Initiation Of Rituximab Therapy Research Articles

Rituximab Induces an Inflammatory Cytokine Response with Increased IP-10 (CXCR10) in Patients with Infusion Reactions

Most patients initiating anti-CD20 monoclonal antibody (mAb) therapy for CLL have a disruptive infusion reaction that can cause serious complications and be fatal. A better understanding of the risk factors and etiology of infusion reactions is required to improve preventative measures and management. We report a study to test the hypothesis that IV rituximab induces an inflammatory cytokines response with differences in individual cytokine concentrations correlating with infusion reactions. We designed a clinical trial (NCT03788291) for initial treatment of patients with progressive CLL that provided clinical data and blood specimens from 37 patients treated with 50 mg of IV rituximab infused at 25 mg/h. Blood specimens were collected immediately prior to initiation of rituximab (baseline), one hour later (1h), at the end of the infusion (post-infusion) and at 48 h after initiation of therapy (48h). Infusion reactions (CTCAE grade ≥2 events) were managed by interrupting the infusion and initiating symptomatic treatment. We measured circulating CLL cell counts and CD20 levels, and serum rituximab concentration, complement levels, and cytokine concentrations of IFN-γ, IL-10, IL-18, IL-2, IL-4, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α using standard methods. Twenty-four (65%) patients had 25 infusion reactions (all CTCAE grade 2) at a median of 78 minutes (range 35-128) after initiation of rituximab therapy (median dose 32 mg, range 15-50). All patients completed the 50 mg rituximab infusion (median time 150 minutes, range 119-195). Patient and CLL characteristics including baseline CLL cell counts did not predict the risk of infusion reactions. Median CLL counts at 1h decreased to 14.7% of baseline with no further changes post-infusion and no significant difference between patients with or without infusion reactions (60x109/L vs. 45x109/L, p=0.61). Median CLL cell membrane CD20 levels (x103 molecules/cell) decreased from 4.77 at baseline to 3.10 at 1h (p=0.002) and 1.59 post-infusion (p<0.0001 vs. baseline and 1h) with no significant differences between patients with or without an infusion reaction. The median estimated number of circulating CLL cell membrane CD20 molecules (x1012 molecules/L) decreased from 325.8 at baseline to 34.1 at 1h (p<0.0001) and 14.5 post-infusion (p<0.0001 vs. baseline, p<0.03 vs. 1h) with no significant differences between patients with or without an infusion reaction. There was no correlation between risk of infusion reaction and serum levels of rituximab or serum complement. Thirty-five (95%) patients had a ≥4 fold increase in serum concentration of ≥1 cytokine with resolution of the cytokine response at 48h. All patients with an infusion reaction had significantly higher median post-infusion serum concentrations of IP-10, IL-6 and IL-8. All 17 patients with IP-10 serum concentrations above the limit of detection (40,000 pg/ml) post-infusion had an infusion reaction, and all 24 patients with an infusion reaction had a ≥4 fold increase in serum IP-10 concentrations. Of 13 patients without an infusion reaction, the highest measured serum IP-10 concentration was 22,013 pg/ml and only 3 (23%) had ≥4 fold increases in serum IP-10 concentrations. Slow infusion of a reduced dose of rituximab induced a cytokine response in 95% of patients and therapy disrupting infusion reactions occurred at a comparable rate (65%) to standard rituximab therapy. Infusion reactions were associated with increased levels of IP-10, IL-6 and IL-8. IP-10 levels were increased by ≥4 fold in all patients with an infusion reaction compared to 23% without an infusion reaction. These data suggest that rituximab infusion reactions are caused by inflammatory cytokines produced by cytotoxic effector cells activated by rituximab independent of the pre-treatment amount of circulating CLL cells or CD20 levels, or efficacy of rituximab in reducing the circulating CLL cell count. Infusion reactions occurred after at least 35 minutes of therapy concurrent with a rapid decrease in circulating CLL cells. This observation suggests that cytokine release could be a result of activation of effector cells responsible for CLL cell elimination. Our data provides novel insights into the potential mechanism of infusion reactions and could form the basis of further research to determine methods to control this clinically important and therapy limiting complication.

Rituximab as Adjunct Maintenance Therapy for Refractory Juvenile Myasthenia Gravis

BackgroundJuvenile myasthenia gravis is a pediatric autoimmune disorder of the neuromuscular junction associated with substantial morbidity, for which standard therapies are not always efficacious. The objective of our study was to assess the tolerability and efficacy of rituximab use in children with refractory juvenile myasthenia gravis. MethodsWe conduced a retrospective cohort study at a single tertiary care referral center to evaluate children with juvenile myasthenia gravis who were treated with rituximab. The clinical status of these participants before and after initiation of rituximab therapy was measured, focusing on numbers of hospital admissions, numbers of immunomodulatory or immunosuppressive medications needed, and Myasthenia Gravis Foundation of America severity class. ResultsFive children with juvenile myasthenia gravis were ascertained who received rituximab as part of their regimen, four of whom had elevated acetylcholine receptor antibodies and one of whom had elevated muscle-specific kinase antibodies. After initiation of rituximab therapy, all participants experienced reduced numbers of immunomodulatory medications during the follow-up period (mean 11.6 months). Four of the five subjects experienced fewer juvenile myasthenia gravis-related hospital admissions and reduced (improved) Myasthenia Gravis Foundation of America classes, with no subjects having moderate or severe symptoms following treatment with rituximab. No significant adverse events were recorded for any of the participants. ConclusionRituximab was well-tolerated and efficacious in this juvenile myasthenia gravis cohort. The beneficial effect of rituximab was most pronounced in the one participant with muscle-specific kinase antibodies.

Stopping oral steroid-sparing agents at initiation of rituximab in myasthenia gravis

Rituximab is a chimeric monoclonal antibody that binds CD20 and causes the depletion of B-cell subsets. Although initially designed to treat lymphoma, it has found wide use in the management of various autoimmune conditions, including myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction. Treated myasthenia patients are often on an oral steroid-sparing agent. To determine the safety of stopping oral steroid-sparing agents at the initiation of rituximab therapy and its effectiveness we reviewed the records of 27 MG patients with rituximab, including 13 with anti-MuSK+ MG, 10 with anti-AChR+ MG, and 4 double seronegative MG patients. All patients that were on an oral steroid-sparing agent (21 of 27) were able to stop it, and they did not require re-introduction of the medication. Also, the daily prednisone dosage was significantly decreased in 20/24 patients across all three serotype groups. MGFA post intervention status analysis also showed 15/27 of all patients achieved minimal manifestation status or remission across all groups. Antibody titers decreased dramatically and promptly in anti-MuSK+ MG patients. Our data suggests that stopping oral steroid-sparing agents at initiation of rituximab therapy is safe. Also, our data indicates that rituximab is highly effective in the management of seropositive MG patients.

Therapeutic efficacy of rituximab for the management of adult-onset steroid-dependent nephrotic syndrome: a retrospective study.

Recent reports have described the efficacy of rituximab in treating steroid-dependent nephrotic syndrome (SDNS) in pediatric patients. However, few reports describe data regarding adult-onset SDNS. We investigated the efficacy of rituximab for the management of adult-onset SDNS. We performed a retrospective cohort study investigating eight patients with adult-onset SDNS who were treated with rituximab. Clinical data were obtained at the initiation of rituximab therapy. The primary outcomes evaluated were successful suppression of relapses and CD19+ cells after rituximab treatment. The corticosteroid- and immunosuppressant-sparing effect and adverse events were additionally evaluated. All eight patients were diagnosed with minimal change nephrotic syndrome and received immunosuppressants in addition to corticosteroid. Total number of relapses was 10.5 times as a median value. Rituximab administration was repeated in two patients, whereas six received single-dose rituximab. Three of eight (37.5%) patients showed relapse after rituximab therapy. A rituximab-induced depletion in CD19+ cells noted initially was followed by their reappearance in all patients. There were cases with no relapse after the reappearance of CD19+ cells. The median relapse time pre- and post-rituximab therapy showed a decrease from 1time/year (interquartile range [IQR] 1-3times/year) to 0time/year (IQR 0-1time/year). Rituximab treatment induced a significant reduction in the required doses of corticosteroid and cyclosporine (P < 0.01). No serious adverse events were observed. Rituximab treatment was effective not only in childhood-onset but also in adult-onset SDNS. Further studies are needed to establish optimal treatment regimens.

Efficacy and safety of rituximab therapy in patients with pemphigus vulgaris: first report from Turkey.

Pemphigus vulgaris (PV) is a severe, chronic, and potentially life-threatening autoimmune blistering disease that affects the skin and mucous membranes. Rituximab is a monoclonal anti-CD20 antibody which has been used increasingly in the therapy of PV. The present study sought to test the efficacy and safety of rituximab as an adjuvant therapy by retrospective analysis of clinical and immunological data for 29 patients with PV who were treated with rituximab between 2010 and 2015. Response to therapy, duration of clinical remission, serology of the response, and adverse effects of rituximab were evaluated. The mean ± standard deviation (SD) follow-up time was 17.48 ± 13.18 months. In all patients, findings showed either a decrease in antibody titers or that antibodies were completely undetectable after therapy. Rituximab use resulted in a significant reduction in steroid dosage during follow-up. At the end of the follow-up period, 26 patients (96.2%) had achieved complete remission with or without therapy (one patient had no follow-up and one patient had died, most probably as the result of a thromboembolic event). In 44.4% of patients, a clinical relapse occurred after a mean ± SD period of 13.1 ± 4.7 months after the initiation of rituximab therapy. Relapses were managed with additional infusions of rituximab. Rituximab is a beneficial and relatively safe adjuvant treatment for PV that facilitates prolonged clinical remission and has a significant steroid-sparing effect.

Chronic hepatitis B virus screening prior to rituximab: A quality improvement project.

199 Background: Patients’ with chronic hepatitis B (HBV) are at risk for HBV reactivation and liver failure with initiation of rituximab therapy. HBV testing prior to rituximab for patients with non-Hodgkin lymphoma was a quality measure for the American Society of Clinical Oncology’s Quality Oncology Practice Initiative in Spring 2011. Methods: We assessed the pre-intervention HBV screening rate retrospectively from July 2009 to July 2011. Patient demographics, pathology, regimen, and prescriber were abstracted from the electronic medical record. Screening was complete if serum HBVsurface antigen was checked within 3 months prior to rituximab. A quality improvement (QI) intervention was initiated and all prescribers were informed of the screening rate in December 2011. Post-intervention, patients who received rituximab from January 2012 to July 2012 were identified and the same data was abstracted. HBV screening rates across categories pre and post-intervention were analyzed with Fisher’s exact test and multivariate logistic regression analysis. Results: A total of 146 patients (127 pre-intervention, 19 post-intervention) were included. There were more male and rituximab combination therapy in the post-intervention group. The HBV screening rate increased from 59% to 90% (p&lt;0.01) after our QI project. In univariate analysis, factors associated with HBV screening were (1) prior treatment with rituximab (no: 72% vs. yes: 46%, p&lt;0.01), (2) treatment regimen (rituximab alone: 68% vs. combination: 42%, &lt;0.01) and (3) prescriber (full time: 69% vs. part time: 7%, &lt;0.01) In multivariate logistic regression analysis, the odds of HBV screening increased 4.8 times in the post-intervention group compared to pre-intervention group although this was statistically not significant (p=0.07). Prior rituximab (Odds Ratio (OR) 0.4, 95%CI 0.2-0.9), combination regimen (OR 3.2, 95% CI 1.5-7.2), and full-time prescriber (OR 25.1, 95% CI 2.8-255.4) were statistically significant for HBV screening. Conclusions: The HBV screening rate improved after QI intervention although statistically insignificant in multivariate analysis. We identified characteristics associated with low screening rates which will guide future QI strategy.

Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium

Rituximab displays therapeutic benefits in the treatment of patients with rheumatoid arthritis (RA) resistant to tumor necrosis factor (TNF) blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. We undertook this study to investigate the global molecular effects of rituximab in synovial biopsy samples obtained from anti-TNF-resistant RA patients before and after administration of the drug. Paired synovial biopsy samples were obtained from the affected knee of anti-TNF-resistant RA patients before (time 0) and 12 weeks after (time 12) initiation of rituximab therapy. Total RNA was extracted, labeled according to standard Affymetrix procedures, and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction experiments were performed to confirm the differential expression of selected transcripts. According to Student's paired t-tests, 549 of 54,675 investigated probe sets were differentially expressed between time 0 and time 12. Pathway analysis revealed that genes down-regulated between time 0 and time 12 were significantly enriched in immunoglobulin genes and genes involved in chemotaxis, leukocyte activation, and immune responses (Gene Ontology annotations). In contrast, genes up-regulated between time 0 and time 12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (Gene Set Enrichment Analysis). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy. Rituximab displays unique effects on global gene expression profiles in the synovial tissue of RA patients. These observations open new perspectives in the understanding of the biologic effects of the drug and in the selection of patients likely to benefit from this therapy.

A woman with severe lupus nephritis and difficult to control diabetes mellitus

A woman with severe lupus nephritis and difficult to control diabetes mellitus

Rituximab Treatment for Epstein-Barr Virus DNAemia after Alternative-Donor Hematopoietic Stem Cell Transplantation

We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies.