Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes
2019; Elsevier BV; Volume: 97; Issue: 2 Linguagem: Inglês
10.1016/j.kint.2019.09.033
ISSN1523-1755
AutoresEugene Yu-hin Chan, Hazel Webb, E. Yu, Gian Marco Ghiggeri, Markus J. Kemper, Alison Lap‐tak, Tomohiko Yamamura, Aditi Sinha, Arvind Bagga, Julien Hogan, Claire Dossier, Marina Vivarelli, Isaac Desheng Liu, Koichi Kamei, Kenji Ishikura, Priya Saini, Kjell Tullus,
Tópico(s)Amyloidosis: Diagnosis, Treatment, Outcomes
ResumoRituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes. Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes. Idiopathic nephrotic syndrome (NS) is an uncommon childhood disease. Incidence varies considerably by ethnicity, with an average incidence of 4.7 (range, 1.15–16.9) per 100,000 persons.1Chanchlani R. Parekh R.S. Ethnic differences in childhood nephrotic syndrome.Front Ped. 2016; 4: 39Crossref PubMed Scopus (87) Google Scholar The majority of these children respond promptly to steroid therapy. A small group of patients will suffer only a single episode of NS, while a larger group will develop steroid dependence and/or frequently relapsing (FR) course. These children have a high chance of developing significant steroid toxicity due to repeated and protracted courses of glucocorticoid. To minimize steroid side effects, additional immunosuppressive drugs, including levamisole, cyclophosphamide, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), are frequently used. Nonetheless, there is a subgroup of children who run a complicated course and continue to relapse in spite of multiple therapies or have significant medication side effects. Rituximab is a chimeric anti-CD20 monoclonal antibody originally used to treat B-cell non-Hodgkin's lymphoma with four infusions of 375 mg/m2. Rituximab was first reported to induce remission in a 16-year-old boy with complicated steroid-dependent NS (SDNS) and idiopathic thrombocytopenia.2Benz K. Dötsch J. Rascher W. et al.Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy.Pediatr Nephrol. 2004; 19: 794-797Crossref PubMed Scopus (170) Google Scholar Since then, success of rituximab in NS was observed in multiple observational studies and randomized control trials.3Iijima K. Sako M. Nozu K. et al.Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.Lancet. 2014; 384: 1273-1281Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 4Ravani P. Rossi R. Bonanni A. et al.Rituximab in children with steroid-dependent nephrotic syndrome: a multicenter, open-label, noninferiority, randomized controlled trial.J Am Soc Nephrol. 2015; 26: 2259-2266Crossref PubMed Scopus (140) Google Scholar, 5Basu B. Sander A. Roy B. et al.Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: a randomized clinical trial.JAMA Pediatr. 2018; 172: 757-764Crossref PubMed Scopus (82) Google Scholar, 6Ruggenenti P. Ruggiero B. Cravedi P. et al.Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.J Am Soc Nephrol. 2014; 25: 850-863Crossref PubMed Scopus (187) Google Scholar Data directly comparing dosing regimens are, however, scarce.7Kemper M.J. Gellermann J. Habbig S. et al.Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome.Nephrol Dial Transplant. 2011; 27: 1910-1915Crossref PubMed Scopus (111) Google Scholar, 8Webb H. Jaureguiberry G. Dufek S. et al.Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2016; 31: 589-594Crossref PubMed Scopus (31) Google Scholar, 9Hogan J. Dossier C. Kwon T. et al.Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2019; 34: 253-259Crossref PubMed Scopus (35) Google Scholar As a result, there is a significant variation in the rituximab prescription worldwide, between 375 and 1500 mg/m2 per treatment course.10Prytuła A. Iijima K. Kamei K. et al.Rituximab in refractory nephrotic syndrome.Pediatr Nephrol. 2010; 25: 461-468Crossref PubMed Scopus (128) Google Scholar,11Deschênes G. Vivarelli M. Peruzzi L. Variability of diagnostic criteria and treatment of idiopathic nephrotic syndrome across European countries.Eur J Pediatr. 2017; 176: 647-654Crossref PubMed Scopus (19) Google Scholar Previous reports have described a longer relapse-free period in patients receiving high-dose rituximab of 1125 to 1500 mg/m2,7Kemper M.J. Gellermann J. Habbig S. et al.Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome.Nephrol Dial Transplant. 2011; 27: 1910-1915Crossref PubMed Scopus (111) Google Scholar,8Webb H. Jaureguiberry G. Dufek S. et al.Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2016; 31: 589-594Crossref PubMed Scopus (31) Google Scholar while recently lower initial dose (375 mg/m2) became an attractive option after a number of trials showed satisfactory outcomes.4Ravani P. Rossi R. Bonanni A. et al.Rituximab in children with steroid-dependent nephrotic syndrome: a multicenter, open-label, noninferiority, randomized controlled trial.J Am Soc Nephrol. 2015; 26: 2259-2266Crossref PubMed Scopus (140) Google Scholar,12Ahn Y.H. Kang H.G. Kim S.H. et al.Efficacy and safety of rituximab in children with refractory nephrotic syndrome: a multicenter clinical trial.Kidney Res Clin Pract. 2014; 33: A1-A2Crossref PubMed Google Scholar Hogan et al.9Hogan J. Dossier C. Kwon T. et al.Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2019; 34: 253-259Crossref PubMed Scopus (35) Google Scholar examined 61 SDNS children receiving their first course of rituximab therapy at total doses of 100 mg/m2, 375 mg/m2, and 750 mg/m2 and withdrawal of immunosuppression within 2 months. Lower initial dose was associated with a shorter B-cell depletion time and a higher risk of relapse. Another controversy is the concomitant use of other immunosuppression. In Japan, maintenance immunosuppression after rituximab, notably with MMF, is utilized to prolong remission time.13Kamei K. Ogura M. Sato M. et al.Risk factors for relapse and long-term outcome in steroid-dependent nephrotic syndrome treated with rituximab.Pediatr Nephrol. 2016; 31: 89-95Crossref PubMed Scopus (24) Google Scholar, 14Ito S. Kamei K. Ogura M. et al.Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome.Pediatr Nephrol. 2013; 28: 257-264Crossref PubMed Scopus (67) Google Scholar, 15Ito S. Kamei K. Ogura M. et al.Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome.Pediatr Nephrol. 2011; 26: 1823-1828Crossref PubMed Scopus (70) Google Scholar These results have not been confirmed in other reports, where relapse rates were similar irrespective of cotherapy.7Kemper M.J. Gellermann J. Habbig S. et al.Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome.Nephrol Dial Transplant. 2011; 27: 1910-1915Crossref PubMed Scopus (111) Google Scholar,16Sinha A. Bhatia D. Gulati A. et al.Efficacy and safety of rituximab in children with difficult-to-treat nephrotic syndrome.Nephrol Dial Transplant. 2015; 30: 96-106Crossref PubMed Scopus (65) Google Scholar While rituximab appears to be safe in children,17Iijima K. Sako M. Nozu K. Rituximab for nephrotic syndrome in children.Clin Exp Nephrol. 2017; 21: 193-202Crossref PubMed Scopus (64) Google Scholar,18Bonanni A. Calatroni M. D'alessandro M. et al.Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome.Br J Clin Pharmacol. 2018; 84: 1238-1249Crossref PubMed Scopus (35) Google Scholar serious adverse events do occur infrequently.19Tsutsumi Y. Kanamori H. Mori A. et al.Reactivation of hepatitis B virus with rituximab.Expert Opin Drug Saf. 2005; 4: 599-608Crossref PubMed Scopus (124) Google Scholar, 20Chaumais M.-C. Garnier A. Chalard F. et al.Fatal pulmonary fibrosis after rituximab administration.Pediatr Nephrol. 2009; 24: 1753-1755Crossref PubMed Scopus (101) Google Scholar, 21Boren E.J. Cheema G.S. Naguwa S.M. et al.The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases.J Autoimmun. 2008; 30: 90-98Crossref PubMed Scopus (119) Google Scholar, 22Sellier-Leclerc A.-L. Belli E. Guérin V. et al.Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome.Pediatr Nephrol. 2013; 28: 1875-1879Crossref PubMed Scopus (57) Google Scholar To identify the optimal rituximab regimen in children with complicated steroid-dependent/frequently relapsing nephrotic syndrome (SDFRNS), we performed an international, multicenter, retrospective cohort study to evaluate the outcomes of rituximab therapy with different combinations of dose and maintenance immunosuppression. A total of 511 children (343 male) treated with rituximab from 2005 to 2016 were included (Table 1). The median age at presentation and first rituximab administration were 3 (interquartile range [IQR], 2.1–4.9) and 11.5 (IQR, 8.1–14.3) years. A total of 191, 208, and 112 patients received their first course of rituximab at low dose (375 mg/m2), medium dose (750 mg/m2), and high dose (1125–1500 mg/m2), respectively. Two hundred eight-three patients (55%) received maintenance immunosuppression (mIS). The distribution of rituximab dose and mIS use among investigating centers are presented in Table 2.Table 1Baseline characteristics of 511 children with SDFRNS receiving rituximab between 2005 and 2016CharacteristicAll (N = 511)Low doseaChildren received rituximab at 3 dose amounts: low dose (375 mg/m2), medium dose (750 mg/m2), and high dose (1125–1500 mg/m2). (n = 191)Medium doseaChildren received rituximab at 3 dose amounts: low dose (375 mg/m2), medium dose (750 mg/m2), and high dose (1125–1500 mg/m2). (n = 208)High doseaChildren received rituximab at 3 dose amounts: low dose (375 mg/m2), medium dose (750 mg/m2), and high dose (1125–1500 mg/m2). (n = 112)Without mIS (n = 46)With mIS (n = 145)Without mIS (n = 117)With mIS (n = 91)Without mIS (n = 65)With mIS (n = 47)Sex Male343 (67)36 (78)93 (64)79 (68)59 (65)44 (68)32 (68) Female168 (33)10 (22)52 (36)38 (32)32 (35)21 (32)15 (32)EthnicitybMissing data in 3 subjects. White151 (30)28 (61)56 (39)15 (13)18 (20)25 (38)9 (20) South East Asian121 (24)4 (9)72 (50)2 (2)12 (13)19 (29)12 (26) South Asian193 (38)4 (9)8 (6)88 (76)56 (62)20 (31)17 (37) OtherscIncludes mainly Blacks, Hispanics, and Arabs.43 (8)10 (22)8 (6)11 (9)5 (5)1 (2)8 (17)Age (yr) At presentation3.0 (2.1–4.9)3.4 (2.4–5.5)4.3 (2.6–7.2)2.7 (1.8–4.2)2.5 (2.0–3.8)3.1 (2.6–5.1)2.4 (1.9–3.8) At rituximab11.5 (8.1–14.3)11.1 (7.4–15.0)12.8 (8.5–15.2)11.2 (8.1–13.6)11.4 (8.2–13.5)11.0 (7.9–13.4)11.4 (8.2–13.7)Time from presentation to rituximab (yr)6.7 (3.7–10.0)6.2 (2.8–9.2)5.9 (2.3–9.3)7.6 (4.8–10.0)7.2 (4.8–10.7)5.5 (3.8–9.8)8.4 (5.0–10.8)Late steroid resistancedMissing data in 1 subject. No397 (78)41 (89)112 (77)102 (88)55 (60)55 (85)32 (68) Yes113 (22)5 (11)33 (23)14 (12)36 (40)10 (15)15 (32)Renal biopsy performed No194 (38)30 (65)28 (19)73 (62)21 (23)32 (49)10 (21) Yes317 (62)16 (35)117 (81)44 (38)70 (77)33 (51)37 (79)Minimal change disease235 (74)12 (75)90 (77)34 (77)45 (64)26 (79)28 (76)Focal segmental glomerulosclerosis65 (21)3 (19)20 (17)7 (16)21 (30)5 (15)9 (24)Others17 (5)1 (6)7 (6)3 (7)4 (6)2 (6)0 (0)Type of prior immunosuppression Calcineurin inhibitor417 (82)41 (89)133 (92)69 (59)78 (86)50 (77)46 (98) Cyclophosphamide306 (60)15 (33)51 (35)90 (77)69 (76)51 (78)30 (64) Levamisole177 (35)7 (15)7 (5)81 (69)40 (44)26 (40)16 (34) Mycophenolate mofetil242 (47)16 (35)55 (38)71 (61)53 (58)24 (37)23 (49)Number of prior immunosuppression(s) 1138 (27)23 (50)71 (49)14 (12)10 (11)14 (22)6 (13) 2174 (34)14 (30)51 (35)38 (32)30 (33)23 (35)18 (38) 3140 (27)8 (17)19 (13)39 (33)34 (37)21 (32)19 (40) 459 (12)1 (2)4 (3)26 (22)17 (19)7 (11)4 (9)mIS, maintenance immunosuppression; SDFRNS, steroid-dependent/frequently relapsing nephrotic syndrome.Data are expressed as n (%) or median (interquartile range).a Children received rituximab at 3 dose amounts: low dose (375 mg/m2), medium dose (750 mg/m2), and high dose (1125–1500 mg/m2).b Missing data in 3 subjects.c Includes mainly Blacks, Hispanics, and Arabs.d Missing data in 1 subject. Open table in a new tab Table 2Rituximab and immunosuppression policies among investigating centersInvestigating sitesRituximab regimenaThe first course of rituximab was prescribed by 3 dosing levels: low, 375 mg/m2; medium, 750 mg/m2; and high, 1125 to 1500 mg/m2.Low doseMedium doseHigh doseWithout mISWith mISWithout mISWith mISWithout mISWith mISLondon00845038Genoa3932161300Hamburg200100700Hong Kong001080010Kobe025001758New Delhi22533076Paris24182771311Rome0970300Singapore838030024Tokyo47900161Toronto03046204mIS, maintenance immunosuppression.Values are percentages.a The first course of rituximab was prescribed by 3 dosing levels: low, 375 mg/m2; medium, 750 mg/m2; and high, 1125 to 1500 mg/m2. Open table in a new tab mIS, maintenance immunosuppression; SDFRNS, steroid-dependent/frequently relapsing nephrotic syndrome. Data are expressed as n (%) or median (interquartile range). mIS, maintenance immunosuppression. Values are percentages. Three hundred seventeen children (62%) received kidney biopsies. The predominant histologic finding was minimal change disease (74%) and was similar between different regimens (P = 0.54). The mean follow-up duration following rituximab therapy was 4.3 (IQR, 2.7–5.9) years. Following rituximab therapy, 412 children (81%) experienced a relapse. The overall median relapse-free period was 12.5 months (95% confidence interval [CI], 11.3–14). The relapse-free survival was similar among the 3 dosing groups (log-rank test P = 0.36). The outcomes in patients with or without mIS were also not different (log-rank test P = 0.71). Data pertaining to relapse-free survival following rituximab therapy are presented in Table 3.Table 3Primary outcomes: relapse-free survival following rituximab therapyRelapse-free time (mo)P valueLow doseMedium doseHigh doseAll11.8 (10.1–15.8)11.9 (10.4–14.3)13.0 (11.8–17.4)0.36Without mIS8.5 (7.2–13.3)12.7 (10.4–16.9)14.3 (12.0–18.4)0.03With mIS14.0 (11.0–18.1)10.9 (10.0–14.2)12.0 (9.0–22.0)0.17mIS, maintenance immunosuppression.Values are medians (95% confidence intervals). Open table in a new tab mIS, maintenance immunosuppression. Values are medians (95% confidence intervals). On Kaplan-Meier curve analysis, the median relapse-free period without mIS was significantly shorter in the low-dose group than in those treated with medium and high doses (log-rank test P = 0.03). With mIS, the relapse-free survival among children receiving low-dose rituximab was similar to those receiving medium and high doses (log-rank test P = 0.17). The Kaplan-Meier curves stratified by mIS are presented in Figure 1. Similar to the aforementioned log-rank tests, the risk of relapse was not different when dose and use of mIS were considered independently in univariable analyses (Table 4). However, multivariable Cox proportional hazards regression demonstrated significant interaction terms between rituximab dose and mIS on treatment outcomes (Ps ≤ 0.048) (Table 4). Children receiving a low-dose rituximab without mIS were more susceptible to a relapse than any other regimens (adjusted hazard ratio [HRadj], 0.50–0.6; 95% CI, 0.33–0.94; Ps ≤ 0.023), although it did not reach statistical significance for medium dose with mIS (Table 5). With mIS, the risk of relapse in low-dose rituximab was comparable to medium- and high-dose regimens, regardless of mIS (Table 5).Table 4Association with relapse: univariable and multivariable Cox regression analysesUnadjustedAdjustedaAdjusted hazard ratio controlling for sex, ethnicity, age at presentation, age at first rituximab, number of prior immunosuppression, late steroid resistance in a multivariable Cox regression model.HR (95% CI)P valueHR (95% CI)P valueMale1.18 (0.96–1.46)0.121.20 (0.97–1.48)0.10Ethnicity White1 [Reference]1 [Reference] South East Asian1.08 (0.83–1.41)0.561.23 (0.92–1.65)0.17 South Asian0.97 (0.76–1.23)0.780.81 (0.60–1.10)0.18 Others0.78 (0.53–1.15)0.210.70 (0.46–1.06)0.09Age at presentation (yr)0.97 (0.94–1.00)0.080.99 (0.96–1.03)0.64Age at first rituximab (yr)0.96 (0.94–0.99)0.0020.95 (0.93–0.98)0.002Prior immunosuppression(s)1.08 (0.98–1.19)0.131.19 (1.05–1.35)0.006Late steroid resistance1.14 (0.90–1.44)0.281.00 (0.77–1.30)0.98Rituximab dose Low1 [Reference]1 [Reference] Medium0.97 (0.78–1.21)0.800.62 (0.41–0.94)0.02 High0.83 (0.64–1.08)0.170.50 (0.33–0.77)0.002mIS1.04 (0.85–1.26)0.710.60 (0.41–0.89)0.01Interaction terms of rituximab dose and mIS Low × mIS (reference)——1 [Reference] Medium × mIS——1.99 (1.22—3.24)0.006 High × mIS——1.81 (1.01–3.25)0.05CI, confidence interval; HR, hazard ratio; mIS, maintenance immunosuppression.a Adjusted hazard ratio controlling for sex, ethnicity, age at presentation, age at first rituximab, number of prior immunosuppression, late steroid resistance in a multivariable Cox regression model. Open table in a new tab Table 5Adjusted HR for different rituximab regimenRegimenReference groupLow dose without mISLow dose with mISHRadj (95% CI)P valueHRadj (95% CI)P valueWithout mIS Low dose1 [Reference]–1.67 (1.13–2.46)0.01 Medium dose0.62 (0.41–0.94)0.021.04 (0.73–1.47)0.85 High dose0.50 (0.33–0.77)0.0020.84 (0.59–1.20)0.34With mIS Low dose0.60 (0.41–0.89)0.011 [Reference]– Medium dose0.73 (0.48–1.14)0.171.23 (0.87–1.75)0.24 High dose0.55 (0.34–0.88)0.010.92 (0.61–1.39)0.70CI, confidence interval; HRadj, adjusted hazard ratio; mIS, maintenance immunosuppression.The adjusted hazard ratios were derived from the same multivariable Cox regression model listed in Table 3 and were presented in reference to 2 regimens, low-dose rituximab without mIS and with mIS. Open table in a new tab CI, confidence interval; HR, hazard ratio; mIS, maintenance immunosuppression. CI, confidence interval; HRadj, adjusted hazard ratio; mIS, maintenance immunosuppression. The adjusted hazard ratios were derived from the same multivariable Cox regression model listed in Table 3 and were presented in reference to 2 regimens, low-dose rituximab without mIS and with mIS. Both age at rituximab and previous immunosuppression were significant relapse predictors (Table 4). Each 1-year increase in age at first rituximab therapy was associated with a 5% reduction in relapse risk (HRadj, 0.95; 95% CI, 0.93–0.98; P = 0.002). On the other hand, for each additional steroid-sparing agent received prior to rituximab, patients were 19% more likely to experience a relapse (HRadj, 1.19; 95% CI, 1.05–1.35; P = 0.006). Significant B-cell depletion 7 to 14 days following rituximab administration was achieved in 97% of patients (442 of 454). The proportions of patients that achieved B-cell depletion were similar among the 6 rituximab regimens (P = 0.47) and are presented in Table 6.Table 6Secondary outcomes in children receiving rituximab therapyAll (N = 511)Low doseMedium doseHigh doseP valueaKruskal-Wallis test, Pearson chi-square test, or Fisher exact test, as appropriate.Without mIS (n = 46)With mIS (n = 145)Without mIS (n = 117)With mIS (n = 91)Without mIS (n = 65)With mIS (n = 47)B-cell depletionbB-cell depletion and repletion were defined as CD19+ B-cell counts being 1% of the total lymphocyte population, respectively.,cB-cell status shortly after rituximab were available as follows: low dose without mIS, n = 46; low dose with mIS, n = 143; medium dose without mIS, n = 101; medium dose with mIS, n = 76; high dose without mIS, n = 52; high dose with mIS, n = 36. (n = 454)0.47 No12 (3)1 (2)3 (2)2 (2)1 (1)3 (6)2 (6) Yes442 (97)45 (98)140 (98)99 (98)75 (99)49 (94)34 (94)Additional RTX327 (64)31 (67)94 (65)68 (58)64 (70)43 (66)27 (57)0.46 Time from first RTX (yr)1.2 (0.8–2.0)0.8 (0.6–1.2)1.2 (0.8–1.9)1.3 (0.9–2.2)1.2 (0.9–1.9)1.5 (0.9–2.4)1.9 (1.2–3.0)<0.001 Reason for additional RTX<0.001Relapse(s)286 (87)30 (97)79 (84)59 (87)52 (81)42 (98)24 (89)B-cell repletionbB-cell depletion and repletion were defined as CD19+ B-cell counts being 1% of the total lymphocyte population, respectively.23 (7)1 (3)5 (5)9 (13)7 (11)1 (2)0OthersdOther reasons included scheduled therapy, patient noncompliance, and excessive toxicity related to corticosteroid and steroid-sparing agents.18 (6)010 (11)05 (8)03 (11)mIS, maintenance immunosuppression; RTX, rituximab.Values are n (%) or median (interquartile range).a Kruskal-Wallis test, Pearson chi-square test, or Fisher exact test, as appropriate.b B-cell depletion and repletion were defined as CD19+ B-cell counts being 1% of the total lymphocyte population, respectively.c B-cell status shortly after rituximab were available as follows: low dose without mIS, n = 46; low dose with mIS, n = 143; medium dose without mIS, n = 101; medium dose with mIS, n = 76; high dose without mIS, n = 52; high dose with mIS, n = 36.d Other reasons included scheduled therapy, patient noncompliance, and excessive toxicity related to corticosteroid and steroid-sparing agents. Open table in a new tab mIS, maintenance immunosuppression; RTX, rituximab. Values are n (%) or median (interquartile range). Among the 228 patients who did not receive mIS, corticosteroids, CNIs, and MMF were withdrawn soon after rituximab therapy at a median time of 3 months (IQR, 2–4), 2 months (IQR, 1–3), and 0 months (IQR, 0–0.5), respectively. All mIS were discontinued in the low-, medium-, and high-dose groups at a median of 2.5 months (IQR, 2–3), 4 months (IQR, 3–4.5), and 3 months (IQR, 1–4), respectively. Of the 283 patients with mIS, 165 (58%), 81 (29%), and 37 (13%) children received 1, 2, and 3 immunosuppressive agents as maintenance therapy. Corticosteroids, CNIs, and MMF were given to 159 (56%), 135 (47%), and 144 (51%) children for a median of 7 months (IQR, 5.8–10.2), 8.6 months (IQR, 5.8–13.8), and 13.6 months (IQR, 8.2–24.1), respectively. Whereas a majority of children continued mIS up to the time of relapse (n = 196, 70%) and censorship (n = 35, 12%), immunosuppression was completely withdrawn in 52 patients (18%) over a median of 7 months (IQR, 6–11). A second course of rituximab therapy was required in 327 patients (64%) after a median of 1.2 years (IQR, 0.8–2 years) (Table 6). While the proportions of patients receiving a second treatment were similar among the 6 treatment groups (P = 0.46), the timing and reasons for retreatment were different (P < 0.001). The predominant reasons of redosing were clinical relapse(s) (87%) and B-cells repletion (7%) (Table 6). Eighteen children (6%) received a subsequent course due to medication noncompliance, excessive toxicity from immunosuppression, and a scheduled therapy. Of note, 245 patients were on immunosuppressive agents at the time of second treatment. Most adverse events were mild and are presented in Table 7. Overall, 85 patients (16%) experienced a total of 158 adverse events. No patients died in the cohort. Acute infusion reactions were present in about 13% patients, but only 2% required early termination of infusion. Only 4% of children had infections, of which most were mild viral illnesses, chickenpox, or herpes zoster. Following a course of rituximab at 375 mg/m2 for 2 weekly doses, 1 patient experienced enterovirus infection and developed fulminant myocarditis, which required heart transplantation. Another patient had atypical Pneumocystis jiroveci pneumonia and fully recovered after antibiotics.Table 7Adverse eventsAll (N = 511)Rate (95% CI)Low doseMedium doseHigh doseWithout mIS (n = 46)With mIS (n = 145)Without mIS (n = 117)With mIS (n = 91)Without mIS (n = 65)With mIS (n = 47)Death00 (0–0.9)000000Any complication(s)8516.6 (13.6–20.2)5 (11)61 (42)4 (3)4 (4)6 (9)5 (11)Early infusion termination122.3 (1.3–4.2)1 (2)4 (3)1 (1)4 (4)1 (2)1 (2)Acute infusion reaction6713.1 (10.4–16.4)5 (11)48 (33)3 (3)2 (2)4 (6)5 (11)Infection203.9 (2.5–6.1)015 (10)2 (2)02 (3)1 (2)Pulmonary fibrosis00 (0–0.9)000000Encephalopathy00 (0–0.9)000000NeutropeniaaNeutropenia was defined as absolute neutrophil count <1 × 109/l: low dose without mIS, n = 45; low dose with mIS, n = 138; medium dose without mIS, n = 115; medium dose with mIS, n = 79; high dose without mIS, n = 65; high dose with mIS, n = 46.13 (n = 488)2.7 (1.5–4.6)1 (2)6 (4)01 (1)1 (2)4 (9)HypogammaglobinemiabHypogammaglobinemia was defined as persistently low IgG at 1 year following rituximab administration: low dose without mIS, n = 41; low dose with mIS, n =123; medium dose without mIS, n = 109; medium dose with mIS, n = 63; high dose without mIS, n = 35; high dose with mIS, n = 29.56 (n = 400)14.0 (10.8–17.9)14 (34)22 (18)8 (7)4 (6)3 (9)5 (17)CI, confidence interval; mIS, maintenance immunosuppression.Values are expressed as n (%)a Neutropenia was defined as absolute neutrophil count <1 × 109/l: low dose without mIS, n = 45; low dose with mIS, n = 138; medium dose without mIS, n = 115; medium dose with mIS, n = 79; high dose without mIS, n = 65; high dose with mIS, n = 46.b Hypogammaglobinemia was defined as persistently low IgG at 1 year following rituximab administration: low dose without mIS, n = 41; low dose with mIS, n =123; medium dose without mIS, n = 109; medium dose with mIS, n = 63; high dose without mIS, n = 35; high dose with mIS, n = 29. Open table in a new tab CI, confidence interval; mIS, maintenance immunosuppression. Values are expressed as n (%) Our current study confirms the treatment role and safety profile of rituximab in children with complicated SDFRNS. Low-dose rituximab without mIS was associated with the shortest relapse-free remission and an increased relapse risk. With mIS, the treatment outcomes for low-dose rituximab improved and were comparable to medium- and high-dose treatments, regardless of mIS. These suggest that low-dose rituximab becomes more effective with mIS. Overall, the adverse event pro
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