Rituximab toxicity

Rituximab demonstrates dose-dependent pharmacokinetics. At a dose of375 mg/nf, the mean serum tj was 76 hours after one dose and 206 hours r er the last dose, with considerable interindividual variation. The wide range oftj likely reflects differences in patient tumor burden and normal B-cell populations. Rituximab toxicities are mostly related to infusion reactions, although there are increasing reports of late-onset neutropenia and rare reports of severe skin toxicity (Table 51-4). 

This hot antibody is linked to yttrium and binds to the CD20 receptor of B lymphocytes (see Rituximab below). Hematologic toxicity may occur several weeks after administration and may take weeks to resolve. 

Is the discovery and development of another blockbuster monoclonal antibody like rituximab a feasible research and development model today Many of the special events that contributed to its success are probably not replicable. As with several other successful drugs, the market turned out to be much larger than anticipated, so competition from other drugs being simultaneously developed was not so intense. Similarly, the ability to manufacture the drug in a cost-effective manner did not exist when the project was initiated, but there were other advantages unique to rituximab. Its toxicity is minimal, a... 

Farag et al. (69) reported that no differences in infusion toxicity or response were foimd according to FCGR3A or FCGR2A polymorphism after rituximab monotherapy (rituximab, stepped-up administration of rituximab from 100 mg to 375mg/m2 during the first week and then given as described previously, three times a week for 4 weeks) in imtreated or previously treated CLL patients n = 30 Table 3). 

Rituximab is a chimeric monoclonal antibody that targets CD20 lymphocytes (see Chapter 55). This depletion takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral cells although this depletion neither correlates with efficacy nor with toxicity. 

Tositumomab is another anti-CD20 monoclonal antibody and is complexed with iodine 131 (131I). Tositumomab is used in two-step therapy in patients with CD20-positive, follicular non-Hodgkin s lymphoma whose disease is refractory to rituximab and standard chemotherapy. Toxicities are similar to those for ibritumomab and include severe cytopenias such as thrombocytopenia and neutropenia. Tositumomab should not be administered to patients with greater than 25% bone marrow involvement. 

Must consider toxicities of rituximab also, since always given in combination hematologic toxicity very delayed in onset, occurring 7 9 weeks after drug administration with 2 weeks for recovery infusion reactions asthenia, nausea, chills, fever tumor pain... 

Aurlien E, Larsen RH, Kvalheim G, Bruland OS. Demonstration of highly specific toxicity of the a-emitting radioimmunoconjugate At-rituximab against non-Hodgkin s lymphoma cells. Br J Cancer 2000 83 1375-1379. 

Rituximab ADCC CDC apoptosis 375 mg/ra IV infusion weekly for 4 weeks Infusion-related toxicity with fever, rash, and dyspnea B-ceU depletion late-onset neutropenia... 

D. Monoclonal Antibodies Rituximab is a monoclonal antibody to a surface protein in non-Hodgkin s lymphoma cells. It is presently used with conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low grade lymphomas. Trastuzumab is a monoclonal antibody to a surface protein in breast cancers that overexpress the HER2 protein. Acute toxicity of these antibodies includes nausea and vomiting, chills, fevers, and headache. Rituximab use is associated with hypersensitivity reactions and myelosuppression. Trastuzumab may cause cardiac dysfunction, including congestive heart failure. 

The first Phase 1 study, single rituximab infusions ranging from 10 to 500 mg m in 15 patients, reached the highest dose without dose-limiting toxicity [20]. The maximum tolerated dose (MTD) was not... 

Rituximab is now a standard component of first-line treatment for DLBCL, the most common NHL subtype (accounting for over 30% of cases) [71]. The addition of rituximab to standard CHOP chemotherapy significantly increases radiographic response rates, event-free survival, and overall survival, without increasing toxicity [2, 72, 73], The benefit of rituximab maintenance in DLBCL appears limited to those patients who have not received rituximab as part of their initial therapy [74]. 

However, in a more recent study in patients with previously treated chronic lymphocytic leukaemia (CLL), pentostatin 4 mg/m with cyclophosphamide 600 mg/m was found to be safe and effective. Another study found that pentostatin 4 mg/m and cyclophosphamide 600 mg/m with or without rituximab 375 mg/m was safe and effective for patients with Waldenstrom s macroglobinaemia. Other studies in patients with previously treated or untreated CLL found that cyclophosphamide 600 mg/m with pentostatin 4 or 2 mg/m and rituximab 375 m m was effective and was either well-tolerated or had only modest toxicity. ... 

Kay ME, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, HeeremaNA, SmithL, Grever MR, Byrd JC. Combination chemoimmu-notherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukaemia. Blood 2007, 109, 405-11. 

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