Tositumomab

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Compound Name:TositumomabMolecular Target:CD20Molecular Structure:murine, monoclonal; covalently bound to Iodine-131Licensed Indication:non-Hodgkins Lymphoma (CD20 positive, follicular) which is refractory to rituximab and relapsed following chemotherapyManufacturer and/or Distributor:GlaxoSmithKlineInitial FDA Approval:1993Summary:Tositumomab (Bexxar®) is a murine IgG2al mAb directed at the B-cell specific surface antgen CD20. It was approved by the FDA in 2003 for the treatment of patients with CD20-expressing, relapsed or refractory, low grade, follicular, or transformed non-Hodgkin’s lymphoma (NHL), including patients with rituximab-refractory lymphomas. It is currently not indicated for the initial treatment of patients with CD20 positive NHL or in rituximab-naïve patients. Tositumomab is indicated for a single course of therapy given in two stages. In an initial dosimetric step, unlabeled drug followed by a smaller amount of I-131 labeled drug are given intravenously. Whole body gamma scans over the following week are used (1) to determine if the biodistribution of the radiolabeled drug is appropriate; and (2) to calculate the dose of I-131 to be used for the therapeutic step. One to two weeks after the dosimetric step, a therapeutic step delivers the same quantities of tositumomab as the dosimetric step, but with I-131 in a much larger amount based on the data from the dosimetric scans. The treatment regimen is tumoricidal in two ways. First, tositumomab is a so-called “next generation” or type II anti-CD20 mAb that triggers caspase-independent B cell lymphoma apoptotic death in vitro. It does not activate complement, which may enhance its ability to kill by ADCC (antibody dependent cellular cytotoxicity). Second, the I-131 conjugated therapeutic dose of tosiumomab delivers a continuous, low-dose of gamma radiation emitted by the radioisotope that is targeted directly to the lymphoma cells. It has been shown to be more effective than unlabeled mAbs in terms of overall and complete response rates in follicular lymphoma patients, even in those resistant to rituximab. Tositumomab-I-131 has “black box” warnings including anaphylaxis as well as prolonged and severe cytopenias. Hypothyroidism is an inherent danger due to the I-131 component, and thyroid-blocking medication must be given prior to its use for dosimetry and therapy. Myelodysplasia and secondary leukemia have been reported. Additionally, prescribers must be trained in the handling of radioisotopes.References

Label insert: http://us.gsk.com/products/assets/us_bexxar.pdf

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2. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2001 Oct 1;19(19):3918-3928.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11579112
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4. Beers SA, Chan CH, James S, French RR, Attfield KE, Brennan CM, et al. Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation. Blood. 2008 Nov 15;112(10):4170-4177.
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