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Mycophenolate Mofetil FollowingRituximab in Children WithSteroid-Resistant Nephrotic SyndromeBiswanath Basu, MDa, T.K.S. Mahapatra, MDb, Nirmal Mondal, MDc
abstract BACKGROUND: Rituximab is being increasingly used in children with idiopathic nephrotic syndromeresistant to standard treatments. In spite of good initial response, rituximab responders always remainprone to further relapse, necessitating either repeat course of rituximab or addition of another steroid-sparing immunosuppressant.
METHODS: A retrospective analysis of baseline clinico-pathologic presentation and treatment outcome(complete remission, partial remission, or no response) was performed among 24 children withrefractory-idiopathic SRNS over a follow-up period of 24 months. Children received 2 to 4 rituximabinfusions (375 mg/m2 weekly) depending on circulating B-cell level. At 3-month follow-up, a secondcourse of rituximab was administered (if .5 B cells/mm3) along with MMF (1200 mg/m2 per day)maintenance therapy.
RESULTS: Of 24 patients, 54% (13/24) and 46% (11/24) had minimal change disease and focalsegmental glomerulosclerosis, respectively, on renal histopathology. After the first course of rituximab,21% (5/24) of children achieved complete remission; however, most (4/5) of them relapsed again at amedian interval of 53 (interquartile range 46–72) days. Depending on response to the first courseof rituximab, MMF was started on 15 children at 3 months. After 6 months, 67% (10/15) of childrenon MMF achieved complete remission and 33% (5/15) remained at partial remission. At 24 monthsoverall, 25% (6/24) and 42% (10/24) of children were in complete remission and partial remission,respectively; 33% (5/15) of children continued sustained complete remission after postrituximab-MMF maintenance therapy in comparison with no sustained complete remission with rituximab aloneat 24 months (P , .001).
CONCLUSIONS: MMF may be an effective and safe maintenance therapy to consider as an additiveimmunosuppressant after induction with rituximab in maintaining remission among children withrefractory SRNS.
WHAT’S KNOWN ON THIS SUBJECT: Treatment ofidiopathic steroid-resistant nephrotic syndromeis challenging, and therapeutic options arelimited. In spite of good initial response withrituximab, responders always remain prone tofurther relapse, necessitating either repeatcourse of rituximab or addition of anothersteroid-sparing immunosuppressant.
WHAT THIS STUDY ADDS: Mycophenolate mofetilmay be an effective maintenance therapy toconsider as an additive immunosuppressantafter induction with rituximab in maintainingremission among children with refractorysteroid-resistant nephrotic syndrome.
aDivision of Pediatric Nephrology, and bDepartments of Pediatrics, and cCommunity Medicine and Statistics, NRSMedical College and Hospital, Kolkata, India
Drs Basu and Mahapatra conceptualized and designed the study, and drafted the manuscript;Dr Mondal carried out the statistical analyses, and reviewed the manuscript; and all authorsapproved the final manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0486
DOI: 10.1542/peds.2015-0486
Accepted for publication Apr 22, 2015
Address correspondence to Biswanath Basu, MD, Division of Pediatric Nephrology, Department ofPediatrics, NRS Medical College and Hospital, Kolkata 700014, West Bengal, India. E-mail:[email protected]
Idiopathic nephrotic syndrome affects1 to 3 per 100 000 children ,16years of age.1 Whereas most of themrespond well to corticosteroidtreatment, as many as 20%experience a complicated course withsteroid resistance (steroid-resistantnephrotic syndrome [SRNS])associated with poor renal survival.1
The most commonly used steroid-sparing protocols in SRNS areintravenous cyclophosphamidecourses and maintenance calcineurin-inhibitor (CNI) therapy.1 But treatingpatients with SRNS who fail torespond to CNI, mycophenolatemofetil (MMF), alkylating agents, orvarious combinations of thesesteroid-sparing agents with orwithout steroid, is challenging, andtherapeutic options are limited ifpatients do not respond even aftermaintaining adequate drug troughlevels. In 3 randomized clinical trials(RCTs), ciclosporin resulted incomplete remission in 31% andpartial remission in 38% during6 months of therapy.2–4 MMF revealed33% complete or partial remission in1 RCT.5 Two RCTs comprising 84children with SRNS demonstrated nosignificant differences in the numberachieving remission withcyclophosphamide and prednisonecompared with prednisone alone.6,7
Complete remission was significantlyhigher with tacrolimus (52.4%) thanwith cyclophosphamide (14.8%) in1 RCT.8 To overcome this therapeuticproblem and long-term adversecomplications of these alternativemedications, rituximab, a recentlyintroduced alternative steroid-sparing therapy, is being increasinglyused in subjects who failed othersteroid-sparing therapies. Rituximab,an anti-CD20 monoclonal antibody,mainly acts by rapidly depletingB lymphocytes in children withnephrotic syndrome. There areseveral reports about the use ofrituximab in children withcomplicated nephrotic syndrome, butit seems that the effects of rituximabmay result in a higher percentage of
remission and cumulative sustainedremission in steroid-dependent(SDNS) and frequent-relapsenephrotic syndrome rather than inSRNS.9,10 In spite of good initialresponse, rituximab respondersalways remain prone to furtherrelapse with regeneration ofB lymphocytes, necessitating eitherrepeat course of rituximab oraddition of another steroid-sparingimmunosuppressant. Reports suggestefficacy of rituximab may varydepending on disease pathology,clinical course, and simultaneous useof other immunosuppressants.11 Inthis retrospective study, we analyzedthe efficacy of MMF maintenancetherapy after rituximab in childrenwith refractory-idiopathic SRNS. Allchildren were treated with a firstcourse of rituximab inductionfollowed by a second course ofrituximab reinfusion (if needed) asper center practice to achieveadequate B-lymphocyte suppressionand daily MMF therapy to maintainthe immunosuppressive effectinduced by rituximab.
METHODS
Study Design and Setting
We retrospectively reviewed themedical records of 24 children withidiopathic SRNS and postrituximabfollow-up of at least 24 months ata tertiary-care medical collegebetween September 2011 and May2014. The study was approved by theinstitutional review board of ourinstitute.
Inclusion and Exclusion Criteria
All patients included in thisretrospective analysis met thefollowing criteria at study entry:(1) age 2 to 16 years, (2) withidiopathic nephrotic syndrome, (3) noresponse despite at least 6 months ofcontinuous therapy with CNIs (withadequate drug trough level of50–150 ng/mL for ciclosporin and5–10 ng/mL for tacrolimus) orpresence of drug-related toxicities
(eg, convulsion, hyperglycemia,progressive deterioration ofestimated glomerular filtration rate[eGFR], hirsutism), (4) eGFR.60 mL/min per 1.73 m2, and (5)either minimal change disease (MCD)or focal segmental glomerulosclerosis(FSGS) on renal histopathology.Exclusion criteria were congenitalnephrotic syndrome, secondarycauses of nephrotic syndrome(known etiology; eg, lupuserythematosus, immunoglobulin Anephropathy, amyloidosis; knownchronic infection like tuberculosis,HIV, hepatitis B or C; and knownmalignancy), considerable glomerularsclerosis (.50% sclerosis) onhistopathology, and previous historyof rituximab treatment.
Definitions
Standard definitions were used fornephrotic syndrome, remission, andrelapses.1 Remission was defined ascomplete (urine protein to creatinineratio [Up/Uc] ,0.2 mg/mg or,20 mg/mmol) or partial (Up/Ucbetween 0.2 and 2 mg/mg, or 20–200mg/mmol; serum albumin .2.5 g/dLor .3.62 µmol/L; and no edema). Noresponse (nonresponder) was definedas the presence of nephrotic rangeproteinuria (Up/Uc .2 mg/mg or.200 mg/mmol), serum albumin,2.5 g/dL (,3.62µmol/L), or edema.“Initial resistance” was defined by thelack of remission at the first episode ofnephrotic syndrome, and “lateresistance” was considered in patientswho were steroid sensitive initially, butshowed steroid resistance duringa subsequent relapse.
Rituximab Therapy
Rituximab was administered topatients with SRNS if there was lackof remission despite at least 6 monthsof continuous therapy with CNI orpresence of drug-related toxicities.We excluded Epstein-Barr virus,cytomegalovirus, HIV, tuberculosis,hepatitis B, and hepatitis C, alongwith any pyogenic focus in allchildren before giving the first dose of
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rituximab. After premedication withsteroids and antihistamine, 2rituximab infusions wereadministered once every week atstandard dose (intravenous infusionof rituximab 375 mg/m2). We directlymeasured circulating B-lymphocytecounts (measured with flowcytometry) 24 hours after rituximabadministration to monitor adequacyof rituximab, instead of measuring itindirectly with CD19 or CD20. If .5B lymphocytes per mm3 wereobserved, they were again measured1 week later. If counts were still .5B lymphocytes per mm3, third andfourth doses of rituximab wereadministered.
Concomitant Therapy
Oral immunosuppressive drugs weretapered down or discontinuedgradually for all patients. MMF andCNI were discontinued immediatelyand prednisone was tapered off over1 month after B-lymphocyte (,5B cells per mm3) depletion. In thosechildren who did not show any sign ofimprovement (nonresponder),immunosuppressive agents werecontinued along with the lowestpossible alternate-day steroid andother experimental drugs as percenter practice.12 Enalapril was givenat 0.5 mg/kg per day in all patientswith hypertension. Furosemide wasused for control of edema, ifindicated. Cotrimoxazole wassystematically given to all patientsduring the period of B-lymphocytedepletion for Pneumocystisprophylaxis.
Intervention at 3-Month Follow-up
At 3-month follow-up, a secondcourse of rituximab infusion (if .5circulating B lymphocytes per mm3)was administered and MMF wasstarted (1200 mg/m2 per day in 2divided doses) to all patients withpartial remission and in patients withsubsequent relapse after completeremission with the first course ofrituximab. To determine the numberof rituximab doses, a similar strategy
was followed depending oncirculating B lymphocytes as in thefirst course of rituximab therapy. Nopatient was treated with more than 2courses of rituximab.
Clinical and Biochemical Assessment
Clinical histories with relapses wererecorded through standardizedscreening of the patients’ hospitalrecords. At every 3 months during the24-month follow-up period, wereviewed number of relapses, sideeffects, proportion of patients withsustained remission, and time to firstrelapse after rituximab infusion andafter adding of MMF. Proteinuriawas assessed by measurement ofa 24-hour urine sample or byassessing Up/Uc. In addition, bloodcount, serum creatinine, serumalbumin, and serum cholesterolvalues were obtained at study entryand every 3 months. GFR wasestimated at baseline and then every6 months by using the modifiedSchwartz formula.13 All patientsperformed regular proteinuriadipstick at home and contacted thetreatment center when 3 to 4+proteinuria occurred for more than2 consecutive days.
Statistical Analysis
Continuous data between subgroupswere analyzed by using Mann-Whitney U test, Wilcoxon signed ranktest, Student’s t test, or analysis ofvariance, as appropriate, and nominaldata were examined using Fisher’sexact test. Kaplan-Meier survivalanalysis was performed separatelyduring the first 3 months after thefirst course of rituximab therapy(n = 24) and thereafter up to 24months after addition of MMFtherapy (n = 15). Throughout the text,data are expressed as means 6 SDs,medians (interquartile range [IQR]),and percentages, as appropriate, andP # .05 was considered statisticallysignificant. The SPSS for Windowsversion 16 software (IBM SPSSStatistics, IBM Corporation, Chicago,
IL) was used for all statisticalanalyses.
RESULTS
Baseline characteristics of 24 childrenwith SRNS (15 children had noresponse with 6 months of CNItherapy and CNI was stopped in9 children due to drug-relatedtoxicities) who were evaluated byretrospective analysis aresummarized in Table 1. Fourteenpatients were initial SRNS and10 patients were late SRNS. Of 24patients treated with rituximab, 13(54%) had MCD and 11 (46%) hadFSGS on histopathology of kidney;38% (5/13) of children with MCDand 64% (7/11) of children withFSGS required a total of 4 doses ofrituximab initially for adequateB-lymphocyte suppression (,5 B cellsper mm3). All patients had varioussteroid toxicities, such as obesity,cushingoid features, and/or poorheight velocity. Five children had earlyposterior subcapsular cataracts.
Outcome at 3 Months (AfterCompletion of First RituximabCourse) and Retreatment
Five (MCD 4; FSGS 1) children of thetotal of 24 (21%) achieved completeremission within 2 weeks ofcompletion of initial rituximab course(Fig 1). The median time to responsewas 12 days (IQR 8–14 days) afterthe last dose of rituximab; however,4 (80%; 4/5) of them who respondedcompletely, relapsed again within 90days of the last rituximab infusion ata median interval of 53 days (IQR46–72 days). Of these 4 children,2 relapsed in spite of continuedadequate B-lymphocyte suppressionand were not considered forrituximab retreatment. MMF wasstarted in all 4 of these children.
Partial remission was achieved in46% (11/24) of children and noresponse was documented among33% (8/24) of children. MMF wasstarted in all 11 children whoachieved partial remission. Children
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who did not respond at all weretreated with other experimental drugsas per center practice.12 All childrenwith partial remission or no remissionachieved adequate B-lymphocytedepletion after rituximab treatment.
Outcome at 6 Months
One child continued sustainedcomplete remission without anysteroid or immunosuppressant afterthe first course of rituximab. Ten(67%) of a total of 15 children whowere on MMF therapy achievedcomplete remission and 5 (33%)remained in partial remission. At6 months, 7 (50%) of 14 patients withinitial SRNS and 9 (90%) of 10 patientswith late SRNS were in complete orpartial remission. Complete or partialremission was seen in 85% (11/13) ofpatients with MCD and 45% (5/11) ofpatients with FSGS. Complete responsein children with MCD was almostdouble in comparison with FSGS.
Only 55% (6/11) of children amongpartial responders (with first courseof rituximab) in comparison with all(4/4) children among initial completeresponders (with first course ofrituximab) achieved completeremission after the second course ofrituximab and addition of MMFtherapy.
Outcome at 12 Months
Of 10 children who achievedcomplete remission at 6 months after
MMF therapy, 60% (6/10) sustainedcomplete remission, but 40% (4/10)relapsed. Trough levels wereobtained in those patients who failedMMF treatment, and adequateconcentrations of .2.5 µg/mL wereobserved. All (4/4) children withinitial complete response (with firstcourse of rituximab) continuedcomplete remission. One childremained in sustained remissionthroughout this study period afterinitial rituximab course.
Outcome at 24 Months
At 24 months of follow-up, overall25% (6/24) and 42% (10/24) ofchildren were in complete and partialremission, respectively. Interestingly,all children with complete remissionwere MCD. Five (33%) of the total 15children who failed to continuesustained complete response with thefirst course of rituximab, attainedsustained complete remission afterMMF maintenance therapy incomparison with no relapse-freesurvival with rituximab alone at24 months (Figs 1 and 2).
Predictive Factors for FavorableClinical Response
Kaplan-Maier curve (Fig 2)depicts relative efficacy of MMFmaintenance therapy afterrituximab in comparison withrituximab alone. Interestingly, allchildren with sustained complete
remission at 24-month follow-upwere MCD (P , .001) and late steroidresistant (P , .001). So, these factorsmight be associated with favorabletreatment response.
Adverse Effects of Drugs
No serious adverse events occurredafter rituximab therapy. One patienthad dizziness and mild dyspnea soonafter infusion, but no furthercomplications. Two other childrendeveloped respiratory tract infectionsthat did not require hospitalization.No patient developed neutropenia(,500 per mm3). During MMFtherapy, 1 child had diarrhea, whichsettled with symptomatic treatment.
DISCUSSION
Our study reveals a high rate ofcumulative sustained remissionamong pediatric patients withidiopathic SRNS treated withrituximab followed by MMF therapy.The point of interest regarding thisreport is a homogeneous rituximabinfusion protocol with adequateB-cell depletion and a systematicrituximab reinfusion to maintainadequate B-lymphocyte suppressionfollowed by daily MMF therapy tomaintain the immunosuppressiveeffect induced by rituximab.
Although there have been manyreports of the excellent steroid-sparing effect of rituximab against
TABLE 1 Baseline Characteristics of Patients According to Outcome at 3 Months After Completion of Initial Rituximab Course (n = 24)
Complete Remission, n = 5 Partial Remission, n = 11 Nonresponder, n = 8
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Relapse (n = 1)(FSGS
FIGURE 1Long-term outcome of children with SRNS (n = 24).
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idiopathic complicated childhoodnephrotic syndrome, most patientswere likely to relapse after recoveryof B lymphocytes.14–16 As a singleinfusion or a single course, rituximabcan deplete B lymphocytes fora limited time only; the efficacy ofadditional rituximab administrationsjust after the reemergence ofB lymphocytes has been reported inchildren with SDNS.17 In our report,67% (16/24) of children achievedcomplete or partial remission ata median interval of 17 days after thefirst course of rituximab therapy.All children revealed adequateB-lymphocyte suppression, yet 33%(8/24) revealed no sign of improvement.Four of 5 children who respondedcompletely relapsed again within90 days of the last rituximab infusion. Ofthese 4 children, 2 relapsed in spite ofcontinued adequate B-lymphocytesuppression and they were notconsidered for rituximab retreatment.Interestingly, all 5 children continuedsustained complete remission at24-month follow-up after the secondcourse of rituximab and MMFtreatment, even after recovery of .5B lymphocytes. Therefore, it may beconcluded that B-lymphocytedepletion or B-lymphocyte recoveryis not the only criterion formaintaining remission or relapse. Butof course immunomodulation of MMFhad an additive impact in maintaining
remission even after B-lymphocyterecovery. In this study, the mean timeinterval from B-lymphocyte recoveryto nephrotic syndrome relapse afterthe first course of rituximab therapywas 1.8 months, but the intervalsignificantly increased to 11.2 monthsafter addition of MMF.
The single child who maintainedcomplete sustained remission afterthe first course of rituximab therapy,and even after regeneration ofadequate B lymphocytes at 5 months,ultimately relapsed after 17 months.We had not treated this child witha second course of rituximab, as theparents of the child did not agree forfurther rituximab and we startedMMF. This case suggests thata relapse may occur even after a longinterval of B-lymphocyte recovery.A child may relapse or may not respondat all with no detectable circulatingB lymphocytes in the peripheralblood, a finding that might be relatedto the escape of some intraorganB cells to rituximab-inducedapoptosis, and the subsequentpersistence of B lymphocytes inspecific body compartments.18 So, therepeated prophylactic use ofrituximab after B-lymphocyterecovery is not always justifiable andmust be individualized. We did nottreat any child with more than 2courses of rituximab infusion becauseit may not be cost-effective and may
produce severe immunosuppressionwith a threat for serious infections.Whether prophylactic periodicmaintenance reinjection of rituximabdepending on B-lymphocyteregeneration should be proposed topatients with a complete clinicalresponse remains a matter of debate.Moreover, response of rituximab inSRNS also depends on multiplefactors, such as degree ofglomerulosclerosis or presence ofpodocytopathy. Advanced glomerularfibrosis, as well as low eGFR, mayadversely affect the treatmentoutcome even after adequateimmunosuppression, depending onthe numbers of actively workingglomeruli. A more important point isto administer rituximab duringremission or at least in partialremission. It is believed that the effectof rituximab is lower during thenephrotic range proteinuria phase, asa significant amount of rituximab islost in urine, resulting in lower serumrituximab levels and faster recovery ofB lymphocytes.16,19
In this study, maintenance therapywith MMF after rituximab in childrenwith SRNS significantly improved thepatient outcome in maintainingremission without repeated exposureof rituximab (Fig 2). We chose MMFfor maintenance therapy afterrituximab, as most of the childrenwere also suffering from variousstages of CNI nephrotoxicity andinterestingly this nephrotoxicitygradually reversed to various extentsover time during rituximab and MMFtherapy after withdrawal of CNI.Severe adverse events are rarelyexperienced with MMF treatment,and MMF treatment can be enduredlong-term. Similar to our study, theeditorial commentary of Filler et al20
regarding management of SDNS alsostated that the addition of MMF to thetherapeutic regimen after rituximabmay provide an effective tool toprevent further relapse once theCD19/CD20 count returns to normal.Ito et al21 performed a cohort studyon SDNS and followed 9 patients who
FIGURE 2Relapse-free survival curve during study period.
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received MMF after rituximabinfusion and 7 patients as the controlgroup without MMF administrationafter rituximab. They found that thenumber of relapses were significantlylower in patients who were treatedwith the combination of rituximaband MMF within 1 year oftreatment.21 Sharma and Filler22
reported that children with FSGScould successfully maintain long-termremission with MMF after rituximab,and described a case treated withrituximab and MMF; relapse did notoccur in this patient despite anincrease in CD19 cells. Fujinagaet al15 reported the value and efficacyof maintenance therapy withciclosporin after a single dose ofrituximab, even for patients withpreviously ciclosporin-refractorySDNS and emphasized theimprovement in drug sensitivity tociclosporin after rituximab treatment andnoted that ciclosporin treatment couldprevent relapse after rituximab. However,the long-term use of ciclosporin increasesthe risk of nephrotoxicity. MMF mayeliminate the need to repeat rituximabinfusions, and consequently reduces theside effects of its repeated doses.21,22 Ourreport suggests that the efficacy ofcombined rituximab and MMF is betteramong children with renal histology ofMCD or with late steroid resistance.
We recognize several limitations toour study. The patient number in eachsubgroup was small and, therefore,statistical analysis may not beconclusive. We did not directlycompare the efficacy of rituximabversus rituximab-MMF amongchildren with SRNS. Also, we did notroutinely perform therapeutic drugmonitoring for MMF, the cost ofwhich exceeds available resources inmost developing countries. A recentreport suggested that individualizeddosing of MMF according topharmacokinetic profiling maymarkedly augment its efficacy innephrotic syndrome.23 Finally,routine evaluation for geneticmutations was not done in ourpatients because of the variability inavailability, significant cost, low toabsent prevalence observed in Indianpopulations, and current uncertaintyabout the individual response totherapy and prognosis whena mutation is identified.
CONCLUSIONS
Although our study is a retrospectivestudy, we conclude that MMF may bean ideal and safe maintenancetherapy to consider as an additiveimmunosuppressant after inductionwith 1 or 2 courses of rituximab in
maintaining remission amongchildren with SRNS. However, an RCTis needed among these children tofurther establish the fact.
ACKNOWLEDGMENTS
We thank all participating childrenand their parents. We also thank theoutpatient nursing staff andlaboratory technician at the pediatricnephrology clinic at NRS MedicalCollege, Kolkata. Additionally, wethank all doctors who referredpatients to us and our healthadministration.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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DOI: 10.1542/peds.2015-0486 originally published online June 22, 2015; 2015;136;e132Pediatrics
Biswanath Basu, T.K.S. Mahapatra and Nirmal MondalNephrotic Syndrome
Mycophenolate Mofetil Following Rituximab in Children With Steroid-Resistant
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