Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation: Journal Club


Published on

Journal Club review of Rituximab as induction therapy in Compatible Kidney Transplantation

Published in: Education
  • The Kidney Disease Solution PDF Download Link ★★★
    Are you sure you want to  Yes  No
    Your message goes here
  • Suffer from Kidney Disease? how his patients avoid dialysis? Aussie Naturopath tells all... click here to find out how ★★★
    Are you sure you want to  Yes  No
    Your message goes here

Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation: Journal Club

  1. 1. Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety Wisit Cheungpasitporn March 13, 2015
  2. 2. Disclosure • None • Off-label use: • Rituximab in renal transplantation
  3. 3. Edwards et al. Nature Reviews Immunology 6, 394–403 (May 2006) B-cell development
  4. 4. Shimabukuro-Vornhagen A et al. Blood. 2009;114(24):4919-27. B-cell functions
  5. 5. Djamali A et al. Am J Transplant. 2014 Feb;14(2):255-71.
  6. 6. Rituximab: mechanism of action Taylor RP et al. Nat Clin Pract Rheumatol. 2007;3(2):86-95
  7. 7. Genberg H et. al. Am J Transplant 2006;6:2418–28. 49 KTx RTX single dose 375 mg/m2
  8. 8. Sidner RA et al. Hum Antibodies 2004;13:55–62. Memory B cells Naïve B cells
  9. 9. Decrease in T-cell activation following rituximab administration. P<0.05 Stroopinsky D et al. Cancer Immunol Immunother 2012;61:1233–41. Patients with non-Hodgkin lymphoma Evaluation at 3 months after rituximab therapy showed restoration of inflammatory cytokine production A significant decline in IL-2 and IFN-γ levels in peripheral blood
  10. 10. Chong AS et al. Nat Rev Nephrol. 2014;10(12):678-80. Bachmann MF et al. EMBO Rep. 2007;8(12):1142-8 IL-2 and IFN-γ produced by activated T cells, in particular, by activated CD4+ T-helper cells
  11. 11. Rituximab in renal transplantation • ABOi transplantation • HLAi transplantation • PTLD • Acute allograft rejection • CAMR • Treatment/Prevention • Recurrent GN following transplantation • Induction therapy in compatible renal transplantation Barnett AN. Transpl Int. 2013 Jun;26(6):563-75.
  12. 12. Macklin PS et. al. Transplantation. 2014 Oct 27;98(8):794-805.
  13. 13. Rituximab in renal transplantation • ABOi transplantation • PTLD • HLAi transplantation • Acute allograft rejection • CAMR • Treatment/Prevention • Recurrent GN following transplantation • Induction therapy in compatible renal transplantation Barnett AN. Transpl Int. 2013 Jun;26(6):563-75.
  14. 14. • Randomized to receive one dose of rituximab 375 mg/m2 BSA vs. placebo within 24 hr before revascularization. • PRA < 50% • Maintenance IS: • TAC+MMF+CS Tydén G et al. Transplantation 2009;87:1325–9.
  15. 15. At 6 months Tydén G et al. Transplantation 2009;87:1325–9. *the study was underpowered to detect a statistically significant reduction in acute rejection rate
  16. 16. • 44/68 pts in the RTX group and 47/68 pts in control group were available for follow-up. • RTX group • 1 graft loss due to chronic rejection • 8 deaths (6 cardiovascular deaths, 1 pulmonary carcinoma, and 1 fungal pneumonia) • 15 patients refused to participate. • Only 1/33 pts had developed anti-HLA DSA. • Control group • 1 graft was lost due to recurrence of primary disease • One death • 6/38 pts had developed anti-HLA DSA. • There was a statistically significant increase in mortality (8/68 patients vs. 1/68 patients, P =0.006) in the rituximab group Tydén G et al. Transplantation 2012;94:e21–2.
  17. 17. van Sijl AM et al. Curr Pharm Des. 2014;20(4):496-9. Lee L et al. Case Rep Hematol. 2012;2012:984986. Poterucha JT et al. Tex Heart Inst J. 2010;37(2):218-20. Armitage JD et al. Clin Lymphoma Myeloma. 2008;8(4):253-5.
  18. 18. Kasi PM et al. Crit Care. 2012;16(4):231..
  19. 19. Perry HM et al. Front Immunol. 2012;3:373.
  20. 20. Clatworthy MR et al. N Engl J Med 2009;360:2683–5. RCT - Despite planning to recruit 120 patients, the study was halted after the first 13 patients due to a high incidence of ACR in the RTX group.
  21. 21. Clatworthy MR et al. N Engl J Med 2009;360:2683–5.
  22. 22. Clatworthy MR et al. N Engl J Med 2009;360:2683–5.
  23. 23. • Rituximab-induced ‘cytokine storm’ • It is possible that these mediators may facilitate antigen presentation, enhance T-lymphocyte activity and predispose to cellular rejection. Clatworthy MR et al. N Engl J Med 2009;360:2683–5.
  24. 24. Am J Transplant. 2015;15(2):407-16.
  25. 25. Objectives • To evaluate the efficacy and safety of RTX as induction therapy in renal transplant patients. • Hypothesis: adding a single dose of RTX to an maintenance immunosuppressive regimen would reduce the incidence of biopsy proven acute renal allograft rejection (BPAR) within 6 months after transplantation.
  26. 26. • A single center, randomized, double-blind, placebo- controlled study • The Radboud University Medical center, the Netherlands • December 2007 to June 2012 • Rituximab vs Placebo as induction immunosuppression • Randomization • 1:1 ratio • Double-blind • Stratified high-risk (PRA >6% or re-transplant) vs. low-risk patients • A computer-generated list of random numbers for each of the four strata, prepared by an independent investigator. Study design and setting
  27. 27. Participants Inclusion criteria • Age ≥ 18 years • Received renal allograft from either a living or deceased ABO compatible donor • a combination of TAC, MMF, steroid used as a maintenance immunosuppressive regimen Exclusion criteria • A HLA-identical living donor • HUS as original kidney disease • FSGS recurred in a previous graft • ≥3 previously failed grafts • A current or historic PRA >85% • WBC <3.0x109 /L • Platelet <75x109 /L • Active infection with HBV, HCV or HIV • A history of TB • Previous treatment with RTX
  28. 28. Intervention Surgery start 30 min after Study medication -A single dose of rituximab 375 mg/m2 IV in 500 ml of 0.9% NaCl -Placebo in an identical 500 ml bag Immunosuppressive Rx -Prednisolone: IV 100 mg/d for 3 d, then 15-25 mg/d PO, tapered to 0.1 mg/kg/d -Tacrolimus: 0.2 mg/kg/d twice daily (Target trough level 15-20 ng/ml week 1-2, 10- 15 ng/ml week 3-6 and 5-10 ng/ml thereafter) -MMF: 2000 mg/d twice daily week 1-2, then 1500 mg/d thereafter + TMP/SMX 480 mg/d for 3 months and 3 times/wk thereafter until 1 year + Valganciclovir during the first 3 months for CMV (-) recipient/ CMV (+) donor Standard antibiotic prophylaxis 100 mg prednisolone 2 mg clemastin Study medication infused at a rate of 60 ml/h, titrate q 30 min to a max rate of 200 ml/h
  29. 29. Outcomes – Efficacy and Safety • Primary outcome • Biopsy proven acute rejection (BPAR) within 6 months after KTx. • Biopsies scored independently by two blinded pathologists according to the updated Banff 07 criteria • Borderline rejections were excluded • Protocol graft biopsies were not performed • Secondary outcomes • eGFR at 6 months • infections and malignancies at 6 and 24 months • Patient and graft survival at 6 months and at end of follow-up • All serious adverse events at 24 months
  30. 30. Statistical analysis • Time to first BPAR, allograft loss, and death were analyzed with the Kaplan–Meier method, and differences were assessed with log-rank test. • All data were analyzed on an intention-to-treat basis. • Sample size calculation • To detect a decrease in rejection incidence from 15% to 5% with 2-sided 5% significance level and a power of 80%, 140 patients per treatment arm were required • Not powered to test superiority in the different strata
  31. 31. Result • One patients in the rituximab group experienced anaphylactic reaction during surgery • Temporary interruption of the infusion, mainly due to hypotension, occurred in 7 (5.1%) rituximab-treated patients compared to 5 (3.5%) placebo-treated patients (P=0.57) • Analysis of peripheral blood in 20 CMV-negative patients without BPAR • nearly depletion of B cell in rituximab-treated patients as compared to placebo-treated patients at 6 months after KTx [0.6 (0-16.4) vs. 141 (31-458); p <0.001]
  32. 32. BPAR within 6 months after KTx in all patients 23 (16.7%) in rituximab group vs 30 (21.1%) in placebo group
  33. 33. BPAR in immunologically low- versus high-risk patients. Group BPAR High-risk -Rituximab -Placebo 17.9 % 38.2 % Low-risk -Rituximab -Placebo 16.4% 15.7% P = 0.06
  34. 34. Pretransplant levels of B cells in immunologically high- vs. low-risk patients • Blood taken immediately before transplantation • B cell phenotype in immunologically high-risk patients was compared with immunologically low-risk matched for age, gender, type of dialysis and CMV status
  35. 35. Result – Incidence and type of BPAR at 6 months ABMR 4/138 (2.9%) in rituximab vs 11/142 (7.7%) in placebo; p =0.11
  36. 36. Result – Maintenance immunosuppression
  37. 37. Patient and graft survival at 6 month and after the median follow-up of 4.0 years (range 1.9-6.4) as well as graft function and proteinuria (at 6 and 24 months are comparable between rituximab and placebo group
  38. 38. P<0.001 The overall incidence of infections or malignancy was not higher after treatment with rituximab compared to placebo
  39. 39. Discussion • A single dose of RTX at the time of KTx is safe but ineffective to reduce the incidence of BPAR in a broad population of renal transplant patients. • Immunologically high-risk patients who did not receive RTX had the highest incidence of BPAR. • A separate analysis on the subpopulation of immunologically high-risk patients showed a clear trend toward a lower incidence of BPAR with rituximab therapy as compared to placebo (the study was not sufficiently powered for this analysis).
  40. 40. Discussion • Altogether, these results suggest a protective effect of RTX against acute rejection in patients who are at higher immunological risk. • With the median duration of follow-up of 4.0 years, this beneficial effect has not resulted in improved graft function or graft survival.
  41. 41. Discussion • High incidence of leukopenia and neutropenia after RTX. • The higher incidence of neutropenia did not lead to more infections.
  42. 42. Limitations • At the time of design of the study, induction therapy with IL-2 receptor antagonists or anti-T cell antibodies was not part of the protocol, and was therefore not used in this trial. • The safety of combining rituximab with these agents needs to be established formally, although in a retrospective analysis and uncontrolled cohort study the combination of pre-transplant rituximab, as part of desensitization therapy, and post-transplant induction therapy with anti-T cell agents appeared to be safe.
  43. 43. Conclusion • Addition of RTX induction therapy to a triple drug immunosuppressive regimen does not reduce the incidence of acute rejection in immunologically low-risk patients. • RTX may reduce the incidence of BPAR in immunologically high-risk patients to a level comparable to that in immunologically low-risk patients
  44. 44.
  45. 45. Questions & Discussion