Proposed rituximab biosimilar BCD-020 versus reference rituximab for treatment of patients with indolent non-Hodgkin lymphomas: An international multicenter randomized trial.

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m2 for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was -20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (-12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab.

Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study.

Previous randomized trials have demonstrated that rituximab maintenance (R-maintenance) can prolong time to progressive disease in patients with follicular lymphoma (FL). The phase IIIb MAXIMA study (NCT00430352) was a large prospective evaluation of R-maintenance in a daily care setting. The primary objective was safety. Secondary objectives included progression-free survival, overall survival, time to next lymphoma treatment, and partial response (PR) to complete response/unconfirmed (CR/CRu) conversion rate. Patients (n = 545) with first-line or relapsed FL who responded to 8 cycles of rituximab-based induction received R-maintenance every 2 months for 2 years. At study entry, 380 patients had CR or CRu, and 165 had PR. The median age was 57.0 years. The most common non-hematologic adverse events (AEs, excluding infusion-related reactions) were cough (9.9 % of patients), fatigue (7.5 %), nasopharyngitis (7.1 %), back pain (6.5 %), diarrhea (6.9 %), arthralgia (6.0 %), headache and hypertension (5.2 % each), and pyrexia (5.1 %). The majority of AEs were grade 1 or 2. Grade 3, 4, and 5 infections occurred in 21 (3.9 %), 2 (0.4 %), and 1 (0.2 %) patient, respectively. Fifty-one hematologic AEs occurred in 6.6 % (n = 35) of patients. Grade 3/4 prolonged neutropenia and hypogammaglobulinemia occurred in 13 (2.4 %) and 5 (0.9 %) patients, respectively. All cases of prolonged neutropenia or hypogammaglobulinemia were manageable and resolved. Fast infusion did not alter the safety profile. Efficacy was comparable with results from previous trials. R-maintenance is safe in a daily care setting for patients with first-line or relapsed FL.

Mucosal Adhesive Chitosan Nanogel Formulations of Antibiotics and Adjuvants (Terpenoids, Flavonoids, etc.) and Their Potential for the Treatment of Infectious Diseases of the Gastrointestinal Tract.

Bacterial infections are usually found in the stomach and the first part of the small intestine in association with various pathologies, including ulcers, inflammatory diseases, and sometimes cancer. Treatment options may include combinations of antibiotics with proton pump inhibitors and anti-inflammatory drugs. However, all of them have high systemic exposure and, hence, unfavorable side effects, whereas their exposure in stomach mucus, the predominant location of the bacteria, is limited. Chitosan and nanogels based on chitosan presumably are not absorbed from the gastrointestinal tract and are known to adhere to the mucus. Therefore, they can serve as a basis for the local delivery of antibacterial drugs, increasing their exposure at the predominant location of therapeutic targets, thus improving the risk/benefit ratio. We have used E. coli ATCC 25922 (as a screening model of pathogenic bacteria) and Lactobacilli (as a model of a normal microbiome) to study the antibacterial activity of antibacterial drugs entrapped in a chitosan nanogel. Classical antibiotics were studied in a monotherapeutic regimen as well as in combination with individual terpenoids and flavonoids as adjuvants. It has been shown that levofloxacin (LF) in combination with zephirol demonstrate synergistic effects against E. coli (cell viability decreased by about 50%) and, surprisingly, a much weaker effect against Lactobacilli. A number of other combinations of antibiotic + adjuvant were also shown to be effective. Using FTIR and UV spectroscopy, it has been confirmed that chitosan nanogels with the drug are well adsorbed on the mucosal model, providing prolonged release at the target location. Using an ABTS assay, the antioxidant properties of flavonoids and other drugs are shown, which are potentially necessary to minimize the harmful effects of toxins and radicals produced by pathogens. In vivo experiments (on sturgeon fish) showed the effective action of antibacterial formulations developed based on LF in chitosan nanogels for up to 11 days. Thus, chitosan nanogels loaded with a combination of drugs and adjuvants can be considered as a new strategy for the treatment of infectious diseases of the gastrointestinal tract.

Predictive modeling of adverse drug reactions to tamoxifen therapy for breast cancer on base of pharmacogenomic testing.

OBJECTIVES: The present study investigated the analysis of adverse drug reactions (ADRs) to tamoxifen (TAM) in breast cancer patients in relation to the carriage of genetic polymorphisms of genes encoding enzymes of CYP system and transporters of P-glycoprotein (Pg) and predictive models based on it. METHODS: A total of 120 women with breast cancer taking adjuvant TAM were examined for the gene polymorphisms such as CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3 and ABCB1 (C3435T). Allelic variants were determined using the real-time polymerase chain reaction method. The research material was double sampling of buccal epithelium. Medical history data and extracts from case histories were used as sources of medical information, on the basis of which questionnaires specially created by us were filled out. RESULTS: An associative analysis showed association with the development of ADRs to TAM indicating their clinical significance from different genetic polymorphisms of CYP2D6, CYP3A5, CYP2C9 and ABCB1. The complex associative analysis performed using mathematical modeling made it possible to build predictive risk models for the development of ADRs such as hot flashes, dyspepsia, bone pain, and asthenia. CONCLUSIONS: Models that include both genetic and non-genetic determinants of ADRs of TAM may further improve the prediction of individual response to TAM.

Ibrutinib in combination with rituximab is highly effective in treatment of chronic lymphocytic leukemia patients with steroid refractory and relapsed autoimmune cytopenias.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are common complications of CLL. The optimal treatment of steroid refractory AIHA/PRCA is not well established. We conducted a multicenter study of ibrutinib and rituximab in patients with relapsed/refractory to steroids AIHA/PRCA and underlying CLL. Protocol included induction (ibrutinib 420 mg/day and rituximab, 8 weekly and 4 monthly infusions) and maintenance phase with ibrutinib alone until progression or unacceptable toxicity. Fifty patients were recruited (44-warm AIHA, 2-cold AIHA, 4-PRCA). After the induction 34 patients (74%) have achieved complete response, 10 (21.7%) partial response. Median time to hemoglobin normalization was 85 days. With regards to CLL response 9 (19%) patients have achieved CR, 2 (4%) patients-stabilization and 39 (78%)-PR. The median follow-up was 37.56 months. In AIHA group 2 patients had a relapse. Among 4 patients with PRCA 1 patient did not respond, and 1 patient had a relapse after CR, 2 remained in CR. The most common adverse events were neutropenia (62%), infections (72%), gastrointestinal complications (54%). In conclusion ibrutinib in combination with rituximab is an active second-line treatment option for patients with relapsed or refractory AIHA/PRCA and underlying CLL.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Patient blood management in oncology in the Russian Federation: Resolution to improve oncology care.

There is accumulating evidence that anemia and iron deficiency, thrombocytopenia, blood loss and coagulopathy are independent risk factors for adverse patient outcomes in oncology and other settings. Patient blood management (PBM) aims to address these factors by managing and preserving a patient's blood. PBM improves patient health, but also reduces resource utilization, including use of allogeneic blood components, which is another risk factor for adverse outcomes. Supported by the World Health Organization and endorsed in WHA63.12, PBM is recommended by an increasing number of health authorities and is about to become a new standard of care. In support of the Russian National Long-Term Oncology Strategy 2030 to improve quality of oncological care, and with support from the National Association of Specialists in PBM, the PBM Oncology Working Group of the Russian Federation was created. In July 2020, this Group met to discuss the rationale and need for PBM in Russian oncology care. The Group recommended to include PBM as an integral part of standard oncology treatment pathways and developed a national resolution as a call to action on this matter, which was adopted in August 2020. This article details the rationale behind the resolution, delineates the action required from facilitating stakeholders (government; healthcare providers; educational facilities; research entities/institutions; funders; patient representatives/advocates), and proposes a roadmap for implementation. The generation of local health-economic and outcome data and the development of educational programs will be important in the implementation of PBM to help alleviate the health, social and economic burden of cancer.