Administration Of Rituximab In Patients Research Articles

Differences in risk of serious infections between patients with secondary versus primary nephropathy following rituximab treatment: a retrospective cohort study.

The incidence of severe infections (SIs) in patients with autoimmune nephropathy after rituximab (RTX) treatment varies significantly. Our study aims to identify high-risk populations, specifically by comparing the differences in the risk of SIs between patients with primary nephropathy and those with nephropathy in the context of systemic autoimmune diseases (referred to as secondary nephropathy). This retrospective cohort study investigated the occurrence of SIs in adult patients with immune-related kidney disease who received RTX treatment at our institution from 2017 to 2022. Multivariable COX regression models were used to analyze the association between the type of nephropathy (primary or secondary) and SIs. Propensity score analyses, subgroup analyses, and E-value calculations were performed to ensure the reliability of the results. Out of 123 patients, 32 (26%) developed 39 cases of SIs during a mean follow-up period of 19.7 ± 14.6 months post-RTX treatment, resulting in an incidence rate of 18.9/100 patient-years. The multivariable COX regression analysis indicated that patients with secondary nephropathy had a significantly higher risk of SIs compared to those with primary nephropathy (HR = 5.86, 95% CI: 1.05-32.63, P = 0.044), even after accounting for confounding variables including gender, age, BMI, history of prior SIs, baseline eGFR, lymphocyte counts, IgG levels, and the utilization of other immunosuppressive therapies. Various sensitivity analyses consistently supported these findings, with an E-value of 5.99. Furthermore, advanced age (HR: 1.03; 95% CI: 1.01-1.06; P = 0.023), low baseline IgG levels (HR: 0.75; 95% CI: 0.64-0.89; P < 0.001), and recent history of SIs (HR: 5.68; 95% CI: 2.2-14.66; P < 0.001) were identified as independent risk factors. The incidence of SIs following RTX administration in patients with autoimmune nephropathy is significant. It is crucial to note that there are distinct differences between the subgroups of primary and secondary nephropathy. Patients with secondary nephropathy, particularly those who are elderly, have low baseline IgG levels, and have a recent history of SI, are more susceptible to SIs.

Analysis of Risk Factors for Infusion-Related Reactions Following Rituximab Administration in Patients with Desensitization before Renal Transplantation.

Infusion-related reactions (IRRs) are the major side effects of rituximab administration. Although several studies have reported predictive markers for IRRs in patients with malignancies, there are no such reports for patients without malignancies. Accordingly, we aimed to clarify the predictive markers for rituximab-induced IRRs in renal transplant recipients. This retrospective study included 116 inpatients aged ≥18 years who received an initial dose of 150 mg/m2 of rituximab for desensitization before renal transplantation with loxoprofen and diphenhydramine before rituximab infusion between June 2007 and February 2022. Overall, 45 patients were evaluated and 71 patients were excluded in this study. IRRs were observed in 12 (26.7%) patients. The proportion of men in the IRRs group was significantly higher than that in the non-IRRs group (p = 0.023). Additionally, body weight, body surface area (BSA), and body mass index (BMI) were significantly higher in the IRRs group than in the non-IRRs group (body weight, p = 0.0058; BSA, p = 0.0051; BMI, p = 0.017). Their cutoff values for predicting rituximab-induced IRRs, based on the receiver-operating characteristic curve, were 74.850 kg, 1.910 m2 and 24.164 kg/m2, respectively. In conclusion, the male sex, high actual body weight, BSA, and BMI may be new predictive markers for rituximab-induced IRRs in renal transplant recipients. Therefore, clinicians should carefully monitor patients who receive rituximab before renal transplantation and present with the predictive markers.

Predictive factors of long-term disease remission after rituximab administration in patients with childhood-onset complicated steroid-dependent nephrotic syndrome: a single-center retrospective study.

Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12months of prednisolone-free remission, IS tapering within 6months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. After RTX initiation, 52 patients (85.2%) relapsed after a median of 665days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3years; median age, 18.3years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5years than in those aged < 13.5years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5years) at RTX initiation. For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

A report on the clinical efficacy of rituximab administration in patients with inborn errors of immunity and autoimmune manifestations

BackgroundRituximab (RTX), an anti-CD20 monoclonal antibody, is considered a novel therapeutic agent in a variable spectrum of immune disorders. Herein, we investigated the clinical efficacy of RTX in inborn errors of immunity (IEIs) with autoimmune manifestations. MethodsPatients with IEIs diagnosed clinically based on European Society for Immunodeficiencies (ESID) diagnostic criteria with at least one autoimmune manifestation referred to Mofid Children's Hospital, Tehran, Iran, between 2010 and 2021 were investigated. Medical records of patients were retrospectively investigated. All patients had received RTX as a course of at least four 375 mg/m2 infusions in weekly intervals. Complete and partial responses were defined as normalization or improvement of biological markers of hemolysis and the requirement for maintenance treatment. ResultsTwenty-three patients (65.2% females and 34.8% males) with common variable immunodeficiency (CVID) (5, 21.7%), unspecified primary immune regulatory disorder (PIRD) (5, 21.7%), LRBA deficiency (4, 17.4%), non-syndromic combined immunodeficiency (CID) (2, 8.7%), STAT3-GOF mutation (2, 8.7%), ataxia-telangiectasia (2, 8.7%), Epstein-Barr virus (EBV)-susceptible PIRD (1, 4.3%), Nijmegen breakage syndrome (1, 4.3%), and familial hemophagocytic lymphohistiocytosis (fHLH) (1, 4.3%) were enrolled.The median (IQR) age at the time of the study, the onset of symptoms, and diagnosis were 12 (6–14), 3 (1–5), and 5 (3–9) years, respectively. Fourteen (60.8%) patients had consanguineous parents. Autoimmune manifestations included cytopenia (17, 73.9%), Kawasaki disease (1, 4.3%), thyroiditis (1, 4.3%), juvenile idiopathic arthritis (JIA) (1, 4.3%), enteropathy (4, 17.4%), mixed connective tissue disease (MCTD) (2, 8.7%), systemic lupus erythematosus (SLE) (2, 8.7%), and Behcet's syndrome (1, 4.3%). The cumulative response rate was 86.8% (complete response: 14, 60.8%, partial response: 6, 26%). At the end of the survey, 8 (34.7%) patients were deceased. ConclusionsRituximab is a promising therapeutic option for autoimmune disorders in the context of IEI. Regular follow-up after the initial rituximab infusion is essential in IEI children.

Repetitive administration of rituximab can achieve and maintain clinical remission in patients with MCD or FSGS

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients’ previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 (p<0.001) and 6 months (p<0.001). Relapse-free survival increased from 4.5 months (95%-CI 3–10 months) to 21 months (95%-CI 16–32 months) (p<0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.

The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis.

ObjectiveTo characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX).MethodsWe conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between “nephrotic” and “nephritic” indications. The primary outcome was the incidence of SI within 12 months after the first RTX application.ResultsA total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m2 versus 26.9 kg/m2, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI.ConclusionsAfter RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.

Efficacy and Safety of Subcutaneous or Intravenous Administration of Rituximab in Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Final Results of the Randomized, Open-Label, Crossover, PrefMab Study

Introduction: Rituximab (R) plus chemotherapy (chemo) is standard of care for patients (pts) with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). A subcutaneous (SC) formulation of R (R-SC) that has a non-inferior pharmacokinetic profile to the intravenous (IV) formulation (R-IV) and similar efficacy and safety in DLBCL and FL pts is now available for clinical use. The randomized, open-label, crossover, Phase 3b PrefMab study (NCT01724021) aimed to explore pt preference and treatment satisfaction for the SC vs IV formulation of R. In the primary analysis (data cut-off, January 19, 2015; Rummel et al. Ann Oncol 2017), a strong pt preference for R-SC over R-IV administration was demonstrated (81% vs 11% at Cycle 8; primary endpoint). In addition, on the Rituximab Administration Satisfaction Questionnaire, median scores were higher for R-SC vs R-IV for ‘Impact on Activities of Daily Living’, ‘Convenience of Therapy’, ‘Satisfaction with Therapy’, and ‘Psychological Impact’. No new safety signals were reported. Here, we present the final analysis of the PrefMab study, which was performed after all pts had completed at least 24 months' follow-up (data cut-off, December 20, 2016) with a focus on long-term pt outcomes and safety.Methods: Pts aged 18-80 yrs with previously untreated CD20+ DLBCL or FL were randomized 1:1 to receive one of two 8-cycle schedules of R in combination with 6-8 cycles of chemo (CHOP, CVP, or bendamustine, as per local practice): Sequence A (n=372), 1 cycle R-IV (375mg/m2) then 3 cycles R-SC (1400mg) then 4 cycles R-IV; Sequence B (n=371), 4 cycles R-IV then 4 cycles R-SC. Maintenance therapy was not mandated by the study protocol; however, pts with FL could receive maintenance at the investigator's discretion. Secondary endpoints reported here include overall (OR) and complete response (CR) rates (assessed according to Cheson 1999 criteria) and investigator-assessed progression-free (PFS), event-free (EFS), disease-free, and overall survival. Safety was also assessed by treatment-emergent adverse event (AE) reporting. Efficacy was analyzed in all randomized pts, safety in all pts who received ≥1 dose of R.Results: Of 743 randomized pts, 740 received study treatment (465 pts with DLBCL [63%], 273 with FL [37%], and 2 other [0.3%]). Demographics and baseline characteristics are presented in Table 1. The median age of pts with DLBCL was 61 yrs and of pts with FL was 59 yrs. The majority of pts with DLBCL and FL received CHOP chemo (Table 1). OR rates were >90% in both DLBCL and FL pts (Table 2). CR rates were 55.1% in pts with DLBCL and 44.4% in pts with FL (Table 2). PFS rates at 3 yrs were 79% in DLBCL pts and 91% in FL pts. Other time-to-event endpoints are presented in Table 2. EFS was shorter in FL pts than DLBCL pts; however, because R maintenance was considered a non-protocol-specified anti-lymphoma therapy, FL pts were censored at the time of starting maintenance therapy. Treatment sequence had no impact on response rates or time-to-event endpoints. Pharmacokinetic serum-level data will be presented.Of pts who received ≥2 cycles of treatment, 653/712 (92%) experienced ≥1 AE on or after Cycle 2. AEs were generally balanced according to administration route and diagnosis, although a higher rate of grade ≥3 AEs and serious AEs occurred in DLBCL pts compared with FL (Table 3). Most AEs occurred in Cycle 1, during which all pts received R-IV (pts with AE in Cycle 1: Arm A, 71%; Arm B, 69%). No administration-related reactions (ARRs) occurred at a frequency of ≥2% in pts receivingR-SC or R-IV on or after Cycle 2. There were no differences in rates of ARRs according to IV or SC administration. FL pts were more likely to experience an ARR than DLBCL pts. At the end of the study, 104 pts had died (85 DLBCL; 19 FL). Fatal AEs related to R, according to the investigator's judgment, included oropharyngeal candidiasis, pneumonia, septic shock, febrile neutropenia, and myocardial infarction (1 case each).Conclusions: In addition to the strong pt preference for SC dosing and improved satisfaction observed in the primary analysis, these findings confirm that R-SC is an efficacious and well-tolerated treatment option in DLBCL and FL pts. Overall, outcomes did not appear to be impacted by treatment sequence. [Display omitted] DisclosuresRummel:Roche: Honoraria, Other: PrefMab is sponsored by F. Hoffmann-La Roche Ltd. Third-party Medical Writing assistance, under the direction of Mathias Rummel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Brugger:AstraZeneca: Employment, Equity Ownership. Re:Gilead: Membership on an entity's Board of Directors or advisory committees. Task:Genentech: Employment, Equity Ownership. McIntyre:Roche: Employment, Equity Ownership. Meier:Roche: Employment. Osborne:Roche: Employment. Smith:Roche: Employment. Grigg:Roche: Other: Funding to attend ASH 2016.

Rituximab Administration in Coronavirus Pandemic Era: A Mini-Review of Clinical Evidence

Rituximab (RTX), as a B cell-depleting agent, is indicated in treating several malignancies and autoimmune diseases. The management of patients currently receiving RTX and patients starting the medication raised concerns in the pandemic era. Theoretically, suppressing the immune response at the beginning of coronavirus disease 2019 (COVID-19) enhances viral replication, but it prevents acute respiratory distress syndrome as the disease progresses. This review aims to investigate the results of RTX administration in patients during the pandemic era. There is insufficient evidence to definitively conclude on the safety of RTX during the pandemic. For this purpose, high-quality controlled cohort studies, as well as registry-based studies, would be helpful.

Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura

INTRODUCTIONImmune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by immunoglobulin G (IgG) antibodies. These antibodies target the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is vital for cleavage of von Willebrand factor. The resulting ADAMTS13 deficiency leads to microthrombi through platelet aggregation to Ultra-Large von Willebrand factor. If untreated the mortality rate in iTTP is in excess of 90%, but the use of plasma exchange (PEX) and immunosuppression has significantly reduced this (to between 10%-20%). Rituximab (a humanised anti-CD20 antibody, MabThera; Roche Pharmaceuticals), is now used routinely in iTTP in relapsed/refractory patients, but also acutely to prolong disease free-survival. The pre-emptive administration of rituximab in patients with a low ADAMTS13 has been shown to be effective in preventing clinical relapse.In 2013 the patent for rituximab expired in Europe and will expire in 2018 in the United States. The European Medicine Agency has now approved two Rituximab biosimilars for use in Europe. Biosimilar products are designed to have no meaningful differences from the reference/originator product. Truxima (CT-P10, a rituximab biosimilar) is approved for the treatment of RA, CLL and NHL in Europe, and we began using Truxima in iTTP in May 2017. Many other rituximab biosimilars exist and are in development.METHODOLOGYHere we report a retrospective cohort study of our patients with iTTP. Data from 84 patients was examined from a two-year time period May 2016-and May 2018, based on our pharmacy registry (having switched to the rituximab biosimilar in May 2017). 45 patients were treated with MabThera and 39 with the rituximab biosimilar Truxima. Laboratory parameters recorded included the patient's platelet counts, ADAMTS13 activity, and CD19 levels at D1, D28 and 3months following treatment. In addition, adverse reactions, and infective complications following treatment were also recorded. Statistical analysis was performed and means +/- 90% confidence interval calculated, with clinical equivalency compared based on clinically significant values.RESULTSFollowing MabThera/Truxima administration on D1, at 28 days the mean platelet count (+/- SEM, x10^9/L) was 263.3 (+/-10.69) in patient treated with MabThera and 263.8 (+/-11.81) with Truxima (90% CI -24.95 to 27.91), and remained similar at 3months at 275.8 (+/- 10.05) and 275.9 (+/- 12.2) respectively (90% CI -25.96 to 26.2). The ADAMTS13 (+/- SEM) at 28 days was 50.87 iu/dL (+/-4.899) in patients treated with MabThera and 50.88 iu/dL (+/- 4.371) for Truxima (90% CI 11.01-11.03), rising to 85.4 iu/dL (+/- 5.237) and 81.35 iu/dL (+/- 4.549) respectively at 3 months (90% CI 15.84-7.71). CD19 levels at 28 days in patients treated with MabThera had fallen to 0.00259 (x10^9/L)(+/- 0.00049) and 0.02151 (+/- 001161) with Truxima (90% CI 0.00073 to 0.037120), and were 0.01782 (+/- 0.01033) and 0.02098 (+/- 0.01042) respectively at 3 months (90% CI -0.02139 to 0.02771), all demonstrating a marked reduction from baseline means of 0.3247(+/-0.05721) and 0.2456 (+/-0.03016) respectively. The median number of infusions in both groups was 4 (range 1-8). Infusion reactions were comparable between both groups, with infusion reactions occurring in 33% of the MabThera treated patients, and 40% in the Truxima group. Infective complications (principally urinary tract infections) were comparable between both groups, 15% in the MabThera group and 18% in the truxima cohort. The mean saving per patient per treatment course cost was >£4000.DISCUSSIONRituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications. DisclosuresCheesman:Celltrion: Other: Speaker Fee; Roche: Other: Advisory board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau.

Cost-effectiveness analysis of two rituximab retreatment regimens for longstanding rheumatoid arthritis.

Rituximab (RTX) is licensed for second-line treatment of rheumatoid arthritis (RA) after first tumor necrosis factor (TNF) inhibitor failure. RTX is generally administered intravenously at 1 gm 2 weeks apart, and the retreatment is scheduled at the time of clinical relapse (regimen 1). A more intensive regimen is proposed with a fixed full cycle after 6 months (regimen 2) if remission is not reached. A cost-effectiveness analysis (CEA) compared these 2 regimens of RTX administration in patients with longstanding RA based on data provided by an observational study. An observational retrospective study was conducted on 102 patients, enrolled in 3 hospitals and followed for ≥12 months. Forty-seven patients followed regimen 1, while 55 patients followed regimen 2. A CEA based on a Markov model was conducted. A lifelong and social perspective was adopted. CEA was conducted for the entire cohort and for the 2 subgroups separately (patients with positive rheumatoid factor and/or anti-cyclic citrullinated peptide and failures to TNF inhibitors). Results for the overall sample show at 10, 20, and 30 years that regimen 1 is less costly and associated with a higher quality of life compared to regimen 2. Probabilistic sensitivity analysis at 10 years estimated a probability of 95.1% for regimen 1 to be cost effective given a willingness to pay of €35,000/quality-adjusted life year, while for seropositive patients and for TNF failures it was estimated to be 92% and 92.7%, respectively. In longstanding RA, cost effectiveness of RTX retreatment at clinical relapse was found to be at least equivalent to the more intensive regimen proposed.

ANTI-B-CELL THERAPY AT IMMUNE INFLAMMATORY RHEUMATIC DISEASES: EFFICACY AND TOLERABILITY IN 229 PATIENTS

Objective: to assess the efficacy and tolerability of Rituximab treatment in patients with serious immune inflammatory rheumatic diseases (IRD) like systemic lupus erythematosus (SLE), systemic sclerosis (SS), systemic vasculitis (SV), Sjogren syndrome (SjS), dermatomyositis/polymyositis (DM/PM). Subjects and methods. The clinical efficacy has been analyzed in 229 patients with IRD: SLE (n=97), SV (n=50), SS (n=40), SjS (n=23) and DM/PM (n=19). Rituximab treatment was accompanied by administration of glucocorticoids and/or immunosuppressive drugs. Most patients demonstrated resistance to or low tolerability of standard therapy. Efficacy of treatment was analyzed in each group with the criteria relevant for each disease. To compare clinical response to the treatment between the groups we used gradations accepted by international registries: complete (good) response, partial response, no response. Average duration of monitoring comprised 72 (1–288) weeks after the first introduction of Rituximab. Average Rituximab dose administered to patients over the period of monitoring was low and varied from 1.6±0.84 in DM/PM to 3.1±1.75 in SV. About 80% of patients received one or two courses of Rituximab except for patients with SS (half of them received three and more courses). Results. «Complete response» was observed in 50.6%, «partial response» – in 35% of patients. Rituximab courses provided positive dynamics in clinical scores and allowed to reduce supportive dose of glucocorticoids and to lower the dose or withdraw of immune-stimulating drugs. Multiple Rituximab courses provided stable and longlasting effect. Recurrences were observed less frequently, whereas efficacy of the therapy increased during a year and longer. Occurrence of adverse events and mortality rate were comparable to data of other national Rituximab registries. Conclusion. The results of the study may prove administration of Rituximab in patients with resistance to standard therapy

Time Savings With Rituximab Subcutaneous (SC) Injection Vs Rituximab Intravenous (IV) Infusion: Final Analysis From a Time-and-Motion Study In 8 Countries

BackgroundRituximab (MabThera®; Rituxan®) is the standard treatment for indolent non-Hodgkin's lymphoma (iNHL). Results from the phase 3 SABRINA study (NCT01200758) showed that a fixed-dose subcutaneous (SC) formulation of rituximab shortened administration time without compromising efficacy or safety compared with intravenous (IV) infusion of rituximab. A switch to the SC formulation is expected to offer healthcare professionals (HCP) time and cost savings. AimsThis study aims to quantify resource utilization in terms of active HCP time (ie, time actively dedicated to a patient) and chair time related to rituximab SC vs rituximab IV in the treatment of patients with iNHL and to estimate potential time and cost savings for the conversion from IV to SC (per administration session and for the first year of treatment). MethodsThis is a multinational, multicenter, prospective, observational time and motion study. Data for rituximab SC injections were collected alongside the MABCUTE (MO25455; NCT01461928) trial, while data for rituximab IV infusions were collected in a real-world setting in the same data collection period and in 23 centers in Italy (IT), Russia (RU), Slovenia (SL), United Kingdom (UK), Spain (SP), France (FR), Austria (AU), and Brazil (BR). Following interviews with a nurse and pharmacy member in each center, generic case report forms for IV, SC, and drug preparation area (including pharmacy) processes were tailored to reflect local site practices. Trained observers recorded both the time that HCPs were actively completing prespecified tasks (using a stopwatch), and patient chair time (based on length of time between patients entering and exiting chairs). This is a descriptive study with convenience-based sample sizes. A random effects regression model was run for each task (pooled sample by country) to generate task mean and 95% confidence interval (CI) using appropriate distributions. IV vs SC process time per patient was calculated as the sum of the mean task times. ResultsThe difference in mean active HCP time saved by switching from rituximab IV to rituximab SC ranged from 6.8 min in AU to 38.4 min in the UK (Table 1). The proportionate reduction in mean HCP time ranged from 27% in SP to 57% in RU. The mean time saved (% reduction) in the treatment room ranged from 0.3 min (2%) in SP to 25.4 min (63%) in the UK. Over the course of the first-year of treatment (6 induction and 3 maintenance sessions), the estimated reduction in total HCP time associated with the switch ranged from 0.9 hr in AU to 5.1 hr in the UK. The differences in mean chair time saved with SC over IV administration ranged from 126.1 min in SL (64%) to 280.1 min (86%) in IT. Simulating these findings for a hypothetical center treating 50 patients for 9 sessions annually indicated that the amount of chair time freed would range from 105.1 (SL) to 233.4 (IT) 8-hour days. Staff opportunity cost estimates will be presented at the conference. ConclusionsThe current analysis indicates that a switch from rituximab IV to rituximab SC leads to a substantial reduction in administration chair time and in active HCP time. These time savings could allow more time to be used for other patient care activities, increasing the number of patients who could be treated and thus increasing the overall efficiency of treatment centers. Disclosures:De Cock:F. Hoffman-La Roche Ltd: Consultancy, Research Funding. Kritikou:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Tao:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Wiesner:Genentech: Employment. Off Label Use: Rituximab, administered as an IV infusion, is approved for use in a number of hematologic indications. The data presented here assess a subcutaneous approach to rituximab administration in patients with indolent Non-Hodgkin's Lymphoma.

A Randomized Comparison Of Maintenance Therapy With Subcutaneous Rituximab For 2 Years Versus Until Progression In Patients With Indolent Non-Hodgkin's Lymphoma: Interim Safety Data From The Mabcute Study

BackgroundRituximab is part of the standard induction and maintenance therapy for most patients with first-line or relapsing indolent non-Hodgkin's lymphoma (iNHL). However, the optimal duration of maintenance is still to be defined. The MABCUTE trial is designed to evaluate the efficacy and safety of maintenance therapy with subcutaneous (SC) rituximab until disease progression (PD). Patients with relapsed or refractory iNHL, who respond to induction and an initial 2 years' maintenance therapy, are randomized to receive additional maintenance therapy or observation. Here we report the findings of a planned interim safety analysis in the first 231 patients enrolled in the trial. MethodsMABCUTE (NCT01461928) is an ongoing multicenter, randomized, parallel-group, phase IIIb study that started in December 2011. Eligible patients were aged ≥18 years with relapsed or refractory CD20+ iNHL (histologically confirmed) following ≥1 line of immunotherapy and/or chemotherapy and/or radiotherapy. Patients were scheduled to receive induction therapy consisting of rituximab every 3–4 weeks for 8 cycles (intravenous [IV] 375 mg/m2 in cycle 1 then SC 1400 mg in cycles 2–8) and 6–8 cycles of standard chemotherapy. Patients who achieved a complete or partial response (CR/PR) continued into standard maintenance (rituximab SC 1400 mg every 8 weeks for 24 months). Upon completion of standard maintenance, patients in sustained CR/PR will be randomized to receive additional maintenance (rituximab SC 1400 mg every 8 weeks) until PD, or observation. ResultsAt data cut-off (January 16, 2013), the safety population consisted of 216 patients who had received ≥1 dose of rituximab SC: 70 (32%) had completed induction therapy, 122 (57%) were receiving induction therapy, and 24 (11%) had discontinued induction therapy. A total of 58 (27%) patients had continued into standard maintenance, with 2 patients having subsequently discontinued maintenance therapy. Patients had a median age of 64.5 years (range, 20–90). At screening, the most common types of iNHL were follicular NHL (n=131, 61%), marginal zone lymphoma (n=41, 19%), and Waldenström's macroglobulinemia (n=31, 14%). The most commonly used chemotherapy regimens were bendamustine (n=137, 63%), CHOP (n=31, 14%) and CVP (n=21, 9.7%). During therapy, AEs occurred in 174 (81%) patients (Table), grade 3 or higher AEs in 70 (32%) patients and serious AEs (SAEs) in 44 (20%) patients. Administration-related reactions (ARRs) were reported by 61 (28%) patients after 1 dose of rituximab IV and by 89 (41%) patients after a median (range) of 5 (1–11) doses of rituximab SC. The majority of ARRs were mild to moderate and transient, and expected with the change in the route of administration. Overall, 25 patients had grade 4 hematological events, most commonly neutropenia (22 patients). Only 4 cases of neutropenia lasted >14 days and these resolved without interruption to treatment. One patient had a grade 4 non-hematological event (thrombosis and pulmonary embolism that resolved after 12 days). Among the 26 patients who discontinued study treatment, reasons given were AEs (n=8; skin reactions [3], neutropenia [2], general health problems [2], and oseophagitis [1]), patient or investigator request (n=6), PD (n=5), death (n=2), and other (n=5). One patient died of bronchopneumonia and sepsis due to leucopenia and 1 died of myocarditis; neither was considered by the investigator to be related to the study drug.Table. Summary of AEsAdverse eventNumber of patients (%)SAE44 (20)Grade 3 or higher AE70 (32)Any grade AE occurring in ≥10% of patients174 (81)Neutropenia44 (20)Pyrexia35 (16)Asthenia24 (11)Nausea41 (19)Constipation23 (11)Diarrhea22 (10) ConclusionsRituximab SC is associated with ARRs that are transient and mainly mild to moderate in severity. The incidence and intensity of other hematological and non-hematological toxicities are within the expected range for rituximab SC or IV administration. No new safety signals or concerns associated with rituximab SC were identified during induction and maintenance therapy in this interim safety analysis, as confirmed by the Independent Data Monitoring Committee. Rituximab SC appears to be well tolerated and the study continues. Disclosures:Rule:Pharmacyclics, Inc: Consultancy; J&J: Consultancy; F. Hoffmann-La Roche: Consultancy. Off Label Use: Rituximab, administered as an IV infusion, is approved for use in a number of hematologic indications. The data presented here assess a subcutaneous approach to rituximab administration in patients with indolent Non-Hodgkin's Lymphoma. Briones:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartris: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria. Casasnovas:F. Hoffmann-La Roche: Consultancy, Research Funding. Pocock:F. Hoffmann-La Roche: Honoraria. Osborne:F. Hoffmann-La Roche: Employment. Smith:F. Hoffmann-La Roche: Employment. Zaja:F. Hoffmann-La Roche: Consultancy.

Bone marrow involvement is predictive of infusion-related reaction during rituximab administration in patients with B cell lymphoma

The purpose of this study is to evaluate risk factors for infusion-related reaction (IRR) following rituximab administration in patients with B cell non-Hodgkin lymphoma. A retrospective analysis was conducted of patients with newly diagnosed B cell lymphoma who have received rituximab-included immunochemotherapy with appropriate premedication and commonly used schedule of infusion rate. IRRs were graded by review of the patients' electronic medical record according to the Common Terminology Criteria for Adverse Events version 4.0. One hundred and sixty-nine patients were included in the analysis and most of the patients (150; 88.8 %) had diffuse large B cell lymphoma (DLBCL). Thirty-six patients (21.3 %) had any grade of IRRs: 23 patients were grade (G) 1 (13.6 %), 13 had ≥G2 IRRs (7.7 %), and only 4 had ≥G3 IRRs (2.4 %). All except one patient had IRR during the first cycle and only two had repetitive IRR thereafter. Bone marrow (BM) involvement was the strongest risk factor for IRR in multivariable analysis (odds ratio 4.06, 95 % confidence interval 1.67-9.89; p = 0.002). A subgroup analysis confined to patients with DLBCL showed very similar results when compared with the entire population, and patients with DLBCL who had ≥G2 IRR showed shorter event-free and overall survival when compared to those who did not. BM involvement is predictive of occurrence of IRR during rituximab administration in patients with B cell lymphoma. More intensive premedication and careful observation for IRR during rituximab administration are required for patients with B cell lymphoma who have BM involvement.

Pre-Emptive Rituximab for Epstein-Barr Virus Reactivation Post Stem Cell Transplant: High CRP and PTLD At Initiation of Treatment Confer Inferior Outcome

Abstract 3007▪FN2▪This icon denotes a clinically relevant abstract Background:Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) is an important complication of allogeneic stem cell transplantation (alloSCT). Quantitative PCR monitoring of EBV genomes in blood and pre-emptive administration of Rituximab in patients with high viral load is emerging as a strategy to reduce mortality from PTLD. However, factors predicting for response in this patient population are not well understood. Aim:To report the frequency and characteristics of patients treated for EBV reactivation and to identify factors predicting outcome. Methods:This retrospective analysis examined all patients needing treatment with Rituximab for EBV reactivation after undergoing alloSCT at University Hospital Birmingham, UK between June 2009 and February 2011. A total of 92 T-deplete and 9 cord blood transplant patients were monitored weekly with quantitative EBV PCR testing of whole blood for a minimum of 6 months. Patients with EBV reactivation were given Rituximab pre-emptively when viral DNAemia exceeded 30, 000 copies/ml, whereas patients presenting with PTLD were treated irrespective of viral load. A maximum of 4 weekly doses of Rituximab 375mg/m2 were given until PCR negativity or resolution of symptoms. Cases of PTLD were either biopsy-proven or diagnosed as probable PTLD if viral DNAemia was associated with clinicoradiologic evidence of disease. Results:Of 101 patients undergoing alloSCT monitored by quantitative EBV PCR testing 24 (24%) were treated with Rituximab for EBV reactivation. The median age of treated patients was 58 years and 75% were male. Two patients received myeloablative and 22 received reduced intensity conditioning. Donor stem cells were sibling in 6, unrelated in 14 and cord blood in 4 patients. EBV DNAemia over 30, 000 copies/ml occurred in 23 of 24 treated patients. Of these, 14 had no evidence of PTLD whilst 9 of 23 had evidence of either probable (6 cases) or biopsy-proven (3 cases) PTLD at the time of initiating treatment. One patient was treated for biopsy-proven PTLD with a viral load that never exceeded 30, 000 copies/ml.The median interval from alloSCT to first PCR positivity was 99 days (IQR 70 – 146 days) and the median interval from first PCR positivity to exceeding the 30, 000 copies/ml threshold was only 7 days (IQR 0 – 14 days). Notably, treated patients with PTLD became PCR positive significantly earlier after alloSCT than those without PTLD (median 71 vs. 119 days; p=0.01*). Median viral loads at first PCR positivity, at the 30, 000 copies/ml threshold and at peak viral load were 1.1×104, 8.2×104 and 2.2×105 copies/ml respectively, of which peak viral load was significantly higher in patients with PTLD (median 1.1×106 vs. 1.4×105 copies/ml; p=0.01*).Patients reactivating EBV without PTLD received a median of 3 doses of Rituximab whilst patients with PTLD received a median of 4 doses. Complete response (defined by PCR negativity and clinioradiologic resolution of disease) was seen in 13/14 (93%) patients without PTLD versus 6/10 (60%) patients with PTLD. Notably, among patients who achieved PCR negativity the median interval from initiation of treatment to PCR negativity was significantly longer in those with PTLD (median 28 vs. 13 days; p=0.005*). All 4 patients with Rituximab-refractory PTLD died despite further treatment with chemotherapy in 3 cases. All-cause mortality for treated patients was 10/24 (42%).Regarding predictors of response to Rituximab, a diagnosis of PTLD at treatment initiation showed a clear tendency to significance (p=0.056**) whilst raised CRP >30 was highly significant (p=0.003**). Other variables including age, sex, conditioning, donor type, viral load, LDH and albumin were not significant. Conclusions:Focussing exclusively on alloSCT patients treated with Rituximab under a pre-emptive management strategy, this study demonstrates that patients who require treatment typically display an early and vigorous EBV DNAemia. Notably, among patients treated for EBV reactivation those with PTLD become EBV PCR positive earlier, have higher peak viral loads and take longer to reach PCR negativity after treatment. Rituximab responsiveness is a key determinant of outcome, as patients with refractory disease have poor survival irrespective of chemotherapy. Among patients who reactivate, those with PTLD or with raised CRP experience inferior outcomes.*Mann-Whitney U Test **Fisher's Exact Test Disclosures:No relevant conflicts of interest to declare.

Macrophage Polarization and Acquired Resistance to Rituximab in CNS Lymphoma.

Abstract 3749Poster Board III-685Macrophages are a critical component of anti-tumor immunity but may be subverted from the classically-activated, or M1 phenotype, which mediates tumor elimination, to an alternatively-activated, M2 phenotype, which promotes tumor progression. Interleukin-4 (IL-4) signaling is a pivotal regulator of macrophage polarization to the M2 phenotype.The efficacy of rituximab appears to be mediated predominantly by antibody-dependent cellular cytotoxicity (ADCC) with tumor-associated macrophages being the dominant effector cell. We hypothesize that the phenotype of tumor-associated macrophages (M1 vs. M2) may be a potential determinant of rituximab efficacy or resistance. Relevant to this hypothesis is our demonstration of the intratumoral expression of IL-4 by CNS lymphoma (Blood, 2006; Clin Cancer Res., 2009) as well as our observation that the M2 polarization of macrophages by IL-4 treatment in vitro (18 h) results in an 8-fold decrease in rituximab-mediated ADCC of Raji lymphoma cells compared to ADCC-mediated by naïve or M1 polarized macrophages (p<0.001).There is an extreme paucity of molecular information regarding the role and phenotype of tumor macrophages in non-Hodgkin lymphoma in general, including CNS lymphoma. While macrophages from the cerebrospinal fluid (CSF) are routinely quantified in cytospin analyses, to date there is no established information regarding the phenotype and state of differentiation of macrophages within the leptomeningeal compartment. We have developed a novel flow-cytometry-based protocol for the isolation and phenotypic characterization of macrophages from the CSF of patients with CNS lymphoma. We have used candidate markers of M2 differentiation based upon our gene expression studies of CD14+ activated CSF macrophages, including CD206 and Factor XIII (each of which have previously been shown to be induced in macrophages upon IL-4 stimulation). We have identified M1 differentiation of CSF CD14+ macrophages by high fluorescence when incubated with DAF-FM diacetate, a cell-permeable marker of nitric oxide synthase (iNOS). Using flow-cytometry to evaluate the relative expression of DAF-FM and CD206, we demonstrate the presence of at least four subpopulations of activated macrophages in the CSF of CNS lymphoma patients. M1 macrophages, which highly express iNOS are denoted as DAF-FM(+)/CD206(-). M2 macrophages, which weakly express iNOS but which highly express CD206 are denoted as DAF-FM (-)/CD206(+). In addition, we have detected a mixed phenotype with features of both M1 and M2 macrophages, DAF-FM(+)/CD206(+), which we have termed dual-activated. A fourth subpopulation of activated macrophages within the CSF do not express iNOS or CD206.Thus far, CSF macrophage subpopulations have been characterized and sorted from thirty-five subjects: 18 patients with CNS lymphoma and 17 control subjects with non-neoplastic conditions. We demonstrate for the first time the association of M2 macrophages within the CSF with the pathogenesis of CNS lymphoma: there was a greater than six-fold increase in the proportion of macrophages with M2 features in immunocompetent subjects with CNS lymphoma compared to controls (p<0.001). By contrast, the proportion of macrophages with M1 features was similar between lymphoma and controls.In addition, we reproducibly detected an increase in the ratio of M1:M2 macrophages which correlated with therapeutic response to intrathecal methotrexate or cytarabine (within 94 h) in CNS lymphoma patients. By contrast, the intraventricular administration of rituximab was reproducibly associated with a greater than three-fold increase in the relative ratio of M2:M1 macrophages which was sustained compared to macrophages analyzed pre-intrathecal rituximab (p<0.001). In each of four cases, increases in M2 macrophage polarization anticipated the onset of intrathecal rituximab resistance and tumor progression.We believe this to be the first application of flow-cytometry to define the polarization states of intratumoral macrophages in non-Hodgkin lymphoma as well as the first description of dynamic changes in macrophage phenotypes during the evolution of resistance to rituximab therapy. The elucidation of distinct macrophage subpopulations based upon the expression of candidate markers of M1 vs. M2 phenotype may provide insight into tumor pathogenesis and prognosis. Disclosures:Off Label Use: While we describe the use of intrathecal administration of rituximab in patients with recurrent CNS and intraocular lymphomaa, the focus of our study is on the relationship between M2 macrophage polarization and the pathogenesis of CNS lymphoma as well as the potential relationship of macrophage polarization to acquired resistance to rituximab in CNS lymphoma patients.

Targeted monitoring of patients at high risk of post‐transplant lymphoproliferative disease by quantitative Epstein–Barr virus polymerase chain reaction

Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disease (PTLD) is a serious complication after allogeneic stem cell transplantation (SCT). The likelihood of PTLD is increased in the presence of specific risk factors. Monitoring of EBV DNA load and early administration of rituximab in patients with high EBV loads is recommended for high-risk patients. Patients at high risk of EBV-associated PTLD were defined as those showing an EBV serological mismatch between donor and recipient, those with lymphoma, those given cord blood grafts, and those with primary EBV disease before SCT. High-risk patients were prospectively monitored by weekly measurement of EBV DNA by quantitative polymerase chain reaction assay, and rituximab was given when the EBV load reached 10,000 copies/mL or symptoms were suggestive of EBV disease. During the study period (July 2005 to the end of June 2007) 131 patients underwent SCT, of whom 53 had high risk factors. A historical control group transplanted between January 2003 to the end of June 2005 was retrospectively used to evaluate the effect of the prospective monitoring strategy. Of the patients, 30% were positive for EBV DNA at least once; 10% of patients with EBV DNAemia developed PTLD. Risk factors of EBV DNAemia were younger age (P=0.04), receiving transplants from mismatched family or unrelated donors (P=0.01), and acute graft-versus-host disease grades II-IV (P=0.001). The overall frequency of PTLD was 3%; 5.7% in the high-risk group and 1.3% in the standard-risk group. Previous splenectomy (P=0.046) was the only significant risk factor associated with PTLD. In the control group, 6 of 150 patients (4%) developed PTLD; 5/53 (9.4%) in the high-risk group and 1/97 (1%) in the standard-risk group. Human leukocyte antigen-mismatched donors (P<0.01) and EBV-positive donors/EBV-negative recipients (P=0.01) had a significant impact on the risk of PTLD. A targeted monitoring strategy among patients at a high risk of EBV-associated PTLD might be helpful to decrease the risk of development of PTLD. However, larger prospective studies are needed to verify this hypothesis.

Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL). The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients. The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis

B cell depletion may affect T cell activation and costimulation status in rituximab-treated patients with SLE. We examined whether rituximab administration in patients with active lupus nephritis is related to changes in mRNA expression of genes that define regulatory T cells (Tregs) in peripheral blood lymphocytes, measured by real-time PCR. At the early phase of B cell depletion mRNA levels of CD25, CTLA-4, GITR and the bona fide Treg functional marker FOXP3 increased significantly in all 7 patients examined. In contrast, mRNA levels of the costimulatory/activation T cell molecule CD40L were profoundly reduced, while mRNA levels of TGF-beta, a cytokine contributing to Treg induction, increased significantly in all. During follow-up, increased FOXP3 mRNA persisted in those patients in clinical remission, while in those patients with active disease subsequent decreases were noted. Further studies should examine whether modulation of Tregs by therapeutic B cell depletion contributes and/or predicts lupus disease remission.

Hierarchy of Human B Cell Regeneration after Rituximab Therapy.

Constant immunoglobulin levels throughout life-time may be maintained by either long lived plasma cells or continuous formation of immunoglobulin secreting cells (ISC). Rituximab therapy targets CD20+ B cells, thus selectively spares B progenitor cells and plasma cells, providing an in vivo model to investigate human B cell homeostasis.After weekly administration of rituximab in patients with follicular lymphoma, peripheral blood B cells are virtually absent (<0,01%), and no ISC are detected. In contrast, during rituximab maintenance therapy (administered in two months intervals) small numbers of B cells can be detected. These carry the phenotype of new formed plasma blasts (CD27++/CD38++/icIg+++ and Ki67+) and are identified as ISC in ex vivo ELISPOT assay.Surprisingly, ISC detected in treated patients were the same as in healthy donors in absolute numbers, while B cells were still reduced by 100-fold. Only 4 to 6 months after therapy human naive and memory B cells were detected in peripheral blood again. Thus, regeneration of human peripheral blood B lymphocytes follows a hierarchy: Recirculating ISC recover rapidly to normal steady state levels, while B cells with naive or memory phenotype require longer time periods. This hierarchy may represent two elements within the B cells system: a primary system sustaining constant antibody levels and a secondary system providing a diverse repertoire for adaptive immune responses.