Intravenous Infusions Of Rituximab Research Articles

A Single Arm Phase II Pilot Study of Low Dose Vemurafenib Plus Rituximab in the Front-Line and Relapsed/Refractory Treatment of Hairy Cell Leukemia

Introduction: Hairy Cell Leukemia (HCL) is a rare, low-grade B-cell malignancy that is characterized by cytopenias, infections and splenomegaly. Given the chronic and incurable nature of this disorder, limiting therapy-related toxicity is of paramount importance. Though purine nucleoside analogs have an established track record of durable efficacy, they are associated with significant myelosuppression and immunosuppression as well as late secondary malignancies. Mechanistic exploitation of aberrant BRAF V600E activation with vemurafenib in combination with CD20 targeting with rituximab has provided an effective means of eradicating leukemic cells without significant myelosuppression or immunosuppression. However, vemurafenib at the standard dose of 960 mg twice daily is often poorly tolerated and frequently requires dose reduction. We conducted a pilot study of rituximab and low-dose vemurafenib (240 mg twice daily) in patients with untreated or relapsed HCL, with a focus on providing a non-cytotoxic regimen that minimizes toxicity with potentially comparable treatment outcomes. Methods: This phase 2, open-label, single-arm, investigator-initiated pilot trial was designed, conducted, and managed at Scripps Clinic in La Jolla, California. We enrolled adult patients with HCL and mutated BRAF V600E who met standard treatment initiation criteria defined by an ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K. The treatment plan consisted of eight weeks of oral vemurafenib 240 mg twice daily and eight intravenous rituximab infusions at 375 mg per square meter of body-surface area administered every two weeks. The primary outcome was complete hematologic response. Secondary endpoints included time to complete hematologic response, clearance of minimal residual disease determined by BRAF V600E allele frequency in the bone marrow, safety and progression-free, relapse-free and MRD-free survival. Results: From March 2022 to July 2023, a total of six patients were enrolled in the study. Three patients had previously received a purine analog and three patients were previously untreated. The median age of patients was 61 years, and all were male. At the interim efficacy analysis, all five (5/5) evaluable patients had demonstrated a complete hematologic response with resolution of cytopenias and splenomegaly. 6-month bone marrow biopsy data were available for 3 patients. In 2 of these patients, MRD assessment by allele-specific PCR for BRAF V600E was absent in the bone marrow. In the third patient, though residual disease was present by MRD assessment, he had a hematologic response and requires no subsequent treatment to date. At a median follow-up time of 303 days, the relapse-free survival rate was 100%. There were no adverse grade 3 or 4 adverse events and no vemurafenib dose limiting toxicity was observed. Conclusions: Interim results to-date suggest that rituximab and low-dose vemurafenib (240 mg twice daily) have efficacy and good tolerability in patients with untreated or relapsed HCL. With accruing patient data and further enrollment on study, more information will guide the durability, efficacy and tolerability of this treatment approach.

Study protocol for a randomized controlled trial with rituximab for psychotic disorder in adults (RCT-Rits)

BackgroundThe role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance.The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture.MethodsA proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research.DiscussionThis is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma.Trial registrationNCT05622201, EudraCT-nr 2022–000220-37 version 2.1. registered 14th of October 2022.

Clinical significance of Epstein-Barr Virus detection in the cerebrospinal fluid of patients who underwent hematopoietic stem cell transplantation

Objective: To analyze the detection rate, clinical significance, and prognosis of Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of patients following allogeneic hematopoietic stem cell transplantation. Methods: A retrospective analysis was performed on 1100 patients who underwent the CSF virus test after allogeneic hematopoietic stem cell transplantation in Peking University People's Hospital between January 2017 and June 2022. Among them, 19 patients were screened positive for EBV in their CSF, and their clinical characteristics, treatment, and prognosis were analyzed. Results: Among 19 patients with EBV-positive cerebrospinal fluid, 12 were male and 7 were female, with 5 patients aged <18 years and 12 aged ≥18 years, with a median age of 27 (5-58) years old. There were 7 cases of acute myeloid leukemia, 8 of acute lymphocytic leukemia, 2 of aplastic anemia, 1 of Hodgkin's lymphoma, and 1 of hemophagocytic syndrome. All 19 patients underwent haploid hematopoietic stem cell transplantation, including 1 secondary transplant. Nineteen patients had neurological symptoms (headache, dizziness, convulsions, or seizures), of which 13 had fever. Ten cases showed no abnormalities in cranial imaging examination. Among the 19 patients, 6 were diagnosed with EB virus-related central nervous system diseases, with a median diagnosis time of 50 (22-363) days after transplantation. In 9 (47.3%) patients, EBV was detected in their peripheral blood, and they were treated with intravenous infusion of rituximab (including two patients who underwent lumbar puncture and intrathecal injection of rituximab). After treatment, EBV was not detected in seven patients. Among the 19 patients, 2 died from EBV infection and 2 from other causes. Conclusion: In patients who exhibited central nervous system symptoms after allogeneic hematopoietic stem cell transplantation, EBV should be screened as a potential pathogen. EBV detected in the CSF may indicate an infection; however, it does not confirm the diagnosis.

Rituximab for treatment-resistant schizophrenia and/or obsessive-compulsive disorder (OCD): functional connectivity and cytokines associated with symptomatic improvements

IntroductionImmunological mechanisms may contribute to the causation of mental illness. Autoimmunity is most convincingly shown for anti-NMDA-R encephalitis and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS); disorders that overlap clinically with schizophrenia and OCD. Altered inflammatory cytokine production, glial activation and auto-antibodies have also been associated with schizophrenia and OCD. In these disorders, however, the treatment results with anti-inflammatory or immunomodulating drugs have hitherto been limited and inconsistent. Yet other targets within the immune system may still be effective and new options are warranted for treatment-resistant patients. Rituximab targets B-lymphocytes and is often used in autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and anti-NMDA-R encephalitis.ObjectivesWe aimed to investigate whether rituximab is clinically effective, safe and tolerable as add-on therapy in markedly ill, treatment-resistant adult psychiatric patients with schizophrenia or OCD. We also wanted to identify putative mediating mechanisms in treatment responders, such as cytokine changes and functional connectivity (FC).MethodsIn an open pilot study, adults (18-39 years) with treatment-resistant schizophrenia and/or OCD were included. They received an intravenous infusion of rituximab 1000 mg, once at baseline, in addition to their regular psychiatric medication and were followed for 1 year. The main outcome measures were the Positive and Negative Syndrome Scale (PANSS) or Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Clinical Global Impression-Improvement scale (CGI-I) and the Personal and Social Performance scale (PSP). Treatment response was defined as ≥ 40 % decrease in PANSS or ≥ 35 % decrease in Y-BOCS, and much improved according to CGI-I. Resting-state fMRI was applied at baseline and after 5 months. Plasma cytokines were measured at 0, 3 and 5 months. Cognitive tests and the recently developed PsychoNeuroinflammatory Related Signs and Symptoms Inventory (PNISSI) were used to identify and measure symptoms related to neuro-inflammation and cognitive function.ResultsNineteen patients were treated with rituximab. 3-5 months after treatment, 6/9 patients with schizophrenia and 1/10 with OCD responded. One schizophrenia patient continues with rituximab every 6 months and has reportedly done well for almost 3 years. No severe side effects were reported apart from recurrent abdominal pain in a schizophrenia patient and one case of post-COVID-19 syndrome. Significant changes of FC were detected in responders only and correlated with PSP changes.ConclusionsAberrant B-cell activities may contribute to treatment-resistant schizophrenia and be amenable to treatment with rituximab. However, the results of this pilot study need confirmation in placebo-controlled trials.Disclosure of InterestNone Declared

Eltrombopag Combining Rituximab Versus Eltrombopag for Treatment of Adult Immune Thrombocytopenia: A Single Center, Retrospective Cohort Study

Introduction: Immune thrombocytopenia (ITP) is the most common hematological acquired hemorrhagic disease characterized by antibody-mediated platelet destruction and/or megakaryocyte maturation disorders. Eltrombopag and other thrombopoietin receptor agonists can rapidly increase the platelet count of patients with ITP by promoting megakaryocyte maturation and immune regulation, and effectively reducing the risk of bleeding. However, platelet levels often fall to baseline levels in the short term after drug withdrawal. Rituximab prevents the excessive destruction of platelets in patients by eliminating the autoantibody-secreting B cells. Although it takes a long time to act, some patients can achieve long-term remission. To explore the feasibility of the combination of two drugs with different mechanisms, we retrospectively analyzed the efficacy and safety of patients treated with eltrombopag combined with rituximab or eltrombopag monotherapy in our center. Methods: Collected the clinical data of patients with immune thrombocytopenia admitted to our center from October 2017 to December 2021. Patients included in the analysis were required to meet the following inclusion and exclusion criteria: 1) aged more than 18 years; 2) without acute infection, liver or kidney injury; 3) without high-risk factors for thrombosis; 4) not accompanied by severe immunodeficiency disease. All patients accepted eltrombopag or a combination regimen with rituximab. The initial dose of eltrombopag was 50mg/75mg daily, and the combination group received an intravenous infusion of rituximab (375mg/m2, once) within 1 month of the initiation of eltrombopag. During follow-up, the dose of eltrombopag was adjusted according to the patient's platelet count. The primary endpoints were complete response (CR), response (R), and overall response (OR) after 8 weeks, 12 weeks, and 24 weeks of treatment. Platelet counts should be confirmed on two separate occasions at least 7 days apart when defining responses (CR: platelet count ≥ 100×109/L and absence of bleeding; R: platelet count ≥ 50 × 109/L and at least a doubling of baseline and absence of bleeding; OR: platelet count ≥30 × 109/L or ≥2-fold increase of the baseline platelet count or bleeding). Secondary endpoints included sustain response off therapy (SRoT), duration of response, and adverse events (AEs). Results: 152 patients were enrolled in our study, 80 patients received eltrombopag plus rituximab and 72 patients received eltrombopag monotherapy. 6 patients in the combination group, and 9 patients in the monotherapy group did not receive the allocated intervention (5 and 7 for adding other treatments, 1 and 2 due to the diagnosis change). 5 and 10 lost to follow-up in combination and monotherapy groups, respectively. Eventually, 69 patients in the eltrombopag plus rituximab group and 53 patients in the eltrombopag group analyzed the efficacy and safety. The median follow-up time was 46 weeks (4-177w) vs 30 weeks (4-190w), respectively. Results showed that after 12 weeks and 24 weeks of treatment, the percentage of patients who reached R in the combination group was higher than in the monotherapy group (72.3% vs 54.0%, P=0.042; 70.0% vs 50.0%, P=0.041). And the OR after 12 weeks of treatment was also higher in the eltrombopag plus rituximab group (80.0% vs 64.0%, P=0.055). 17 patients (24.6%) in the combination group, and 5 patients (9.4%) in monotherapy can discontinue the eltrombopag successfully and maintain the platelet count ≥30 × 109/L for more than 2 months (P=0.03). There was no significant difference in the incidence of abnormal liver function and infection between the two groups (P>0.05). 11 patients (15.9%) reported medicated alopecia and 1 patient developed deep vein thrombosis of the lower extremity. Conclusion: The combination of eltrombopag and rituximab was safe and active in patients with immune thrombocytopenia, showing a sustained response, some patients can be successfully discontinued. This regimen provides a new possibility of drug combination therapy with different mechanisms for the long-term efficacy of ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis.

IntroductionThe aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS.MethodsPatients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months.ResultsA total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months.ConclusionsThe majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA.Trial registrationClinicalTrials.gov identifier, NCT01750697.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00433-0.

Efficacy of rituximab in patients with polymyalgia rheumatica: a double-blind, randomised, placebo-controlled, proof-of-concept trial

Background Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoid-sparing agents with a strong evidence base in polymyalgia rheumatica are absent. As B cells have been implicated in the pathogenesis of polymyalgia rheumatica, we aimed to evaluate the efficacy of rituximab for the treatment of polymyalgia rheumatica. Methods We did a double-blind, randomised, placebo-controlled, proof-of-concept trial at Sint Maartenskliniek, Nijmegen, Netherlands. We enrolled patients with polymyalgia rheumatica according to the 2012 European League Against Rheumatism and American College of Rheumatology criteria, who were recently diagnosed or who had relapsed on prednisolone and were unable to taper their dose to less than 7·5 mg per day. Participants were randomly assigned (1:1) to a single intravenous infusion of rituximab 1000 mg or placebo, with a 17-week glucocorticoid tapering scheme. Participants and care and research personnel were masked to treatment assignment and randomisation sequence. The primary outcome was glucocorticoid-free remission at 21 weeks after infusion in patients who completed the study. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). Findings Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled. 47 patients (38 who were recently diagnosed, nine who had relapsed on prednisolone) completed the study: 23 (49%) in the rituximab group and 24 (51%) in the placebo group. Mean age (SD) in years was 64 (8) in the rituximab group and 66 (10) in the placebo group, the proportion of women was 11 (48%) of 23 versus 13 (54%) of 24, and all participants were White. 11 (48%) of 23 patients in the rituximab group and five (21%) of 24 in the placebo group achieved glucocorticoid-free remission at 21 weeks (difference 27% [one-sided 95% CI 4]; relative risk 2·3 [1·1]; p=0·049). Ten infusion-related complaints occurred in the rituximab group versus three in the placebo group (relative rate 3·5 [one-sided 95% CI 1·3]). One serious adverse event occurred (pulmonary embolism; in the rituximab group), and there were no deaths. Interpretation Rituximab was shown to be efficacious in combination with 17-week glucocorticoid treatment compared with glucocorticoid treatment alone in terms of glucocorticoid-free remission in patients with polymyalgia rheumatica. If these findings are confirmed by larger trials, rituximab could be a valuable glucocorticoid-sparing treatment for patients with polymyalgia rheumatica. Funding Sint Maartenskliniek. Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoid-sparing agents with a strong evidence base in polymyalgia rheumatica are absent. As B cells have been implicated in the pathogenesis of polymyalgia rheumatica, we aimed to evaluate the efficacy of rituximab for the treatment of polymyalgia rheumatica. We did a double-blind, randomised, placebo-controlled, proof-of-concept trial at Sint Maartenskliniek, Nijmegen, Netherlands. We enrolled patients with polymyalgia rheumatica according to the 2012 European League Against Rheumatism and American College of Rheumatology criteria, who were recently diagnosed or who had relapsed on prednisolone and were unable to taper their dose to less than 7·5 mg per day. Participants were randomly assigned (1:1) to a single intravenous infusion of rituximab 1000 mg or placebo, with a 17-week glucocorticoid tapering scheme. Participants and care and research personnel were masked to treatment assignment and randomisation sequence. The primary outcome was glucocorticoid-free remission at 21 weeks after infusion in patients who completed the study. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled. 47 patients (38 who were recently diagnosed, nine who had relapsed on prednisolone) completed the study: 23 (49%) in the rituximab group and 24 (51%) in the placebo group. Mean age (SD) in years was 64 (8) in the rituximab group and 66 (10) in the placebo group, the proportion of women was 11 (48%) of 23 versus 13 (54%) of 24, and all participants were White. 11 (48%) of 23 patients in the rituximab group and five (21%) of 24 in the placebo group achieved glucocorticoid-free remission at 21 weeks (difference 27% [one-sided 95% CI 4]; relative risk 2·3 [1·1]; p=0·049). Ten infusion-related complaints occurred in the rituximab group versus three in the placebo group (relative rate 3·5 [one-sided 95% CI 1·3]). One serious adverse event occurred (pulmonary embolism; in the rituximab group), and there were no deaths. Rituximab was shown to be efficacious in combination with 17-week glucocorticoid treatment compared with glucocorticoid treatment alone in terms of glucocorticoid-free remission in patients with polymyalgia rheumatica. If these findings are confirmed by larger trials, rituximab could be a valuable glucocorticoid-sparing treatment for patients with polymyalgia rheumatica.

Dynamics of the level of calprotectin in patients with rheumatoid arthritis during rituximab biosimilar (Acellbia “Biocad”) therapy

Objective.To study the relationship between the level of calprotectin (CP) and RA activity, the level of acute phase reactants, proinflammatory cytokines, chemokines and growth factors, to assess its dynamics during rituximab (RTM) biosimilar therapy.Material and methods.20 patients with RA were examined. All patients received 2 intravenous infusions of RTM (Acellbia®) at a dose of 600 mg with an interval of 2 weeks against the background of methotrexate therapy. The level of CP in blood serum was measured by ELISA.Results.Before starting DAS28 (5.6 [4.9–6.8]), SDAI (27.17 [23.08–39.9]) and CDAI (26.6 [22.25–37.0]) corresponded to the high disease activity. A decrease in disease activity was noted after 12 and 24 weeks of therapy: the DAS28 value was 4.28 [3.24–4.75] and 4.14 [3.11–4.66], respectively (p&lt;0.05). Before the start of therapy, patients with RA had a higher CP level compared with healthy donors 9.68 (4.5–21.5) and 2.39 (1.52–4.45) μg/ml, respectively (p&lt;0.05). Against the background of RTM therapy, there was a decrease in the CP level 12 weeks after the first infusion of the drug in the group as a whole by 26.5% from the initial level, among patients with moderate/no effect of therapy – by 32.7% from the initial level.Conclusion.The CP level significantly decreases during therapy and can be used to monitor the effectiveness of therapy. The predictive value of this laboratory parameter requires further study.

Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26). We enrolled 30 children 4-15years who had developed SDNS 6-12months before and were maintained in remission with low prednisone doses (0.1-0.4mg/Kg/day). Participants were randomized following a non-inferiority design to continue prednisone alone (n 15, controls) or to add a single intravenous infusion of rituximab (375mg/m2, n 15 intervention). Prednisone was tapered in both arms after 1month. Children assigned to the control arm were allowed to receive rituximab to treat disease relapse. Proteinuria increased at 3months in the prednisone group (from 0.14 to 1.5g/day) (p < 0.001) and remained unchanged in the rituximab group (0.14g/day). Fourteen children in the control arm relapsed within 6months. Thirteen children assigned to rituximab (87%) were still in remission at 1year and 8 (53%) at 4years. Responses were similar in children of the control group who received rituximab to treat disease relapse. We did not record significant adverse events. Rituximab was non-inferior to steroids for the treatment of juvenile SDNS. One in two children remains in remission at 4years following a single infusion of rituximab, without significant adverse events. Further studies are needed to clarify the superiority of rituximab over low-dose corticosteroid as a treatment of SDNS.

Evaluation of rituximab infusion therapy in patients with recalcitrant pemphigus vulgaris

The usual approach is to treat pemphigus vulgaris by corticosteroids and in some cases, immune suppressive agents may be indicated. The response is often satisfactory to the patient and acceptable clinically; however, the use of such agents is not free of side effects. Adverse effects associating the use of corticosteroids and immune-suppressing agents are numerous, but the principal side effects are those of fatal infections and neoplastic disorders. Therefore, the search for other forms of treatment modalities has been proven necessary, especially in resistant and recalcitrant types of the disorder. A number of studies have shown role Rituximab in the treatment of pemphigus vulgaris; however, results were conflicting. Therefore we planned and conducted the current study to assess the efficacy of this drug in the treatment of recalcitrant cases of pemphigus vulgaris in a sample of Iraqi patients in the Mid-Euphrates region.&#x0D; to assess the efficacy of Rituximab in the treatment of recalcitrant cases of pemphigus vulgaris in a sample of Iraqi patients in the Mid-Euphrates region. The current cohort study included 10 patients with pemphigus vulgaris. Those patients were selected from the pool of patients visiting the dermatology consultation unit at Al-Diwaniyah teaching hospital, Al-Diwaniyah Province, Iraq during the period from January 2017 through June 2019. Age, gender, duration of disease, previous treatment, and maintenance treatment were the main variables included in the study; the outcome was a response to treatment classified as satisfactory, partially satisfactory and unsatisfactory. All patients were given an intravenous infusion of Rituximab in a dose of a 375 mg/m2 in a weekly basis. The patients were followed for a minimum of 6 months. All patients were treated by intravenous rituximab and followed for a period of 6 up to 18 months, mean of 11.30 ±3.83 months. Four (40.0 %) patients developed a satisfactory response, 5 (50.0 %) had partial satisfaction, and a single patient had an unsatisfactory response. Response to treatment was no significantly correlated to patients' age, gender or duration of disease; however, there was a significant positive correlation between duration of treatment and response to it. Good rate of satisfaction can be obtained following the use of weekly based intravenous retuximab in patients with recalcitrant pemphigus vulgaris.

Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.

AimsRituximab is a chimeric IgG‐1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell‐related pharmacodynamics of rituximab in children with autoimmune disease.MethodsRoutine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose–response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first‐order kinetics.ResultsIn total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days−1 and CD19+ turnover was 0.02 (41%) days−1 corresponding to half‐lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35‐fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6‐month suppression of CD19+ lymphocytes to current dosing.ConclusionsRituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.

A Randomized, Multiple-Dose, Multicenter, Comparative Parallel Study to Evaluate the Safety and Efficacy of Intravenous Infusion of Rituximab (Hetero) and Reference Medicinal Product (Rituximab, Roche) in Indian Patients of Non-Hodgkin's Lymphoma (HERILY)

Abstract Objective: To compare the antitumor efficacy, safety, and pharmacodynamic (PD) characteristics of Hetero-rituximab (test) with reference medicinal product (rituximab, Roche) in non-Hodgkin's lymphoma. Patients and Methods: One hundred and thirty-five patients with diffuse large B-cell lymphoma (DLBCL) were randomized to receive intravenous infusion of either test or reference product. Efficacy (best overall response [BOR] rate [primary end point]), safety, PD (CD19), and immunological assessments (secondary end points) were done at the end of cycle 3 and cycle 6. Results:: At the end of 6 cycles, BOR rate was 73.47% in Hetero-rituximab test arm compared to the 69.09% in reference arm. Anti-rituximab antibodies were found to be negative at cycle 3 and cycle 6 for all patients. Patients treated with Hetero-rituximab show a significant depletion in CD19+ cell which was comparable with reference drug. Safety and immunogenic potential of the test drug was comparable to the reference drug in the patients of DLBCL. Conclusion: BOR rate at cycle 3, cycle 6, and end of the study lies within the prespecified limit for noninferiority which concludes that test product is therapeutically noninferior to reference medicinal product.

Paraneoplastic retinopathy and optic neuropathy with Waldenström Macroglobulinemia

PurposeTo report the clinical, electrophysiologic and immunopatholologic findings in a patient with progressive visual loss due to retinal and optic nerve degeneration associated with a Waldenström's macroglobulinemia (WM).MethodsA 77‐year old man with mild stage WM, complained of progressive bilateral visual loss, with photopsia, intense photophobia and loss of color perception. Patient developed severe legs pain and unsteadiness.Complete ophthalmological, neurological and hematological examinations were realized, and patient followed over a period of 2 years. Immunohistochemical studies to determine the presence of serum antiretinal antibodies were performed.ResultsVisual acuity was gradually reduced to 1/10 RE and 2/10 LE, with a severe loss of color perception. The visual field showed a deep central and peripheral visual loss in both eyes. Optic nerves were pale and excavated, macular remained normal as peripheral retina. Cerebral CT scan did not show anomalies in the brain as in the optic nerves, lumbar puncture was unremarkable. Neurological revealed a rest less leg syndrome. Electroretinogram showed a reduce rod response and a delayed combined and cone response. Hematologic evaluations confirmed the WM and immunohistochemistry showed reactivity of the patient's serum against the photoreceptors.The patient was treated with 4 intravenous infusions of Rituximab, followed 1 month later by 1gr of Methylprednisolone for 3 days. Improvement of central vision (4/10 RE, 6/10 LE) and peripheral visual fields was reported.ConclusionsThe visual loss in this patient is due to a combined dysfunction in the retina and the optic nerve and presumed to result from antibodies IgM‐subtype reacting to proteins in different retinal antigens.

Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial.

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

BACKGROUND: There is an unmet need for effective therapies for relapsed/refractory primary and secondary central nervous system (CNS) and intraocular lymphomas (IOL), complications that are increasing in frequency among patients age >60. Whole brain irradiation, broadly utilized in the relapsed setting, yields insufficient efficacy and considerable morbidity, particularly in older patients. Implementation of new agents that selectively target survival pathways upregulated in refractory CNS lymphoma would have significant impact. Lenalidomide (CC-5013) has established activity as a single agent in aggressive NHL, particularly in ABC-type DLBCL. We recently demonstrated the activity of lenalidomide, at modest doses, in the treatment of recurrent/refractory intraocular and CNS lymphoma (J. Clin Oncol, 2011). We also provided evidence of cereblon-dependent efficacy of lenalidomide in preclinical models of patient-derived CNS DLBCL (ASH, 2013). These observations are the basis for this first trial of IMiD® immunomodulatory compound therapy in CNS NHL, as monotherapy, and in patients with inadequate responses to lenalidomide, in combination with combined intravenous plus intraventricular rituximab. (NCT01542918).METHODS: The primary objective of this phase I study is to evaluate the safety and efficacy of lenalidomide at three dose levels (10, 20, and 30mg) in relapsed/refractory CD20+ CNS NHL, with staging evaluations involving brain, CSF and intraocular compartments. Key secondary endpoints include: (1) determination of extent of CSF penetration by lenalidomide; (2) feasibility and activity of combined intraventricular and intravenous rituximab plus lenalidomide in patients with recurrent CNS lymphoma, not responsive to lenalidomide monotherapy; (3) evaluation of the effects of lenalidomide on the tumor microenvironment, including effects on tumor metabolism and immune cell infiltration and phenotypes.RESULTS: Thus far, seven subjects with relapsed CNS DLBCL (6 PCNSL, 1 SCNSL) have been treated on protocol at UCSF (median age 63, range 46-77). Each had methotrexate-resistant disease and 4 had lymphoma refractory to high-dose chemotherapy. In general, lenalidomide has been well-tolerated in the CNS lymphoma population with one DLT (non-hematologic) noted at the 20 mg dose level: fatigue and memory loss. Clinical benefit has been noted in 3 out of 4 patients with IOL, with 1 PR > 6 months duration and 1 SD > 10 months duration, each to lenalidomide monotherapy. Brain parenchymal responses to lenalidomide monotherapy (20 mg) have been demonstrated at restaging MRI, including 1 CR and 1 PR. There has been 1 CR in the leptomeninges with resolution of B-cell lymphoma in CSF, quantified by serial flow-cytometry. Combined intraventricular (20 mg) plus intravenous infusion of rituximab was well-tolerated in 3/3 patients and, with 10 mg lenalidomide, resulted in 1 PR in highly refractory IOL. Using GC/MS, we demonstrated lenalidomide penetration in ventricular CSF (0.6-7.9 ng/ml) in each of 4 patients, 12-15 hours after dosing at the 20 mg level, but trough lenalidomide concentrations >0.5 ng/ml were detected in only 1 of 3 patients receiving 10 mg lenalidomide. Serial metabolomic profiling revealed that CSF lactate correlated with clinical response to lenalidomide. Finally, we demonstrated that lenalidomide is reproducibly associated with a rapid and reversible effect on peripheral blood macrophage polarization to an M1, iNOS+ phenotype.CONCLUSIONS: These preliminary results provide evidence that lenalidomide is well-tolerated at 10 and 20 mg dose levels in CNS lymphoma. We demonstrate for the first time lenalidomide penetration in ventricular CSF, with higher trough concentrations detected at 20 mg compared to the 10 mg dose level. Encouraging evidence of lenalidomide efficacy in relapsed CNS DLBCL has been demonstrated in intraocular, CSF and brain compartments. Combined intraventricular and intravenous infusion of rituximab is feasible and represents a novel strategy to the potentiation of immunotherapeutic strategies in brain tumors. Studies are in progress to further elucidate the safety, pharmacokinetics and mechanisms involved in this biological approach to the treatment of refractory CNS lymphomas.Supported by NCI, Leukemia and Lymphoma Society, UCSF Helen Diller Comprehensive Cancer Center, Celgene and Genentech DisclosuresOff Label Use: Intrathecal administration of rituximab. Wang:Celgene: Employment. Chen:Celgene: Employment.

Plasmapheresis combined with rituximab for refractory idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) is known to be one of the most common causes of nephrotic syndrome in adults [1]. Severe therapy-refractory IMN is a life-threatening disease and demands new treatment options. We report the first successful treatment for severe therapy-refractory INM with a combination of plasmapheresis and rituximab. A 34-year-old male Caucasian was admitted to the hospital with newly developed peripheral edema. Kidney function was normal, whereas proteinuria exceeded 6.2 g protein/g creatinine (normal value: \0.15 g protein/g creatinine) and the serum albumin level was decreased (2.6 g/ dl, normal value: 3.5–5.4 g/dl). Kidney biopsy showed typical membranous glomerulopathy with subepithelial immunoglobulin-containing deposits along the glomerular basement membrane. The causes of secondary membranous nephropathy (MN) such as hepatitis, HIV, autoimmune disease and cancer were excluded. A high titer of anti-phospholipase A2 receptor antibody was detected in serum (1:640) by indirect immunofluorescence. Initially, the patient was treated with an angiotensinconverting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), an anticoagulant and prednisolone (60 mg/day, progressively tapered to 5 mg/day). Six months later, his condition deteriorated. Serum creatinine level increased to 1.5 mg/dl (135 lmol/l) while serum albumin declined to 1.5 g/dl (15 g/l). The patient was still heavily proteinuric (4.6 g protein/g creatinine). The treatment was then complemented by cyclosporine (CsA) and switched later to tacrolimus (Tac) due to side effects. However, his condition further deteriorated rapidly with increased protein excretion (8.8 g protein/g creatinine). He gained 20 kg in 3 weeks and showed increased peripheral edema and dyspnea. We decided to perform a combined treatment with plasmapheresis (d1-3, d5, d7) followed by two infusions of rituximab (d8 ? d28). Each plasmapheresis was performed over 2–3 h, using 5,000 ml of fresh frozen plasma (FFP), approximately 1.2 times the circulating plasma volume, as a replacement fluid. Subsequently, the patient received intravenous infusions of rituximab (375 mg/m, d8 ? d28). Complete remission of nephrotic syndrome was achieved 8 weeks later. The concentration of anti-PLA2R antibodies in the serum was continuously reduced during the treatment and eventually disappeared during remission (Fig. 1). Protein excretion was below 0.3 g/day in eight consecutive visits under ACE inhibitor/ARB treatment. Despite numerous studies, the optimal treatment for IMN remains disputable. Remuzzi et al. [2] reported the therapeutic benefit of rituximab in high-risk patients with IMN. However, remission was achieved in a relatively long time frame, between 3.2 and 12.0 months. As our patient was non-responsive to conservative treatment and immunosuppression including steroids, CsA and Tac, his condition was too critical to allow time for exclusive rituximab treatment to take effect. Therefore, the patient received plasmapheresis treatments in order to rapidly eliminate all possible antibodies and immune M. Wen C. Kuchle O. Sarkar L. Renders U. Heemann C. Schmaderer (&) Department of Nephrology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strase 22, 81675 Munich, Germany e-mail: christoph.schmaderer@lrz.tu-muenchen.de

AB0509 Comparative effectiveness of tocilizumab (TCZ) and rituximab (RTM) using different disease activity indices (DAS 28, SDAI and CDAI) in patients with rheumatoid arthritis (RA)

BackgroundHumanized anti-interleukin-6 (IL-6) receptor monoclonal antibody (TCZ) and chimeric monoclonal antibody against CD 20 positive B cells (RTM) are effective and safe preparations for the treatment of RA. Taking into...

Neuromyelitis optica

Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disease of the central nervous system that is characterized mainly by recurrent optic neuritis and longitudinally extensive transverse myelitis. The aim of this article is to present current knowledge on the clinical features, diagnosis, pathogenesis and treatment of the condition. The article is based on a discretionary selection of English-language original articles, meta-analyses and review articles found in PubMed, and on the authors' own experience with the patient group. Neuromyelitis optica was previously assumed to be a variant of multiple sclerosis (MS), but the discovery of aquaporin-4 antibodies in patients with neuromyelitis optica has led to this view being revised. The cause of the condition is still unknown, but it has been shown that the antibodies bind selectively to a water channel expressed mainly on astrocytes at the blood-brain-barrier, which has an important role in the regulation of brain volume and ion homeostasis. Clinically, the condition presents as optic neuritis and/or transverse myelitis. A diagnosis is made on the basis of case history, clinical examination, MRI of the brain and spinal cord, analysis of cerebrospinal fluid, visual evoked potentials and a blood test with analysis of aquaporin-4 antibodies. Once a diagnosis has been made, rapid treatment is important. In the acute phase, intravenous methylprednisolone is recommended. There are several options for preventative treatment, but the primary recommendations are oral prednisolone and azathioprine or intravenous infusion of rituximab. Treatment is distinct from the treatment of MS and some of the immunomodulatory drugs commonly used in MS can lead to worsening of neuromyelitis optica. The condition is an important differential diagnosis of MS, but differs from MS in terms of clinical features, prognosis and treatment. Patients have a high risk of sequelae following relapses, and therefore early diagnosis and treatment is important.

Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial

Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.

An open-label trial of rituximab therapy in pulmonary alveolar proteinosis

Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean ± sem 15 ± 2% to <0.05% (n = 10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5 ± 2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n = 8) but unchanged in sera (n = 9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.