Human or Chimeric Monoclonal Anti-CD20 Antibodies for Children with Nephrotic Syndrome: A Superiority Randomized Trial

BackgroundThe chimeric anti-CD20 monoclonal antibody rituximab is effective in steroid-dependent and calcineurin inhibitor–dependent forms of nephrotic syndrome, but many patients relapse at 1 year. Because ofatumumab, a fully human anti-CD20 monoclonal antibody, has a more extended binding site and higher affinity to CD20 compared with rituximab, it might offer superior efficacy in these patients.MethodsWe designed a single-center randomized clinical trial to compare the long-term efficacy of ofatumumab versus rituximab in children and young adults with nephrotic syndrome maintained in remission with prednisone and calcineurin inhibitors. We randomized 140 children and young adults (aged 2–24 years) to receive intravenous ofatumumab (1.50 mg/1.73 m2) or rituximab (375 mg/m2). After infusions, oral drugs were tapered and withdrawn within 60 days. The primary outcome was relapse at 1 year, which was analyzed following the intent-to-treat principle. The secondary endpoint was relapse within 24 months from infusion, on the basis of urine dipstick and confirmed by a urine protein-to-creatinine ratio <200.ResultsAt 12 months, 37 of 70 (53%) participants who received ofatumumab experienced relapse versus 36 of 70 (51%) who received rituximab (odds ratio [OR], 1.06; 95% confidence interval [95% CI], 0.55 to 2.06). At 24 months, 53 of 70 (76%) participants who received ofatumumab experienced relapse, versus 46 of 70 (66%) who received rituximab (OR, 1.6; 95% CI, 0.8 to 3.3). The two groups exhibited comparable B cell subpopulation reconstitution and did not differ in adverse events.ConclusionsA single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission in children with steroid-dependent and calcineurin inhibitor–dependent nephrotic syndrome.Clinical Trial registration numbers:ClinicalTrials.gov (NCT02394119) and https://www.clinicaltrialsregister.eu/ctr-search/search (2015–000624–28).

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab134.002 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Pietro Ravani ◽

Manuela Colucci ◽

Maurizio Bruschi ◽

Marina Vivarelli ◽

Michela Cioni ◽

...

Keyword(s):

Monoclonal Antibody ◽

Nephrotic Syndrome ◽

B Cell ◽

Controlled Trial ◽

Safety Data ◽

Oral Drug ◽

Younger Adults ◽

Steroid Dependent ◽

One Year ◽

Anti Cd20

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.

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Rituximab vs Low-Dose Mycophenolate Mofetil In Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults

JAMA Pediatrics ◽

10.1001/jamapediatrics.2020.6150 ◽

2021 ◽

Cited By ~ 1

Author(s):

Pietro Ravani ◽

Francesca Lugani ◽

Stefania Drovandi ◽

Gianluca Caridi ◽

Andrea Angeletti ◽

...

Keyword(s):

Young Adults ◽

Nephrotic Syndrome ◽

Mycophenolate Mofetil ◽

Low Dose ◽

Steroid Dependent ◽

Children And Young Adults ◽

Steroid Dependent Nephrotic Syndrome

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Randomised controlled trial comparing rituximab to mycophenolate mofetil in children and young adults with steroid-dependent idiopathic nephrotic syndrome: study protocol

BMJ Open ◽

10.1136/bmjopen-2021-052450 ◽

2021 ◽

Vol 11 (11) ◽

pp. e052450

Author(s):

Francesca Lugani ◽

Andrea Angeletti ◽

Pietro Ravani ◽

Marina Vivarelli ◽

Manuela Colucci ◽

...

Keyword(s):

Young Adults ◽

Nephrotic Syndrome ◽

Mycophenolate Mofetil ◽

Idiopathic Nephrotic Syndrome ◽

Link Type ◽

Steroid Dependent ◽

Study Results ◽

Long Term Treatment ◽

Children And Young Adults ◽

Steroid Sparing

IntroductionGlucocorticoids induce remission in 90% of children with idiopathic nephrotic syndrome (INS). Some become steroid-dependent (SD) and require the addition of steroid sparing drugs such as calcineurin-inhibitors (CNI) or cyclophosphamide, to maintain remission. Considering the toxicity of these drugs, alternative interventions are needed for long-term treatment. The anti-CD20 antibody rituximab has shown promising steroid-sparing properties, with conflicting results in complicated forms of SD-INS. Mycophenolate mofetil (MMF) resulted effective in maintaining free-steroid remission, however, studies are limited to few uncontrolled trials with reported different dose of MMF.Methods and analysisThis open-label, two-parallel-arm, superiority controlled randomised clinical trial will enrol children with SD-INS maintained in remission with oral glucocorticoids or CNI. Children and young adults will be randomised to either MMF (1.200 mg/m2) or rituximab (375 mg/m2) infusion. After enrolment, glucocorticoids will be tapered until complete withdrawal. We will enrol 160 children and young adults to detect as significant at the two-sided p value of 0.01 with a power >0.8 a reduction in the risk of 1-year relapse (primary end-point). As secondary endpoints, we will compare the amount of glucocorticoids required to maintain complete remission at 6 and 24 months.Ethics and disseminationThe trial was approved by the local ethics boards (Comitato Etico Regione Liguria CER Liguria https://www.portalericerca-liguria.it/). We will publish the study results at international scientific meetings.Trial registration numbersNCT004585152.

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