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Rituximab CJASN Journal Club Presentation Transcript

  • 1. Dr Sidharth Kumar Sethi MD, FISN, FIPNA https://www.pediatric-nephrology.com Journal Club
  • 2. Efficacy and Safety of Treatment with Rituximab for Difficult Steroid-Resistant and Dependent Nephrotic Syndrome: Multicentric Report Ashima Gulati, Aditi Sinha, Stanley C. Jordan, Pankaj Hari, Amit K. Dinda, Sonika Sharma, Rajendra . Srivastava, Asha Moudgil, and Arvind Bagga Divisions of Pediatric Nephrology and Genetics, and Department of Pathology, AIIMS, New Delhi, India; Nephrology and Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles; and Nephrology and Kidney Transplant, Children’s National Medical Center, Washington, DC
  • 3. Nephrotic syndrome- why occurs?
    • T cell disease
      • Steroids, Immunosuppressives
      • Remission after Measles
      • Occurs in NHL
    • Now a B cell disease too!
      • Either a circulating permeability factor
      • Aberrant cross talk between B and T cells
    Pediatr Nephrol (2009) 24:1433–1438
  • 4. Evidence in support of B cell disease
    • Recurrence after renal transplantation,
    • Total B-cell count reduction during remission
    • Remission by depletion of B-cells
  • 5. Pro-B Pre-B1 Pre-B2 Immature B Mature B Plasma MHC II CD19 CD22 CD34 Ig  VpreB,  5 CD10 CD20
  • 6. Rituximab and B cells
    • Targets the CD-20 antigen
      • NOT expressed on stem cells, plasma cells, dendritic cells, and other normal tissues
    • CD20 act to signal phosphorylation or as a calcium channel in human B-lymphocytes
    • CD20 good target for monoclonal antibody therapy as it is highly expressed, not shed or internalized upon antibody binding, and is minimally present in soluble form.
  • 7. Mechanism of Actions
    • Depletion of B-cells
      • In patients with NHL, circulating B-cells are depleted within the first three doses of Rituxan therapy
      • B-cells remain depleted for up to 6 to 9 months post-treatment
      • Recovery occurring at approximately 6 months after completion of treatment.
      • Median B-cell levels return to normal by 12 months following completion of treatment.
  • 8.  
  • 9. Rituximab and Cell death
    • Rituximab invokes cell death through
      • antibody dependent
      • cell-mediated toxicity,
      • complement-dependent cytotoxicity,
      • induction of apoptosis, and
      • sensitivity to cytotoxic agents or corticosteroids
  • 10. Course of Nephrotic Syndrome 40% 10-15% ISKDC. J Am Soc Nephrol 8: 769–776, 1997 Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol 4: 1593–1600, 2009
  • 11. Difficult to manage
    • Steroid dependents- risk of toxicity
    • Steroid resistants-
      • Complicated course
      • Risk of ESRD
    • Risk of complications
    • Immunosuppressive drugs
    • Progressive kidney injury
    Pediatr Nephrol 24: 1525–1532, 2009; Pediatr Nephrol 22: 215-221, 2007
  • 12. Rituximab
    • Approved for Non Hodgkin’s Lymphoma
    • Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin’s B-cell lymphoma. Biochem Soc Trans 25: 705–708, 1997
    • Also used successfully in
      • rheumatoid arthritis,
      • systemic lupus erythematosus,
      • vasculitis, and
      • nephrotic syndrome
    Semin Arthrit Rheum 36: 71–81, 2006 Pediatr Nephrol 24: 1433–1438, 2009
  • 13. Rituximab in Nephrotic Syndrome
    • Previous reports
    • Immediate Outcome
    • No data on Long term outcome
    • Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25: 461–468, 2010
    • Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544, 2010
    • Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356: 2751–2752, 2007
    • Bagga A, Sinha A, Moudgil A: Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356: 2751–2752, 2007
  • 14.  
  • 15. Material and Methods
    • Records reviewed
    • SDNS; SRNS (Early/ Late)
    • Jan 2006- Feb 2009
    • Minimum Follow up 12 months
    • Centres
      • AIIMS, India,
      • CNMC, Washington DC,
      • CSMC, Los Angeles
  • 16. Definitions
      • Steroid Resistance (Early/ Late)
      • Lack of remission to Prednisone 2 mg/kg X 4 wks
      • Initial SRNS screened for NPHS1 and NPHS2, sequencing
    • Steroid Dependence
      • relapses on two occasions while receiving prednisone on alternate days or within 14 days of its discontinuation.
  • 17. Methods
    • Clearances
      • Ethical committee
      • DCGI
    • Parental consent
      • Information on Efficacy
      • Off Label use
      • Potential side effects
  • 18. Rituximab Therapy in SRNS
    • Lack of remission despite therapy with
    • intravenous cyclophosphamide (500 mg/m 2 monthly for 6 months) and/or
    • calcineurin inhibitors (cyclosporine 5 to 6 mg/kg per day; tacrolimus 0.1 to 0.15 mg/kg per day for 6 months),
    • disease recurrence after stopping prolonged (3-yr) calcineurin inhibitor therapy, or
    • Presence of nephrotoxicity (striped pattern of
    • interstitial fibrosis or tubular atrophy and/or
    • arteriolar medial hyalinosis)
  • 19. Rituximab therapy in SDNS
    • Lack of steroid sparing effect (inability to sustain remission at a prednisone dose of 0.5 mg/kg every other day) or
    • Presence of steroid toxicity (cataract, or body mass index 95 th percentile for age),
      • despite treatment with oral cyclophosphamide (2 mg/kg per day X 12 wks), levamisole (2.5 mg/kg X 6 mths), mycophenolate mofetil (MMF; 1000 mg/m 2 X 6 mths), and calcineurin inhibitors.
    • Patients with relapses after prolonged (3 yrs) therapy with Calcineurin inhibitors or those showing nephrotoxicity
  • 20. Rituximab not used
    • Estimated GFR <60 ml/min per 1.73 m2,
    • infantile onset of nephrotic syndrome,
    • underlying hepatitis B or HIV positivity, Systemic lupus erythematosus, amyloidosis, Henoch Schonlein purpura, IgA nephropathy, membranoproliferative glomerulonephritis or membranous nephropathy,
    • more than one episode of serious infections (e.g., peritonitis, lower respiratory infection, cellulitis) in the past 12 months, or
    • current or previous therapy for tuberculosis.
  • 21. Rituximab Therapy
    • Dose 375 mg/m 2 weekly 4 doses SRNS and 2 doses SDNS.
    • Dissolved in normal saline (concentration 2 mg/ml), infused over 3 to 4 hours after 30-minute premedication with oral acetaminophen and diphenhydramine ; intravenous hydrocortisone (4 mg/kg)
    • SDNS, rituximab was given during corticosteroid-induced remission, not possible in SRNS.
    • Monitored for infusion-related reactions and
    • Screened at each visit for infections.
  • 22. Concomitant therapy
    • Oral prednisone was given every other day at a dose of 1.5 mg/kg for 2 weeks, 1 mg/kg for 4 weeks, 0.75 mg/kg for another 4 weeks, and then 0.5 mg/kg
    • Calcineurin inhibitor dose reduced to 50% at 3 months, with cessation, if possible, at 6 months.
    • Other immunosuppressive agents discontinued before treatment with rituximab, except in two adult patients with SRNS who received long-term therapy with MMF.
    • Enalapril 0.5 mg/kg per day all SRNS; SDNS with hypertension.
    • Furosemide if indicated.
    • SRNS and blood LDL-cholesterol >130 mg/dl atorvastatin
  • 23. Follow-Up
    • Daily urine albumin testing with a dipstick.
    • Spot urine protein/creatinine ratio (Up/Uc) in the first morning sample was done at 1, 3, 6, and 12 months after the last dose of rituximab.
    • Complete blood counts and levels of creatinine, albumin, and cholesterol were obtained at baseline and every 3 months thereafter.
  • 24. Results
    • n=57
      • 24 SDNS
      • 33 SRNS (3 Adults)
  • 25.  
  • 26. SRNS patients
    • Rituximab mean dose of 410 + 26.6 mg/wk for 4 weeks (except 5)
      • (one dose in 3 adults and 1 child; 2 doses in 1 child).
    • Cotrimoxazole prophylaxis to the first 16 patients for 6 months
      • As no increased risk of infections
      • Normal levels of IgG
      • Discontinued.
  • 27.
    • Median time to response was 32 days (range, 8 to 60 days) after the last dose of rituximab.
    • Prednisone continued in all patients at 0.5 mg/kg every other day,
    • Calcineurin inhibitors were stopped in 2, and
      • and tapered to 50% in 2 patients.
  • 28. Longer follow up
    • At a mean follow-up of 21.5 + 11.5 months (range, 12 to 48 months), remission was sustained in 15 patients (complete in 7 and partial in 8); no response was seen in 18 patients.
    • Nine patients (all non responders) had an estimated GFR 60 ml/min per 1.73 m 2 at 12 months, including five with CKD stage 5.
    • On multivariate logistic regression , none associated with response to rituximab therapy:
    • duration of nephrotic syndrome; initial or late resistance; renal histology, tubulointerstitial damage and calcineurin inhibitor nephrotoxicity; and prior response and duration of treatment with calcineurin inhibitors.
  • 29. SRNS- Retreatment
    • A repeat course (2 doses each)- 3 patients
      • 2 patients with complete and
      • 1 patient with partial remission,
    • 12 to 24 months after the first course.
    • At follow-up of 9 to 18 months,
      • 2 patients partial remission
      • 1 no response.
  • 30.  
  • 31. SDNS patients
    • Rituximab given at a mean dose of 400 + 20.7 mg/wk for 2 weeks;
      • four patients concomitant therapy with calcineurin inhibitors.
    • Relapse Rates at 12 Months
    • Sustained remission in 20 (83.3%)
      • The time to first relapse was 11.2 + 2.7 months; (range, 8 to 14 months).
    • Mean number of relapses
      • before therapy was 4.0 + 0.4 episodes/patient per year
      • Reduced significantly to 0.2 + 0.3 episodes/patient per year in the next 12 months (mean difference, 3.9; 95% CI, 3.6, 4.1; P 0.000, ANOVA).
    • At a mean follow-up of 16.8 + 5.9 months (range, 12 to 38 months),
      • Sustained remission 17 (71%) patients
  • 32. SDNS patients
      • One or more immunosuppressive medications withdrawn in 12
        • In 8 additional patients, dose of prednisone tapered to 0.3 to 0.5 mg/kg every other day.
        • One patient multiple relapses 11 months after the first course of treatment. Received two additional doses of rituximab and is in remission 10 months later.
  • 33. SDNS Patients
  • 34.  
  • 35. B-Cell (CD19) Depletion
    • Data available in 14 patients
    • (5 SRNS and 9 SDNS).
    • Baseline CD 19 12.6 + 3.4% TLC
      • After therapy, CD19 levels after two and four doses in patients with SDNS and SRNS, respectively.
      • 0.2 + 0.1 %
      • 0.3 + 0.2%
  • 36. Side Effects
    • 3 with SRNS and 1 with SDNS
      • mild infusion-related reactions
      • (3- chills; 1-myalgia).
    • No differences in TLC at baseline or 6 and 12 months after therapy.
    • None had peritonitis, cellulitis, thrombosis, or any other serious infection or adverse event on follow-up.
  • 37. Discussion
    • Efficacy of rituximab in difficult nephrotic syndrome; remission
      • 48.5% patients SRNS
      • 95% reduction relapse frequency SDNS.
    • Mostly SRNS or SDNS with unsatisfactory response to multiple immunosuppressive agents
    • Demonstration of complete or partial remission in 16 of 33 patients with SRNS valuable.
    • Similar outcomes
      • initial and late resistance
    • Trend toward better response rates in patients with steroid-resistant MCD compared with FSGS
  • 38. SDNS patients
    • Favorable long-term
    • Sustained remission 83.3%
    • Steroid-sparing effect 75% at 12 months.
    • Potential role in difficult SDNS.
  • 39.  
  • 40.  
  • 41.  
  • 42. Sustained remission in 19 patients (86.3%),
  • 43.
    • An international, multicenter report
    • 28 patients with SDNS, 27 patients with SRNS, and 15 patients with post-transplant recurrence
    • variable severity
    • heterogeneity regarding treatment regimens and the dose
    • At a median follow-up of 5 months, 44% of patients with refractory SRNS showed reduction of proteinuria with normalization of serum albumin.
    • No difference in response based on underlying histology.
    • Although the authors found satisfactory initial response in 82% patients with SDNS, only 40% had sustained remission at a follow-up of 4.5 months .
  • 44.  
  • 45. Critical Appraisal
    • Includes ethnically different populations,
    • Uniform inclusion and exclusion criteria.
    • Therapies for SRNS and SDNS similar.
    • Follow up:
      • SRNS 21.5 + 11.5 months
      • SDNS 16.8 + 5.9 months
    • Extended follow-up of SDNS emphasizes the impact of rituximab in
      • causing sustained remission and marked corticosteroid sparing.
    • Also confirms previous experience
      • satisfactory short-term results 5 patients with difficult SRNS.
  • 46. Side Effects
    • Multicentric French report
      • transient adverse effects 45%
      • 1 P. carinii pneumonia
    • Prytula et al
      • acute reactions in 27% patients
      • high incidence severe side effects including anaphylaxis and serious infections.
    • Reversible cytokine shock and neutropenia
  • 47. New Fatal Side Effects
  • 48. Limitations
    • Lack of a control group.
    • Prospective controlled trials necessary to confirm the efficacy
    • Obtaining CD19 counts, serial monitoring not done.
    • Number of doses of rituximab used based on experience rather than targeting specific CD19 levels, dose?
    • Potential urinary losses of rituximab, more doses used in SRNS
  • 49. Conclusions
    • Might be a bias for reporting favorable outcomes
    • Rituximab benefits a proportion of patients with difficult SDNS or SRNS.
    • Trend toward better response in MCD
    • Future studies needed to analyze clinical, histologic,and other features associated with a satisfactory response
  • 50. Conclusions
    • Expensive (500 mg rituximab costs approximately $800–1200 in India and $8000 in the United States)
    • Need for a RCT comparing the efficacy and safety of rituximab to a calcineurin inhibitor (e.g., tacrolimus)
    • Relative safety profile and lack of nephrotoxicity, might be preferred to long term therapy with calcineurin inhibitors.
    • Until then, consider in patients with SRNS and SDNS refractory to other medications or show evidence of calcineurin inhibitor nephrotoxicity.