Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas.

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

Assessment of therapeutic effect of CD20-targeted immunoliposome in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a form of extranodal non-Hodgkin's B-cell lymphoma limited to the CNS. The treatment of PCNSL is ineffective partly due to the blood-brain barrier (BBB) restriction of delivery of many drugs including anti-CD20 (Rituximab; RTX) which is a standard treatment for systemic B-cell lymphomas. In this study, liposome with tween-80 surface modification was fabricated and conjugated with RTX for enhancing BBB penetration to target lymphoma cells in the CNS. Physicochemical characterizations of Lip/RTX were performed and spherical shape liposomes with narrow size distribution were demonstrated by TEM. An average diameter of Lip/RTX was 168.57 ± 1.57 nm with the percentage of RTX conjugation at 90.94. Cell internalization monitored by flow cytometry confirmed that conjugation of RTX promoted liposome entry into Raji cells expressing CD20. Antitumor activity of Lip/RTX was comparable to free RTX indicating that RTX moieties on liposome remained their therapeutic function. In addition, Lip/RTX inhibited tumor aggressiveness by limiting cell migration and invasion. Systemic administration of Lip/RTX significantly prolonged survival of mice harboring intracranial lymphoma xenografts. Taken together, Lip/RTX presents a new potential treatment for patients with PCNSL.

A Prospective Economic Analysis of Early Outcome Data From the Alliance A041202/ CCTG CLC.2 Randomized Phase III Trial Of Bendamustine-Rituximab Compared With Ibrutinib-Based Regimens in Untreated Older Patients With Chronic Lymphocytic Leukemia.

INTRODUCTION: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted. CONCLUSIONS: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver.

Flow cytometry-based assessment of direct-targeting anti-cancer antibody immune effector functions.

Monoclonal antibody-based therapies are increasingly being used to treat cancer. Some mediate their therapeutic effects through modifying the function of immune cells globally, while others bind directly to tumor cells and can recruit immune effector cells through their Fc regions. As new direct-binding agents are developed, having the ability to test their Fc-mediated functions in a high-throughput manner is important for selecting antibodies with immune effector properties. Here, using monoclonal anti-CD20 antibody (rituximab) as an example and the CD20+ Raji cell line as tumor target, we describe flow cytometry-based assays for determining an antibody's capacity for mediating antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). These assays are sensitive, reliable, affordable and avoid the use of radioactivity.

Multifaceted assessment of rituximab biosimilarity: The impact of glycan microheterogeneity on Fc function.

Biosimilars are poised to reduce prices and increase patient access to expensive, but highly effective biologic products. However, questions still remain about the degree of similarity and scarcity of information on biosimilar products from outside of the US/EU in the public domain. Thus, as an independent entity, we performed a comparative analysis between the innovator, Rituxan® (manufactured by Genentech/Roche), and a Russian rituximab biosimilar, Acellbia® (manufactured by Biocad). We evaluated biosimilarity of these two products by a variety of state-of-the-art analytical mass spectrometry techniques, including tandem MS mapping, HX-MS, IM-MS, and intact MS. Both were found to be generally similar regarding primary and higher order structure, though differences were identified in terms of glycoform distribution levels of C-terminal Lys, N-terminal pyroGlu, charge variants and soluble aggregates. Notably, we confirmed that the biosimilar had a higher level of afucosylated glycans, resulting in a stronger FcγIIIa binding affinity and increased ADCC activity. Taken together, our work provides a comprehensive comparison of Rituxan® and Acellbia®.

Assessment of structural and functional similarity of biosimilar products: Rituximab as a case study.

Biosimilars are products that are similar in terms of quality, safety, and efficacy to an already licensed reference/ innovator product and are expected to offer improved affordability. The most significant source of reduction in the cost of development of a biosimilar is the reduced clinical examination that it is expected to undergo as compared to the innovator product. However, this clinical relief is predicated on the assumption that there is analytical similarity between the biosimilar and the innovator product. As a result, establishing analytical similarity is arguably the most important step towards successful development of a biosimilar. Here, we present results from an analytical similarity exercise that was performed with five biosimilars of rituximab (Ristova®, Roche), a chimeric mouse/ human monoclonal antibody biotherapeutic, that are available on the Indian market. The results show that, while the biosimilars exhibited similarity with respect to protein structure and function, there were significant differences with respect to size heterogeneity, charge heterogeneity and glycosylation pattern.

Assessment of the Effects of Rituximab Monotherapy on Different Subsets of Circulating T-Regulatory Cells and Clinical Disease Severity in Severe Pemphigus Vulgaris.

BACKGROUND: Robust evidence for the efficacy of rituximab monotherapy in pemphigus is lacking. The effects of rituximab on T-regulatory cells (Tregs) in pemphigus have not been studied. OBJECTIVE: The primary objective was to assess the efficacy of rituximab monotherapy in severe pemphigus vulgaris. The secondary objectives were to assess whether counts of different subsets of Tregs in the peripheral blood correlate with baseline clinical severity and whether clinical response in severe pemphigus is associated with an alteration in the Treg count. METHODS: Eighteen eligible subjects with severe pemphigus vulgaris were recruited and were treated with 1 g of intravenous rituximab on days 0 and 15. Efficacy was assessed in terms of disease control, time to disease control, complete remission off therapy, and relapse. Flow cytometric analysis of CD4+CD25+FoxP3, IL-10-secreting Tr1, and TGF-ß secreting Th3 regulatory cells was performed. Clinical evaluation and flow cytometric analysis of Tregs was performed periodically until follow-up at 26 weeks. RESULTS: Rituximab monotherapy was able to induce complete remission in all but 5 (68.75%) patients and was well tolerated. No direct relationship between clinical severity and CD4+CD25+FoxP3 cell counts was found. There were inverse correlations between serially measured values of the cutaneous and mucosal Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Th3 cell count. CONCLUSION: Rituximab is a safe and effective monotherapy option for severe pemphigus. As the immunological findings were somewhat different from those observed in other autoimmune conditions treated with rituximab, further studies are required to substantiate the findings of our study in pemphigus patients.

Assessment of physicochemical properties of rituximab related to its immunomodulatory activity.

Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity.