Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety

Wisit Cheungpasitporn

March 13, 2015

Disclosure• None

• Off-label use: • Rituximab in renal transplantation

Edwards et al. Nature Reviews Immunology 6, 394–403 (May 2006)

B-cell development

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

B-cell functions

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

Rituximab: mechanism of action

Taylor RP et al. Nat Clin Pract Rheumatol. 2007;3(2):86-95

Genberg H et. al. Am J Transplant 2006;6:2418–28.

49 KTxRTX single dose 375 mg/m2

Sidner RA et al. Hum Antibodies 2004;13:55–62.

Memory B cells

Naïve B cells

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

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

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.

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

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.

• 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.

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

• 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.

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.

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

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

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.

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

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

• 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.

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

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.

• 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

ParticipantsInclusion 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

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 prophylaxis100 mg prednisolone2 mg clemastin

Study medication infused at a rate of 60 ml/h, titrate q 30 min to a max rate of 200 ml/h

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

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

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]

BPAR within 6 months after KTx in all patients

23 (16.7%) in rituximab group vs 30 (21.1%) in placebo group

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

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

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

Result – Maintenance immunosuppression

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

P<0.001

The overall incidence of infections or malignancy was not higher after treatment with rituximab compared to placebo

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).

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.

Discussion

• High incidence of leukopenia and neutropenia after RTX.

• The higher incidence of neutropenia did not lead to more infections.

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.

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

ClinicalTrials.gov

Questions & Discussion