Rituximab In Children Research Articles

FC 131OFATUMUMAB OR RITUXIMAB FOR CHILDREN WITH STEROID-DEPENDENT NEPHROTIC SYNDROME. A RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims The chimeric anti-CD20 monoclonal antibody rituximab has been successfully used in steroid-dependent forms of nephrotic syndrome (SDNS) to maintain oral-drug-free remission, but relapses at one year occur in almost half of the patients. Ofatumumab, a fully human anti-CD20 monoclonal antibody, may be superior to rituximab in maintaining remission of SDNS. We compared the efficacy and safety of ofatumumab vs. rituximab in children and young adults with SDNS (NCT02394119) and evaluated the risk of relapse following steroid and calcineurin-inhibitor tapering and withdrawal. Method We randomly assigned 140 children and younger adults (age 2-24 years) with SDNS maintained in remission with steroids and calcineurin-inhibitors to receive intravenous ofatumumab (1.500 mg/1.73 m2; intervention) or rituximab (375 mg/m2; control). Following infusions, oral drugs were tapered and withdrawn. Participants were followed for 24 months. The primary outcome was relapse at one year, defined by protein-creatinine ratio ≥2000 mg/g or >3+ protein on urine dipstick for 3 consecutive days. Cellular and safety data were also assessed. Results At 12 months, 36 patients (51.4%) relapsed in the rituximab arm and 37 (52.8%) in the ofatumumab arm (Odds Ratio [OR] 1.06; 95% confidence interval [CI] 0.55 to 2.06). At 24 months, 46 children relapsed in the rituximab arm (65.7%) and 53 in the ofatumumab arm (75.7%). In both arms, circulating B cell levels declined following treatment and recovered between 3 and 9 months. Higher pretreatment levels and faster recovery after decline of memory B cells predicted relapse. Conclusion In children and younger adults with SDNS, ofatumumab is not superior to the chimeric anti-CD20 antibody rituximab. Immune phenotyping data indicate that anti-CD20 therapies alter the course of the disease by interfering with memory B cell populations and can be used to predict response to anti-CD20 treatment.

A dose substitution of anthracycline intensity with dose-dense rituximab in children and adolescents with good-risk mature B-cell lymphoma.

A dose substitution of anthracycline intensity with dose-dense rituximab in children and adolescents with good-risk mature B-cell lymphoma.

Safety and Efficacy of Rituximab in Children with Steroid-Dependent or Resistant Nephrotic Syndrome

Backgroundand Aim:Rituximab is a novel therapy that can help patients with steroid-dependent or resistant nephrotic syndrome.The aim of this study was to evaluate the efficacy of rituximab in children with corticosteroid-dependent and resistant nephrotic syndrome and to determine the factors associated with its efficacy. Methods:In this study, 40 children with corticosteroid-dependent or resistant nephrotic syndrome who were treated with rituximab in Dr. Sheikh Hospital,Mashhad,between 2014 and 2018 were enrolled. Patients with a history of hematuria, severe urinary tract infection, or secondary nephrotic syndrome were excluded. Results:The mean age of patients was 11.9 ± 5.04 years, and 55% were female. The most common underlying pathology of nephrotic syndrome was focal segmental glomerulonephritis (FSGS) (42.5%) followed by membranoproliferative glomerulonephritis (MPGN) and minimal change disease (MCD). Most of the participants (62.5%) were steroid-dependent and the rest (27.5%) were steroid resistant. Only 10% of the patients showed complications following rituximab administration and 57.5% went into complete remission. A negative family history and steroid-dependent nephrotic syndrome were significantly associated with a better treatment response. Moreover, patients with steroid-resistant nephrotic syndrome were more likely to have a positive family history, while factors associated with steroid response included underlying pathology, gender, and family history. Conclusion: Rituximab can cause remission in more than half of the patients with steroid-resistant or dependent nephrotic syndrome. Moreover, the only factors that reduce response to rituximab are a history of corticosteroid resistance and a positive family history of nephrotic syndrome.

Randomized Clinical Trial to Compare Efficacy and Safety of Maintenance Mycophenolate-Mofetil to Cyclosporine After Repeated Courses of Rituximab in Children With Steroid Resistant Nephrotic Syndrome

Background: Approximately 10% of children with children with idiopathic nephrotic syndrome will not achieve complete remission after 6-8 weeks therapy with corticosteroid and have steroid resistant nephrotic syndrome (SRNS). Rituximab (RTX), a B cell depleting monoclonal antibody followed by maintenance mycophenolate-mofetil (MMF) or cyclosporine (CYC) has been shown to be efficacious in children with SRNS. Controlled trial comparing the efficacy and safety of treatment with CYC to MMF after RTX induction is lacking. Methods: A total of 55 children with SRNS were randomized to receive 12 months MMF 1.0 g/m2/day (n=28) or CYC 5 mg/kg/day (n=27) following RTX infusions (375 mg/m2 intravenously) to maintain persistent B cell depletion. The primary outcome was complete remission rate at 12 months and secondary outcome consisted of incidence of treatment-related adverse events among all intention-to-treat population. Results: RTX/MMF therapy was associated with a significantly higher relapse-free survival (complete remission rate) at 12-month [23(82% vs. [15(56%)]; p<0·01). Among patients who experienced relapse; median time to first relapse was significantly longer for patients treated with RTX/MMF (10·3 months) than patients receiving RTX/CYC (7·1 months) (P<0·01). Only 3 patients in the RTX/MMF group had more than 1 relapse during the study period compared with 8 in the RTX/CYC group (p<0·01). Overall, the response to therapy was greater in patients with the FSGS who were receiving RTX/MMF regimen (p<0·01). Moderate to severe infections were twice as common in the RTX/CYC than in RTX/MMF (P=0·05). Interpretation: The study found a superiority of MMF over CYC after RTX in terms of relapse -free survival and adverse events. The findings suggest that MMF therapy following RTX may be considered first line corticosteroid-sparing therapy in the treatment of SRNS. Trial Registration: The study was registered with the WHO International Clinical Trials Registry Platform (ICTRP) and Iranian Registry of Clinical Trials (IRCT20150421021894N; https://irct.ir), registration date 25 March 2019. Funding Statement: None. Declaration of Interests: The authors declare they have no financial competing interests for the overall trial and the study site. Ethics Approval Statement: The study protocol and consent documents were approved (IR.ZAUMS.REC.1397.491) by the Ethics committee (Institutional Review Board) of Zahedan University of Medical Sciences, Iran following approval of institute scientific committee. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research where the study was conducted and with the 1964 Helsinki Declaration and its later amendments as revised in 2013 and confirmed to the CONSORT 2010 checklist guidelines for reporting the randomized clinical trial. Informed written parental consent was obtained from all subjects prior to study.

Final Report of Reduced Anthracycline Dose Intensity with the Addition of Dose Dense Rituximab in Children, Adolescents and Young Adults with De Novo Good Risk Mature B-Cell Non Hodgkin Lymphoma (B-NHL)

Background: Previous studies have demonstrated excellent results with FAB/LMB86 chemotherapy alone and in combination with rituximab in children, adolescents and young adults with mature B-NHL. (Cairo et al, JCO 2012, Goldman et al, Leukemia, 2013, Goldman et al, BJH 2014) The intermediate risk FAB/LMB Group B arm consists of 180mg/m2 of doxorubicin. This was reduced to 120mg/m2 with the addition of dose-dense rituximab. Other standard NHL regimens more commonly used in young adults with advanced stage mature B-NHL, such as R-CHOP, have a total dose doxorubicin of 360mg/m2. These approaches are associated with short term morbidities and long-term health conditions, including anthracycline induced cardiac toxicities.Dose-dense rituximab containing chemoimmunotherapy in high risk mature B-NHL has shown significant improvements in outcomes. We tested the hypothesis that rituximab can be used to even further reduce the burden of anthracycline from 120mg/m2 to 50mg/m2 in patients with good risk B-NHL. Objective: To safely reduce the burden of therapy by reducing the number of IT injections and reducing the total dose of doxorubicin from 120mg/m2 to 50mg/m2 with the addition of liposomal cytarabine and dose-dense rituximab to our prior chemotherapy backbone in children with good risk mature B-NHL. Design/Methods: Multi-institutional Phase II study (NCT01859819). Patients (3-31 years) with CD20+ B-NHL with good risk (FAB Group B GR=Stage I/II, Stage III with any LDH and Stage IV {BM tumor &amp;lt; 25%)}) were eligible. Staging was defined per the IPNHLSS as previously described. (Roselen et al, JCO 2015) All patients received FAB backbone chemotherapy with the addition of six rituximab (375mg/m2) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. Cumulative doxorubicin was reduced from 120 to 50 mg/m2 (25mg/m2 per dose) total. After systemic methotrexate clearance, patients received age-based dosing of IT liposomal cytarabine resulting in a reduction of IT injections from nine to five. The primary outcome was safety and toxic deaths with an estimated 3-year survival above 90%, monitored by an independent DSMB. Response was defined per the IPNHLRC as previously described. (Sandlund et al, JCO 2015) Results: Twenty-five FAB Group B patients were enrolled at 5 treatment centers in the United States. Histology included DLBCL in 13 patients and Burkitt in 12 patients. Table 1. All patients had at least a 20% tumor decrease after the reduction phase. Two patients were upstaged to intensified Group C therapy after residual imaging findings post first consolidation. Therefore, 23/25 patients had a cumulative doxorubicin exposure of 50 mg/m2 while the two patients who received augmented treatment had a total exposure of 170 mg/m2. There were no serious adverse events reported with rituximab administration and no reported CNS or other toxicity reported with liposomal cytarabine intrathecal prophylaxis. During the two induction cycles there were no readmissions for febrile neutropenia or other causes and no reported grade III or higher mucositis. Follow up immune globulin levels on a smaller cohort of patients revealed median IgG levels of 821 (range, 362-1172) at a median follow up of 24 months. All patients are alive and in first remission with an EFS/OS = 100% at a median follow up of 4 years (range, 2-7yr). Figure 1. Echocardiograms revealed stable left ventricular function. Rituximab CSF levels were measured as we previously described and were extremely low (&amp;lt; 10µg/ml) compared to peak serum levels (250-400µg/ml). Conclusions: Our results demonstrate the feasibility of careful reduction of anthracycline dose intensity with the addition of dose-dense rituximab immunotherapy in children, adolescents and young adults with good risk mature B-NHL. Our results demonstrate a 100% EFS/OS with a reduction to only 50mg/m2 total dose of anthracycline. This is consistent with published standard of care outcomes utilizing much higher doses of 120-550mg/m2 of doxorubicin. Our treatment strategy benefits good risk patients with mature B-NHL by using dose-dense rituximab to reduce the cumulative exposure of anthracycline associated short- and long-term toxicities as well as the number of required intrathecal injections. These excellent results require the investigation of this approach in a larger cohort in the future to confirm these preliminary findings. Disclosures Goldman: Jazz Pharmaceuticals, Inc.: Speakers Bureau. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Cairo:Miltenyi: Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Increased toxicities in children with Burkitt lymphoma treated with rituximab: Experience from a tertiary cancer center in India.

Even though rituximab has emerged as standard of care for the management of high-risk pediatric Burkitt lymphoma (BL), its safety in children from the low-middle-income countries (LMICs) remains to be proven. We herein report our experience of using rituximab in children with BL. All patients diagnosed with BL between January 2015 and December 2017 were treated in a risk-stratified manner with either the modified MCP-842 or modified LMB protocol. Patients with poor response to MCP-842 were switched to the LMB-salvage regimen. In addition, rituximab was given to selected high-risk patients. Forty-two (49.4%) of 85 patients with BL received rituximab. The incidence of febrile neutropenia (90.5%vs 67.4%; P=0.02), pneumonia (38.1%vs 11.6%; P=0.005), intensive care unit admissions (54.5%vs 17.6%; P=0.002), and toxic deaths (26.2%vs 9.3%; P=0.04) was higher among BL patients who received rituximab. Pneumonia was fatal in 11 of 16 (69%) patients who received rituximab. On multivariate analysis, rituximab continued to be significantly associated with toxic deaths ( OR: 11.45 [95% CI: 1.87-70.07; P=0.008]). The addition of rituximab to intensive chemotherapy resulted in an inferior one-year event-free survival (49.4% ± 8.1%vs 79.3% ± 6.5%; P=0.025) and one-year overall survival (63.1% ± 8.5%vs 91.8% ± 4.5%; P=0.007) with no improvement in one-year relapse-free survival (78.3% ± 7.3% vs 83.9% ± 6.0%; P=0.817). Rituximab was associated with increased toxicities and toxic deaths in our patients. The potential immunomodulatory effect of rituximab and increased susceptibility to infections in patients from LMICs have to be carefully considered while choosing this drug in the treatment of BL in resource-constrained settings.

Rituximab in children with steroid sensitive nephrotic syndrome: in quest of the optimal regimen.

Rituximab has emerged as an effective and important therapy in children with complicated frequently relapsing and steroid-dependent nephrotic syndrome to induce long-term disease remission and avoid steroid toxicities. The optimal rituximab regimen is not totally well defined, and there are many varying practices worldwide. We will in this review describe how patient factors, rituximab dose, and use of maintenance immunosuppression affect treatment outcomes. Specifically, low-dose rituximab without concomitant immunosuppression is associated with shorter relapse-free duration while other regimens have comparable outcomes. Patients with more severe disease generally have worse response to rituximab. Although rituximab appears to be generally safe, there are growing concerns of chronic hypogammaglobulinemia and impaired immunity especially in young children. Reliable prognostications and biomarkers for guiding subsequent treatments to avoid excessive treatments are yet to be identified. In this review, we will outline the, as we see it, best approach of rituximab in childhood steroid sensitive nephrotic syndrome at the present state of knowledge.

Rituximab is highly effective in children and adolescents with Burkitt lymphoma in Risk Groups R2 to R4

Data regarding the use of rituximab in children and adolescents with Burkitt’s lymphoma (BL) is limited. This study retrospectively analyzed the effect of rituximab on children and adolescents with BL in risk group (R) 2 to R4. Patients underwent chemotherapy according to the revised NHL-BFM-95 protocol. Rituximab was administered at the dose of 375 mg/m2 on day 0 of each cycle. A total of 106 patients were included. Stratified by the number of doses of rituximab, there were 49, 16, and 41 patients in group 1 (no rituximab), group 2 (1–3 doses of rituximab) and group 3 (≥4 doses of rituximab), respectively. The 3-year event-free survival (EFS) rates were 83.2% (95% CI = 72.6%–93.8%), 81.2% (95% CI = 52.3%–93.5%) and 96.8% (95% CI = 78.8%–99.6%) in group 1, group 2 and group 3, respectively (p = 0.077). In R2/R3, the relapse rates were 0 in patients treated with rituximab and 11.8% in those treated without rituximab (p = 0.516). In R4, the relapse rates were 18.8%, 21.4% and 3.0% in group 1, group 2 and group 3, respectively (p = 0.048). Rituximab is highly effective in children and adolescents with BL in R2 to R4. The optimal number of doses was 4–6 in patients with BL in R4.

Study of prednisolone and rituximab in nephrotic syndrome based on novel nanomaterials

In the search for a more reasonable yet effective treatment method, this study explores the application of nanometer magnetic particles and prednisolone combined with rituximab in children with nephrotic syndrome (NS). According to the diagnostic criteria of children with hormone sensitivity and frequent recurrence of primary NS from the nephrology group of the Chinese Academy of Pediatrics, 40 children with NS diagnosed in our hospital from January 2018 to October 2019 were selected. Nanomagnetic α-Fe2O3 particles were prepared by chemical reaction synthesis. Before and after treatment, urine protein, oral hormone dosage, changes in peripheral blood CD19 + B lymphocyte levels, changes in plasma immunoglobulin levels, and patient general improvement were observed, along with the recurrence of renal disease after treatment. Immunoglobulin was measured by the immunoturbidimetric method, and the endpoint of the follow-up was the first relapse after administration. This study shows that the use of nanomagnetic particles and prednisolone in combination with rituximab in the treatment of pediatric NS has a significant effect, improving the renal function indicators of children and effectively controlling the condition of children while maintaining a higher level of safety.

Immunoglobulin serum levels in rituximab-treated patients with steroid-dependent nephrotic syndrome.

Rituximab (RTX) is efficient in steroid-dependent nephrotic syndrome (SDNS) in pediatric and adult patients. The aim of this study is to describe hypogammaglobulinemia as a side effect of RTX treatment. All pediatric patients (< 18 years old) of four French pediatric nephrology centers who received RTX for SDNS between 2010 and 2015 have been included. Clinical and biological data have been analyzed retrospectively before, during, and after RTX treatment. Hypogammaglobulinemia was defined as an IgG level < - 2 standard deviations for patient age. A total of 107 pediatric patients have been included, 65.9% were boys, median age at nephrotic syndrome diagnosis was 3.1 interquartile range [IQ 2.24-5.45] years and age at RTX introduction was 11.7 [IQ 8.6-14.2] years. Twenty-one patients had hypogammaglobulinemia before the initiation of RTX. Of the patients, 25/86 had at least one hypogammaglobulinemia during B cell depletion or after B cell recovery while IgG levels at initiation were normal with a persisting hypogammaglobulinemia for 13 patients 1 year after B cell recovery. Patients who developed hypogammaglobulinemia were younger at RTX initiation with a median age of 8.2 years [IQ 6.3-12.4]. Among all the 46 patients with hypogammaglobulinemia during follow-up, 13 had a concomitant infection. Hypogammaglobulinemia is a frequent complication of RTX treatment in younger children treated for SDNS. The use of RTX in children has to be carefully evaluated and their clinical and biological follow-up should be adapted to the age-dependent risk profile for hypogammaglobulinemia.

Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth.

Background: Since the early 2000s rituximab (RTX) has been thought of as an alternative treatment for steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS).Objective: This study aimed to determine the effects of RTX treatment on disease outcome and growth in pediatric SSNS and SRNS patients.Materials and Methods: The medical records of pediatric SSNS and SRNS patients that began RTX treatment at the mean age of 10.8 ± 5.1 years between 2009 and 2017 were retrospectively reviewed. Additionally, the effect of RTX on growth was evaluated based on patient height, weight, and BMI z scores.Results: The study included 41 children, of which 21 had SSNS and 20 had SRNS. Mean age at diagnosis of NS was 5.8 ± 4.7 years. Mean duration of post-RTX treatment follow-up was 2.3 ± 1.6 years. Among the SSNS patients, 6 and 11 patients were steroid free and calcineurin inhibitor free at the last follow-up visit, respectively. The 1-year cumulative steroid and calcineurin inhibitor doses both decreased after RTX treatment, as compared to before RTX (P = 0.001 and P = 0.015, respectively). The median height z-score at the time of RTX initiation was −1.2 and the median height z-score at the last follow-up visit was −0.6 (P = 0.044). The median BMI z-score decreased from 1.6 (IQR; 0.9–3.0) at the time RTX was initiated to 1.1 IQR; [(−0.7)−2.5] at the last follow-up visit (P = 0.007). At the last follow-up visit 4 SRNS patients had complete remission and 4 had partial remission. The 1-year cumulative steroid dosage in the SRNS patients decreased significantly after RTX, as compared to before RTX (P = 0.001). The median height z-score at the time of RTX initiation was −0.8 and the median height z-score at the last follow-up visit was −0.7 (P = 0.81). The median BMI z-score decreased from 0.3 at the time RTX was initiated to −0.1 at the last follow-up visit (P = 0.11).Conclusion: RTX has a more positive effect on disease outcome and growth in SSNS patients than in those with SRNS.

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.

Long-term observation of Rituximab therapy for children with frequently relapsing nephrotic syndrome

Objective To observe the long-term efficacy and adverse reactions of Rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome (FRNS), and to explore the feasible treatment plan of RTX in children with FRNS. Methods FRNS children with RTX[375 mg/(m2·time), 2-3 times] from Department of Pediatrics, Jinling Hospital, Nanjing Clinical School of Southern Medical University between February 2011 and December 2017 were retrospectively reviewed, and followed up for 12-36 months.Age, gender, number of relapses, dose of steroids and immunosuppressants, adverse reactions and laboratory indicators(peripheral blood CD20+ B lymphocyte count, 24-hour urine protein quantification, etc) were observed. Results Thirty-four patients(23 males and 11 females) with FRNS were included in the present study, and the median age for the first RTX treatment was 6 years (2-12 years). After the first treatment, there was complete remission in 34 patients (100%, 34/34 cases), and 12 patients (35%, 12/34 cases) relapsed during follow-up.The number of relapse after treatment[(0.27±0.45) times]significantly decreased compared with that before treatment[(2.94±1.08) times; t=11.9, P<0.05]. After the second treatment, 3 children relapsed due to and no discomfort was found in the first 6 months; 5 of 23 cases (21.7%, 5/23 cases) relapsed once and 11 were unclear in the following 6 months.There was a difference between the 2 treatment intervals <12 months (12.5%, 2/16 cases) and ≥12 months (55.5%, 10/18 cases). After the third treatment, with an interval of 6 to 15 months, 1 of 15 patients(6.67%) relapsed and the rest were stable.In addition, there was a significant difference in the mean accumulated steroid dose of 20 patients between 6 months before treatment [(2.50±0.87) g ]and 6 months after treatment[(1.30±0.97) g; t=6.05, P=0.001]. Of the 15 patients after RTX treatment for 6-12 months Tacrolimus was reduced from [(1.62±0.77) mg/24 h ] to [(0.62±0.96) mg/24 h; t=6.80, P=0.000]. Two patients after RTX first infusion had chest tightness, palpitations, nausea, vomiting, dizziness, and headache, 3 cases had mild upper respiratory tract infection and 1 case had severe pulmonary infection. Conclusion Long-term follow-up of FRNS children treated with RTX turns out to be safe and effective. Key words: Frequently relapsing nephrotic syndrome; Rituximab; Child; Long-term observation

Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome.

The aim of the study was a multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab (Rtx) in children with steroid-resistant nephrotic syndrome (SRNS) with particular emphasis on the possibility of permanent discontinuation or dose reduction of other immunosuppressive drugs such as glucocorticoids and cyclosporine A after 6months of observation. The study group consisted of 30 children with idiopathic nephrotic syndrome, who were unresponsive to standard immunosuppressive treatment, and hospitalized in the years 2010-2017 in eight paediatric nephrology centres in Poland. The children were administered a single initial infusion of rituximab at the dose of 375mg/m2 of the body surface area. Proteinuria, the daily supply of glucocorticoids, and cyclosporine were assessed at the moment of the start of the treatment and after 6months since its commencement. Before Rtx therapy, complete remission was found in 13 patients (43%) and partial remission was found in 8 patients (26%). These numbers increased to 16 (53%) and 12 (40%), respectively. At the start of the treatment 23 patients (76.6%) were treated with cyclosporine A. After 6months, this number decreased to 15 patients (35%). At the start of the treatment, 18 patients (60%) were treated with prednisone. After 6months, this number decreased to 8 patients (44%). Children with SRNS may potentially benefit from Rtx treatment despite relative risk of side effects. The benefits may include reduction of proteinuria or reduction of other immunosuppressants.

Efficacy and safety of rituximab in childhood-onset, difficult-to-treat nephrotic syndrome: A multicenter open-label trial in Korea.

The anti-CD20 monoclonal antibody rituximab (RTX) has been proposed as a rescue therapy for difficult-to-treat nephrotic syndrome (NS). We conducted a clinical trial to evaluate the efficacy and safety of RTX in children with difficult-to-treat NS dependent on or resistant to steroids and calcineurin inhibitors (CNIs). A multicenter open-label trial was performed at 8 major pediatric nephrology centers in Korea. The investigation consisted of a randomized controlled trial for steroid- and CNI-dependent NS (DDNS; randomization into the RTX group and the control group, at a ratio of 2:1) and a single-arm study of steroid and CNI-resistant NS (DRNS). DDNS patients in the RTX group and DRNS patients received a single dose of intravenous RTX (375 mg/m of body surface area) for B-cell depletion. A second RTX dose was administered at week 2 if the first dose failed to achieve depletion of CD19(+) cells. The primary endpoint was rate of maintaining remission at 6 months after treatment for DDNS and rate of remission achievement for DRNS. Sixty-one children with DDNS were enrolled while in remission and randomized to the control group (21 patients) or the RTX group (40 patients). At 6 months after treatment, the remission rates were 74.3% in the RTX group and 31.3% in the control group (P = .003). The mean duration of remission maintenance was significantly higher in the RTX group than in the control group (9.0 vs 2.9 months, P = .004). Of the 23 patients with DRNS enrolled in the single-arm study and treated with RTX, 9 (39.1%) achieved partial or complete remission within 6 months. Depletion of B cells occurred in all patients with RTX therapy. Thirty patients (50.8% of 59 patients analyzed) experienced mild and transient infusion reaction during RTX administration, and most adverse events were mild. RTX administration was safe and effective in patients with difficult-to-treat NS. One or 2 doses of RTX may be sufficient to deplete B cells and achieve better control of pediatric NS.

Use and effectiveness of rituximab in children and young people with juvenile idiopathic arthritis in a cohort study in the United Kingdom

ObjectivesRituximab (RTX) may be a treatment option for children and young people with JIA, although it is not licensed for this indication. The aim of this study was to describe RTX use and outcomes among children with JIA.MethodsThis analysis included all JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting RTX. Disease activity was assessed at RTX start and at follow-up. The total number of courses each patient received was assessed. Serious infections and infusion reactions occurring following RTX were reported.ResultsForty-one JIA patients starting RTX were included, the majority with polyarthritis: polyarthritis RF negative [n = 14 (35%)], polyarthritis RF positive [n = 13 (33%)] and extended oligoarthritis [n = 9 (23%)]. Most were female (80%) with a median age of 15 years [interquartile range (IQR) 12–16] and a median disease duration of 9 years (IQR 5–11). The median improvement in the clinical Juvenile Arthritis Disease Activity Score (cJADAS; three-variable 71-joint JADAS) from RTX start was 9 units (n = 7; IQR −14–2). More than half reported more than one course of RTX. The median time between each course was 219 days (IQR 198–315). During follow-up, 17 (41%) patients reported switching to another biologic, including tocilizumab (n = 8), abatacept (n = 6) and TNF inhibitor (n = 3). Three patients (7%) reported a serious infection on RTX (rate of first serious infection 6.2/100 person-years). Four patients (10%) reported an infusion reaction.ConclusionsThis real-world cohort of children with JIA, the majority with polyarticular or extended oligoarticular JIA, showed RTX may be an effective treatment option for children who do not respond to TNF inhibitor, with a low rate of serious infections on treatment.

Rituximab in The Management of Pediatric Steroid-Resistant Nephrotic Syndrome: A Systematic Review

To evaluate the efficacy and safety of rituximab in children with steroid-resistant nephrotic syndrome. A systematic review evaluating the efficacy and safety of rituximab in children with steroid-resistant nephrotic syndrome was performed. Data from studies, performed before April 2017 were collected, from MEDLINE, Cochrane Library, Scopus, and Web of Science. Study eligibility criteria included clinical trials and observational studies with a minimal sample size of 5 patients, regarding treatment with rituximab in children with steroid-resistant nephrotic syndrome. Independent extraction of articles by 2 investigators using predefined data fields was performed. We included 7 case series and 1 open-label randomized controlled trial. Among them, 3 studies were multicenter. A total of 226 patients were included. Mean age at onset was 5.6 ± 1.1 years. Mean number of rituximab administrations was 3.1 ± 1.1 infusions per patient. Remission was observed in 89 patients (46.4%). Remission was seen in 40.8% patients with initial steroid-resistant nephrotic syndrome and 52.8% patients with late steroid-resistant nephrotic syndrome. Good initial response to rituximab therapy was observed in 63.2% patients with minimal change nephrotic syndrome, 39.2% patients with focal and segmental glomerulosclerosis, 1 patient had diffuse mesangial hypercellularity, and 1 patient had IgM nephropathy. Sustained remission ranged from 18% to 93.7%. Five serious adverse events were observed. Rituximab exhibited a satisfactory profile regarding efficacy and safety indicating that this agent is a promising therapy for steroid-resistant nephrotic syndrome and should be further investigated by randomized clinical trials.

Efficacy and Safety of rituximab in children with difficult-to-treat nephrotic syndrome; a systematic review

To date, several studies have been done on efficacy and safety of drugs in children with refractory nephrotic (NS). Rituximab (RTX) might be a hopeful treatment for this syndrome. However, the long-term effects and cost-effectiveness of RTX treatment were not fully assessed. This study aims to do a systematic review about the efficacy and safety of RTX in children with difficult-to-treat NS. For this research, an electronic literature search was conducted to identify appropriate investigations. The search term was (nephrotic syndrome or minimal change disease or focal segmental glomerulosclerosis or membranous) and (‘‘rituximab’’ or ‘‘CD20’’). We included all randomized trials and observational studies about using RTX in children with difficult-to-treat NS. Two independent reviewers extracted data from the papers according to the selection criteria. Eligible studies were included in this systematic review. The literature search and reference mining yielded 919 potential relevant papers. We removed 340 articles because of duplication. We also excluded 513 papers after reviewing the titles and abstracts. Finally, 17 studies were included in the systematic review. Efficacy of RTX in children with NS in most of the studies was assessed with relapse-free survival or complete remission rates. Acknowledging the limitations of the study due to the size and nature of the studies included, our systematic review shows that RTX was effective in the treatment of refractory NS in children, and it could reduce the use of steroid and immunosuppressants. However, further large randomized trials are suggested.

Pre-emptive rituximab for Epstein-Barr virus reactivation after haplo-hematopoietic stem cell transplantation.

Epstein-Barr virus-related post-transplantation lymphoproliferative disease (EBV-PTLD) is a serious complication in hematopoietic stem cell transplantation (HSCT) recipients. We conducted a retrospective study to investigate the incidence and potential risk factors for EBV reactivation and to assess the efficacy of the management of EBV reactivation with pre-emptive rituximab in children who had T-cell-replete haploidentical HSCT (TCR-haplo-SCT) with low-dose anti-thymocyte globulin (ATG). EBV-DNA level in peripheral blood (PB) was measured when suspected EBV reactivation were observed. When the EBV-DNA level in PB increased to >1,000 copies/106 peripheral blood mononuclear cells (PBMC), patients were pre-emptively treated with rituximab (375mg/m2 /dose). A total of 19 (50%) of 38 patients received rituximab infusion at a median time of 56days after HSCT (range, 17-270days). The median viral load at initiation of therapy was 2,900 copies/106 PBMC (range, 1,000-650000). Pre-emptive therapy was started after a median of 2days (range, 0-7days). The median number of weekly treatment cycles was 2 (range, 1-3). None of the patients developed PTLD or other EBV-associated diseases. Pre-emptive rituximab therapy could be a useful strategy for EBV-PTLD in TCR-haplo-SCT recipients with low-dose ATG.

Efficacy and Safety of Rituximab in the Management of Pediatric Systemic Lupus Erythematosus: A Systematic Review

To evaluate the efficacy and safety of rituximab for treating pediatric systemic lupus erythematosus (pSLE). We performed a systematic review to evaluate the efficacy and safety of rituximab in children with pSLE. Data from studies performed before July 2016 were collected from MEDLINE, the Cochrane Library, Scopus, and the International Rheumatic Disease Abstracts, with no language restrictions. Study eligibility criteria included clinical trials and observational studies with a minimal sample size of 5 patients, regarding treatment with rituximab in patients with refractory pSLE (aged <18 years at the time of diagnosis). Independent extraction of articles was performed by 2 investigators using predefined data fields. Twelve case series met the criteria for data extraction for the systematic review with a good quality assessment according to an 18-criteria checklist using a modified Delphi method. Among them, 3 studies were multicenter and 3 were prospective. The total number of patients was 272. Studies collected patients with active disease refractory to steroids and immunosuppressant drugs. Refractory lupus nephritis was the most common indication (33%). Acceptable evidence suggested improvements in renal, neuropsychiatric and haematological manifestations, disease activity, complement and anti-double stranded Desoxy-Nucleo-Adenosine, with a steroid-sparing effect. However, there was poor evidence suggesting efficacy on arthralgia, photosensitivity, and mucocutaneous manifestations of SLE in children. An overall acceptable safety profile with few major adverse events was shown. Rituximab exhibited a satisfactory profile regarding efficacy and safety indicating that this agent is a promising therapy for pSLE and should be further investigated.