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Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation: Journal Club

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

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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