AimsPharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B‐cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome.MethodsRituximab serum levels were determined by enzyme‐linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling.ResultsThe data were best described by a two‐compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227–0.279] l day–1 and time‐varying specific clearance of 0.278 (95% CI: 0.181–0.390) l day–1, corresponding to target‐mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day−1 (95% CI: 0.0478–0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4–95.0).ConclusionsThis finding indicates that time‐changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients.

Late-onset neutropenia (LON) following rituximab therapy is a recently recognized adverse effect occurring in various clinical settings. However, the true incidence and pathogenesis of this adverse effect are not fully understood. We retrospectively reviewed the medical records of 160 patients with diffuse large B-cell lymphoma (DLBCL) in complete remission (CR) following first-line treatment with rituximab-containing therapy. The incidence of LON was 26.9% (grade 1, 2, 3 and 4) and the incidence of severe LON (grade 3 and 4) was 7.5%. The risk factors for the occurrence of LON were not identified, and overall survival did not differ between patients who developed LON and those who did not. This study suggests that LON is a quite common complication to rituximab therapy. However, more studies are needed in order to elucidate the true mechanism behind and risk factors for LON.

Rituximab is a monoclonal antibody routinely used in the treatment of B-cell non-Hodgkin lymphomas. It mediates antibody-dependent cellular cytotoxicity of B lymphocytes by bridging them with Fcγ receptors (FcγR) on effector cells. Several polymorphisms in the FcγR genes have been identified to influence rituximab binding to FcγR, thus altering its antitumor effect in indolent lymphomas. In the present study, the impact of FcγRIIa and FcγRIIIa polymorphisms on the survival and response to immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone was evaluated in diffuse large B-cell lymphoma (DLBCL) patients. A total of 29 Slovenian DLBCL patients were studied. Genotyping was conducted for FcγRIIa-27, FcγRIIa-131, FcγRIIIa-48 and FcγRIIIa-158 polymorphisms. The median follow-up time was 29.7 months (range, 9.7–45.4 months). No significant impact of the genotypes was observed on the treatment response, progression-free or overall survival of DLBCL patients. There was a non-significant trend of an improved response to chemotherapy without additional irradiation in patients homozygous for Val at FCγIIIa-158 compared to Phe carriers. The findings of the present study indicate that FcγR polymorphisms have no influence on the survival of DLBCL patients.

Background The Oncology Institute of Ljubljana (OIL) is the main cancer care institution in Slovenia. Extravasation is a serious complication of intravenous chemotherapy. Clinical outcomes vary from minor symptoms to severe tissue damage. The aim of the guidelines is to provide appropriate, professional and clear instructions on how to treat the patients in whom extravasations occur. Purpose To develop guidelines for treating anticancer drug extravasation, which contain the management algorithm of antidotes and treatments that should be performed, as well as risk factors and strategies to prevent extravasation. Furthermore, to statistically review all documented cases of anticancer drug extravasations from January 2010 to September 2013. Materials and methods 47 different intravenous anticancer drugs are available in chemotherapy protocols in OIL. Our extravasation guidelines were based on a literature review, through research and analysis of guidelines and articles obtained. Results Anticancer drugs are classified according to their damage-causing potential as vesicant, non vesicant and irritant; this determines the treatment regimens recommended. From the literature reviewed it was obvious that some anticancer drugs differ in classification according to their injury-inflicting potential and treatment regimens. In our guidelines we did not consider that distinction between vesicant and non-vesicant drugs to be absolute. The measures to be taken when chemotherapy extravasation occurs are based on the classification of their potential, ATC classification and knowledge of the actions of the drug and its antidote. Our guidelines include three specific antidotes: dimethyl sulfoxide, hyaluronidase and dexrazoxane, found in the literature review. A total of 47 anticancer drugs available in our guidelines were divided into 10 vesicants, 10 irritants and 16 non-vesicant drugs. 8 drugs were classified as both vesicant and irritant and 3 drugs as both irritant and non vesicant. Topical application of cold packs is recommended for 20 anticancer drugs, warm packs for 4 drugs, for 5 drugs we can use either of them and 18 drugs require none of the above. Specific management of some anticancer drugs (packs, antidotes) is changed when a large volume and high concentration is extravasated. In the events reported, the extravasated drugs were classified as vesicant in 59% of cases, irritant in 17% and non-vesicant in 24% of cases. In 60 cases specific antidotes and in 77 cases cold packs were administered but in 32 cases further action was required. Antidotes were administered in 11% of cases studied: mainly dimethyl sulfoxide (48%) and hyaluronidase (41%) but also dexrazoxane. Conclusions The guidelines are a valuable tool for our institute as well as for other medical centres throughout Slovenia. In addition each case of extravasation is documented through an anticancer drug extravasation documentation form. No conflict of interest.