of radioimmunotherapy. 1141 16

This article reviews highlights in the field of hematologic malignancies presented at the 2001 annual meeting of the American Society of Clinical Oncology. Targeted therapies continue to proceed from the laboratory to the clinic. Monoclonal antibody-based therapies predominate, and further data on radioimmunoconjugates (RICs) (tositumomab and Iodine 131 tositumomab [Bexxar] and ibritumomab tiuxetan [Zevalin]) are presented. Both agents have high response rates in relapsed B-cell non-Hodgkin's lymphoma (NHL). Results from the first trial directly comparing an RIC (Zevalin) to an unconjugated antibody (rituximab) are presented. A novel application of RIC therapy as part of high-dose therapy for mantle cell NHL is described. A new fusion toxin, BL22, targets the CD22 antigen and shows marked activity in the treatment of hairy cell leukemia. Similarly, the Hu1D10 monoclonal antibody has activity in B-cell NHL and might have a relatively unique mechanism of action. Finally, advances in the treatment of mucositis are described. These abstracts all describe therapies derived from our enhanced understanding of tumor immunology and molecular biology.
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PMID:Hematologic malignancies. 1152 49

The front-line management of stage IV indolent non-Hodgkin's lymphoma has ranged from the watch-and-wait approach to intensive experimental regimens such as high-dose chemotherapy and bone marrow transplant. With this broad spectrum of regimens to choose from the decision has become a challenging exercise for both patients and oncologists. With the recent introduction of new agents such as rituximab, fludarabine, and combinations based on these, the management of relapsed cases can be similarly confusing. More aggressive approaches such as high-dose chemotherapy with autologous bone marrow transplant and more recently allogeneic bone marrow transplant have also been used. Recently the technique of "mini-allo transplants" has been introduced. It utilizes a less myelosuppressive conditioning chemotherapy regimen based on fludarabine which is immunosuppressive enough to allow engraftment of the donor marrow. Since it is less myelotoxic it is better tolerated, and this has allowed us to significantly extend the age cut-off for allogeneic transplants. All these advances provide us with a more extensive armamentarium, but at the same time they confront physicians with new challenges in choosing from a large and continuously growing therapeutic menu. In this review of the alternative therapies a panel of three expert hemato-oncologists each discuss their approach to the management of a 49-year-old patient with a relapsed indolent follicular lymphoma. Dr. Horning discusses the traditional alternatives available for this patient such as standard chemotherapy combinations or the watch-and-wait approach in Section I. In Section II, Dr. Kaminski reviews the different therapeutic monoclonal antibody options such as rituximab, Bexxar (Iodine-labeled anti-CD20) and Ytrium-labeled anti-CD20 antibody. Allogeneic transplants are increasingly more popular for the treatment of indolent lymphomas because they can provide an immune-mediated graft-versus-lymphoma effect. In Section III, Dr. Richard Champlin reviews various transplant options including autologous, allogeneic and mini-allogeneic transplants.
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PMID:Managing Indolent Lymphomas in Relapse: Working Our Way Through a Plethora of Options. 1170 41

Radioimmunotherapy with anti-CD20 antibodies is a promising treatment approach for relapsed low-grade non-Hodgkin's lymphoma. Under revised Nuclear Regulatory Commission regulations (May 1997), patients may be released following treatment provided the maximum dose to any individual is not likely to exceed 500 mrem. Non-Hodgkin's lymphoma patients have been studied to evaluate radiation exposure to caregivers/family members after outpatient treatment with tositumomab and iodine I 131 tositumomab (Bexxar therapy). Estimates of total radiation doses to individuals expected to be maximally exposed to patients posttreatment have revealed that the doses should be within revised guidelines. In a University of Nebraska Medical Center study, the predicted total radiation doses (based on patient dose rate at 1 meter) ranged from 95-423 mrem. Family members were provided radiation-monitoring devices to directly monitor radiation exposure. Measured doses ranged from 10-409 mrem. In this and other studies, estimated and measured dose equivalents to maximally exposed individuals were below 500 mrem. Measured doses were, in most instances, lower than those predicted by patient-specific calculations, thus confirming the validity of the calculated dose predictions. Therefore, radioimmunotherapy with tositumomab and iodine I 131 tositumomab can be safely conducted on an outpatient basis.
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PMID:Feasibility and safety of outpatient Bexxar therapy (tositumomab and iodine I 131 tositumomab) for non-Hodgkin's lymphoma based on radiation doses to family members. 1177 93

Bexxar (131I tositumomab) is a radiolabeled anti-CD20 monoclonal antibody for the treatment of relapsed and refractory follicular/low-grade and transformed non-Hodgkin's lymphoma. It has shown high response rates with durable complete remissions in patients who have received either prior chemotherapy or rituximab (Rituxan, MabThera; IDEC Pharmaceuticals Corp/Genentech/F Hoffmann La Roche). Complications include myelosuppression, secondary acute leukemia, myelodysplasia and hypothyroidism. The role of this promising new agent is being defined in phase II and III trials. In February 2001, ABN Amro Predicted launch in 2001 and sales of US $25 million rising to US $70 million in 2003 [422363]. Corixa and GlaxoSmithKline anticipate a launch in the US in 2002 [424619].
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PMID:Bexxar (Corixa/GlaxoSmithKline). 1205 68

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.
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PMID:A clinical and scientific overview of tositumomab and iodine I 131 tositumomab. 1272 4

Radioimmunotherapy (RIT) is a promising emerging therapy for non-Hodgkin's lymphoma and may ultimately prove useful in the treatment of other tumors. The most extensively investigated RIT agent is tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA, and GlaxoSmithKline, Philadelphia, PA) which has been administered to over 1,000 patients during the past 9 years. As with most drugs, there is considerable interpatient variability in the clearance rate (or total body residence time) of radioimmunoconjugates. The clearance rate of iodine I 131 tositumomab in clinical trials has varied by as much as five-fold. The advantage of RIT with iodine-131, which emits both gamma photons and beta particles, is that by scanning it allows for the determination of the patient-specific total body residence time by the administration of a trace-labeled dose of the radionuclide (ie, dosimetric dose). By administration of the dosimetric (trace-labeled) dose, and determination of the patient's residence time (a measure of how long the radionuclide is retained in the body), the therapeutic dose can be precisely adjusted to maximize the therapeutic effect and minimize toxicity. Tositumomab and iodine I 131 tositumomab is a specific therapeutic at two levels: first, it specifically targets the tumor, delivering a log or more radiation to tumor compared with the rest of the body; and second, the administered dose of radioactivity is patient-specific. The paradigm of a targeted drug with a patient-specific dose may become more routine as targeted therapies are further developed along with better assays to directly measure drug levels. For the present, whole-body dosimetry is routinely applied for RIT with tositumomab and iodine I 131 tositumomab and has proven to be a reliable method to determine the patient-specific maximally tolerated therapeutic radiation dose to maximize efficacy while minimizing organ and bone marrow toxicity.
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PMID:The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab. 1272 5

Radioimmunotherapy with radiolabeled anti-CD20 antibodies is a promising new treatment approach for low-grade non-Hodgkin's lymphoma. However, the administration of radiolabeled antibodies presents some added complexity. At the University of Nebraska Medical Center (Omaha, NE), an institutional model has been developed that ensures the efficient and safe delivery of tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA and GlaxoSmithKline, Philadelphia, PA). An integrated, multidisciplinary treatment team is responsible for managing all aspects of treatment. Using this model, it is possible to administer tositumomab and iodine I 131 tositumomab safely and effectively in the outpatient setting. Patients can usually be released immediately after treatment. Guidelines and instructions for patient release have been developed and validated and are provided herein. These instructions ensure that radiation exposure of family members and caregivers who are exposed to the patient is maintained as low as reasonably achievable and well within regulatory limits.
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PMID:Establishing an institutional model for the administration of tositumomab and iodine I 131 tositumomab. 1272 6

Treatment options for patients with indolent non-Hodgkin's lymphoma historically involved radiation or chemotherapy. Although initial response rates are excellent, treatment is increasingly less effective with each successive relapse. The advent of immunotherapy heralds a new era for the treatment of these patients. Radioimmunotherapy adds the benefits of cytotoxic radiation to immunotherapy and represents a significant addition to the treatment armamentarium. Various antigens for lymphoma have been targeted, of which anti-CD20 antibodies are the furthest in development. Ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA), a (90)yttrium-labeled agent, and (131)iodine-labeled tositumomab (Bexxar; Corixa, Seattle, WA) are approved by the US Food and Drug Administration. Both agents have shown utility in therapy for relapsed and refractory low-grade and transformed lymphomas. This review highlights features of radioimmunotherapy that are relevant to non-Hodgkin's lymphoma, focusing on the two anti-CD20 antibodies.
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PMID:New strategies in radioimmunotherapy for lymphoma. 1289 86

Iodine-131 tositumomab [B1, Bexxar , iodine-131 anti-B1 antibody] is a murine antibody conjugated to iodine 131 that recognises and binds to the B1 (CD20) antigen which is found specifically on B lymphocytes. Iodine-131 tositumomab has a dual mechanism of action. It is capable of initiating a host immune response to those B cells to which it is attached, and it also triggers apoptosis in a significant proportion of the cells to which it binds. The product was first discovered by Coulter Corporation, Miami, in collaboration with the Dana-Farber Cancer Institute and the University of Michigan. The spin-off company Coulter Pharmaceutical, upon its formation, obtained worldwide rights to iodine-131 tositumomab. (Coulter Corporation was acquired subsequently by Beckman Instruments in October 1997. The union of the two companies produced Beckman Coulter.) In December 2000, Coulter Pharmaceutical was acquired by, and merged into, Corixa Corporation.Iodine-131 tositumomab is available for licencing in Japan. Corixa Corporation and GlaxoSmithKline signed an agreement to jointly develop and commercialise iodine-131 tositumomab. The total agreement has a potential value of up to $US132 million, plus shared profits and royalties. The two companies will jointly market the antibody in the US following regulatory approval. Corixa Corporation has announced it expects iodine-131 tositumomab to be approved in the US for non-Hodgkin's lymphoma (NHL). Under the terms of the original agreement, GlaxoSmithKline will receive exclusive marketing rights outside the US, excluding Japan. However, an amended agreement between the two companies will allow Corixa Corporation to also market the product outside the US. In February 2003, the European Commission granted iodine-131 tositumomab orphan-drug designation. Corixa Corporation and GlaxoSmithKline also intend to jointly investigate the use of the product in other indications. GlaxoSmithKline may also receive access to second generation anti-CD20 compounds under its agreement with Corixa Corporation. In May 2003, Corixa Corporation entered into an agreement that will see GlaxoSmithKline market Bexxar in Canada. Under the terms of the agreement, Corixa Corporation will manufacture and supply the product to GlaxoSmithKline, who will register, market and sell it in Canada. In October 2001, Amersham PLC, a supplier of medical equipment, announced that its Amersham Health unit had signed a marketing agreement with Corixa Corporation. The agreement allows Amersham Health to market iodine-131 tositumomab in Europe. Corixa Corporation formed agreements with Boehringer Ingelheim Pharma KG and Lonza Biologics to produce the B1 antibody and radiolabelling of the antibody has been contracted out to MDS Nordion.Iodine-131 tositumomab has received orphan drug and fast track designation for the treatment of NHL. Corixa Corporation submitted a Biologics Licence Application (BLA) to the US FDA in 1999, seeking permission to market Bexxar in the US for the treatment of relapsed or refractory, low grade or transformed low grade B-cell NHL. Following a priority review, the US FDA requested that Corixa Corporation reformat certain sections and perform additional analyses of existing data in its BLA. Corixa Corporation and GlaxoSmithKline resubmitted their BLA to the US FDA in September 2000. The BLA was subsequently accepted by the US FDA in November 2000. However, in March 2001, the US FDA requested additional information in its complete review letter to Corixa Corporation and marketing partner GlaxoSmithKline. The two companies submitted data pertaining to the chemistry, manufacturing and controls section of the BLA, and to the majority of the questions regarding the clinical section of the BLA in August 2001. Corixa Corporation and GlaxoSmithKline submitted the remainder of the response to the US FDA in September 2001, following an independent review of clinical trial data. In March 2002, Corixa Corporation received another complete review letter from the US FDA, which stated that additional clinical trials would have to be conducted in order to provide adequate evidence of the safety and clinical benefit of Bexxa. The US FDA also denied Corixa Corporation's request for accelerated approval, stating that the data provided was inadequate to show that Bexxar filled an unmet medical need. Corixa Corporation has met formally with the US FDA but the two were unable to resolve their differences. Corixa Corporation will now file a formal request for dispute resolution under the Food and Drug Administration Modernisation Act. Corixa Corporation also requested a presentation of Bexxa data to the US FDA's scientific advisors. In June 2002, the US FDA granted the company's appeal for additional regulatory review. In December 2002, the US FDA's Oncologic Drugs Advisory Committee agreed that Bexxar has clinical benefit for patients with NHL. In May 2003, Corixa Corporation and GlaxoSmithKline announced that they had fulfilled many of the steps required for US FDA approval, however the US FDA has extended its review of the application for another 3 months. This extension will allow for further refinement of post marketing commitments and package insert language, and to ensure they are consistent with an updated safety database requested by the US FDA and submitted by Corixa Corporation in early April. GlaxoSmithKline was waiting for the outcome of the situation before deciding on marketing plans for Bexxar. Corixa Corporation and GlaxoSmithKline will conduct a head-to-head study of Bexxar and Idec's Zevalin, planned for mid-2003. The trial will likely be one of three phase IV studies that the US FDA requires for accelerated approval of Bexxar. Corixa Corporation initiated its Expanded Access Program for Bexxar in response to requests from physicians and patients for continued access to Bexxar during the period prior to potential US FDA marketing approval.A phase II multicentre trial of Bexxar in combination with CHOP chemotherapy is underway in the US as first-line therapy in patients with intermediate-grade NHL. Corixa Corporation has initiated a phase II trial of iodine-131 tositumomab in combination with cyclophosphamide, vincristine and prednisone for the treatment of previously untreated low-grade NHL. The trial was initiated while the company was preparing its BLA for Bexxar for use as a single agent for relapsed or refractory NHL. Corixa Corporation intends to pursue additional trials to expand the potential use of iodine-131 tositumomab to other indications, including chronic lymphocytic leukaemia. The agent is also in a clinical trial for preparation in autologous bone marrow transplant patients. The trial is designed to test the combination of iodine-131 tositumomab and chemotherapy. The trial began in 1995 and has so far enrolled 40 patients. In addition, a phase II dose-escalation trial has begun at the University of Nebraska for the combined use of iodine-131 tositumomab and chemotherapy as preparation for autologous bone marrow transplant. Corixa Corporation has received an issued US patent covering methods for administering and dosing radioimmunotherapy for the treatment of B-cell lymphomas. The patent covers iodine-131 tositumomab and other anti-CD20 antibodies used to aid in selective tumour targeting. Corixa Corporation has exclusive rights to the patent.A February 2000 media release from GlaxoSmithKline and Corixa Corporation stated that they had been issued a composition patent relating to radiolabelled monoclonal antibodies (including Bexxar) for the treatment of B-cell lymphomas. On 11 September 2001, IDEC announced that it had filed two separate lawsuits. The first lawsuit is against Corixa Corporation and the University of Michigan on six patents pertaining to products and processes related to radioimmunotherapy. They seek a declaration that Zevalin does not infringe Corixa Corporation's issued US patents. The second lawsuit involves two patents relating to cell culture media, and is against GlaxoSmithKline. IDEC's lawsuit in this case, seeks a declaration that its manufacture of Zevalin does not infringe GlaxoSmithKline's issued US patents. Corixa Corporation and GlaxoSmithKline have also filed a complaint for patent infringement against IDEC. These actions however, should have no effect on the regulatory process that Zevalin is completing, or prevent IDEC from launching the drug before iodine-131 tositumomab.A year earlier, in March 2001, the Financial Times reported that Bexxar could reach peak sales of $US120 million. In 1998, Coulter Pharmaceutical received a licencee fee payment of $US34 million from SmithKline Beecham (now GSK) in the fourth quarter of the year, as part of the joint development and commercialisation agreement for Bexxar.
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PMID:Iodine-131 Tositumomab: (131)I-anti-B1 antibody, (131)I-tositumomab, anti-CD20 murine monoclonal antibody-I-131, B1, Bexxar, (131)I-anti-B1 antibody, iodine-131 tositumomab, iodine-131 anti-B1 antibody, tositumomab. 1289 47

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