Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant. METHODS: Patients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results. RESULTS: Tofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%). CONCLUSIONS: Long-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients.

UNLABELLED: Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. METHODS: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m(2) or greater improvement in estimated glomerular filtration rate from randomization to month 24. RESULTS: The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m(2) or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). CONCLUSIONS: Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus.

A randomized, open-label study of sirolimus versus cyclosporine in primary de novo renal allograft recipients.

BACKGROUND: Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, results in improved long-term renal function. METHODS: This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm. RESULTS: Enrollment was stopped after ≈12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean±SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1±18.7 mL/min) and CsA (66.0±15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001). CONCLUSION: A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended.