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

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. Disclosure
• None
• Off-label use:
• Rituximab in renal transplantation

3. Edwards et al. Nature Reviews Immunology 6, 394–403 (May 2006)
B-cell development

4. Shimabukuro-Vornhagen A et al. Blood. 2009;114(24):4919-27.
B-cell functions

5. Djamali A et al. Am J Transplant. 2014 Feb;14(2):255-71.

6. Rituximab: mechanism of action
Taylor RP et al. Nat Clin Pract Rheumatol. 2007;3(2):86-95

7. Genberg H et. al. Am J Transplant 2006;6:2418–28.
49 KTx
RTX single dose 375 mg/m2

8. Sidner RA et al. Hum Antibodies 2004;13:55–62.
Memory B cells
Naïve B cells

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. 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. 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. Macklin PS et. al. Transplantation. 2014 Oct 27;98(8):794-805.

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. • 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. 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. • 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. 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. Kasi PM et al. Crit Care. 2012;16(4):231..

19. Perry HM et al. Front Immunol. 2012;3:373.

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. Clatworthy MR et al. N Engl J Med 2009;360:2683–5.

22. Clatworthy MR et al. N Engl J Med 2009;360:2683–5.

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. Am J Transplant. 2015;15(2):407-16.

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. • 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. 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. 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. 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. 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

33. 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]

35. BPAR within 6 months after KTx in all patients
23 (16.7%) in rituximab group vs 30 (21.1%) in placebo group

36. 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

37. 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

38. 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

39. Result – Maintenance immunosuppression

40. 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

41. P<0.001
The overall incidence of infections or malignancy was not
higher after treatment with rituximab compared to placebo

42. 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).

43. 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.

44. Discussion
• High incidence of leukopenia and neutropenia after
RTX.
• The higher incidence of neutropenia did not lead to
more infections.

45. 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.

46. 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

47. ClinicalTrials.gov

49. Questions & Discussion