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pancreas recipients: Warsaw transplantation center experience
IMMUNOSUPPRESSION
Use of Daclizumab in the Immunosuppression of High-Risk Kidney and Kidney/Pancreas Recipients: Warsaw Transplantation Center Experience T. Ba˛czkowska, K. Kukula, E. Nowacka-Cieciura, T. Cieciura, D. Lewandowska, R. Ciecierski, T. Grochowiecki, W. Rowinski, J. Szmidt, M. Durlik, and M. Lao
D
ACLIZUMAB is a humanized monoclonal antibody directed against the alpha (CD-25) subunit of the interleukin-2 receptor (IL-2R), a receptor that is expressed solely on activated T lymphocytes. The antibody may therefore induce a selective CDR immunosuppressive effect without increasing the risk of infection and malignancy. The humanization process results in the production of a virtually human antibody with mouse complementarity determining regions (CDRs) only. Plasma half-life of the drug is therefore extended to 20 days. Addition of daclizumab to cyclosporine-based immunosuppression significantly reduces acute rejection incidence.1 Little is known, however, about the efficacy of daclizumab for the treatment of allograft recipients at high risk for rejection;2 the subject of this report which assesses the frequency of acute rejection episodes, side-effect incidence, and long-term outcomes among kidney (group 1) and kidney/pancreas (group 2) recipients treated with a quadruple immunosuppressive protocol.
PATIENTS AND METHODS We examined a population of 31 patients, 14 men and 17 women, undergoing kidney or kidney/pancreas transplantation, deemed to be at high risk for rejection episodes by virtue of a combined kidney/pancreas transplant, PRA above 80%, living unrelated donor kidney recipient, and/or second kidney allograft recipient. The immunosuppressive protocol consisted of daclizumab, cyclosporine (CyA) (or tacrolimus in case of one patient), mycophenolate mofetil (MMF), and prednisone. Daclizumab was administered three times at a dose of 1.07 ⫾ 0.12 mg/kg on the day of procedure and thereafter on days 14 and 28. Cyclosporine was administered at the dose of 8.03 ⫾ 1.85 mg/kg per 24 hours. The dose of mycophenolate mofetil was 2 g/24 h; in the single case of © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 551–552 (2002)
Table 1. Demographic Data and Rejection Rates in the Studied Groups of Patients Kidney Tx
Kidney/ Pancreas Tx
F/M 8/11 9/3 Age (y) 42.7 ⫾ 13.5 38 ⫾ 5.3 Duration of HD treatment 63.7 ⫾ 50.2 37.5 ⫾ 13.3* (mo) First kidney Tx 14 (4 living unrelated donors) — Second kidney Tx 5 — A 1.27 ⫾ 0.5 1.83 ⫾ 0.4* No. of B 1.18 ⫾ 0.8 1.5 ⫾ 0.5 HLA DR 1.0 ⫾ 0.6 1.33 ⫾ 0.8 mismatches GS ⫹ MMF ⫹ CyA 18 12 GS ⫹ MMF ⫹ FK506 1 0 CIT (h) 28.3 ⫾ 10.1 7.6 ⫾ 3.4* ATN (d) 5.5 ⫾ 9.5 2.0 ⫾ 6* Acute rejection episodes 3 (16%) 1 (8%) Treatment of rejection 3 ⫻ 0.5g MP 3 ⫻ 0.5 MP Time to rejection 38 ⫾ 52 109 episodes (d) Graft loss/death 1/1 4/4 *P ⬍ .05.
patient receiving tacrolimus, the mycofenolate dose was 1 g/24 h. The target dose of prednisone was 0.5 mg/kg per 24 hours. The demographic details are presented in Table 1. From the Transplantation Institute, Department of Transplantation and Vascular Surgery; Medical University of Warsaw, Warsaw, Poland Address reprint requests to Teresa Ba˛czkowska, Transplantation Institute, Medical University of Warsaw, 59 Nowogrodzka Street, 02-006 Warsaw, Poland. 0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02842-1 551
552 The study was performed according to the 1964 Helsinki Declaration and its protocol was accepted by the Ethics Committee of the Warsaw Medical University. All patients participating in the study gave their informed consent. Statistical analysis was performed using the Statistica software.
RESULTS Kidney Tx
Acute rejection incidence among high risk kidney recipients was 16% (three cases). Since no steroid resistant episodes were observed, there was no indication for treatment with anti-lymphocyte immunoglobulin. The one grade IIB rejection episode responded to pulse methylprednisolone therapy. The other two rejection episodes were grade IA (1997 modification of Banff classification). Graft and patient survival were both equal to 94.8% (1 patient died with a functioning graft due to an aneurysm rupture). None of the patients experienced more than one rejection episode. Mean time to rejection was 38 ⫾ 52 days. Mean creatinine concentrations at 1 month, 3 months, 6 months, and 12 months were comparable: 1.35 ⫾ 0.37 mg/dL (n ⫽ 19); 1.35 ⫾ 0.36 mg/dL (n ⫽ 19); 1.27 ⫾ 0.27 mg/dL (n ⫽ 14); 1.15 ⫾ 0.24 mg/dL (n ⫽ 12), respectively. None of the patients have yet completed the full follow-up period.
BA˛ CZKOWSKA, KUKULA, NOWACKA-CIECIURA ET AL
DISCUSSION AND CONCLUSIONS
Addition of daclizumab to the triple immunosuppressive regimen of steroids, CyA, and MMF for high-risk allograft recipients yield a low acute rejection rate in our study, namely 13.8% overall including 16% among kidney and 8% for kidney/pancreas recipients. The frequency of acute rejection episodes has been using a regimen of MMF (2 g/24 h), CyA, steroids estimated in other centers to be around 30%. Interestingly, for a normal rejection risk population3 using a protocol of daclizumab, azathioprine, CyA and steroids the incidence of rejection was 22%.4,5 Despite the small number of patients, our data suggest that adding daclizumab to an immunosuppressive protocol with MMF results in a low acute rejection incidence, even among high rejection risk population. The safety assessment of this protocol is difficult to perform, as there was an exceedingly high mortality rate recorded for kidney/pancreas recipients—solely due to fatal sepsis syndromes. However, this seems to be an unfortunate coincidence in this small group of patients since other studies suggest that daclizumab does not increase infection rate in allograft recipients and since the infection rate in the larger kidneyonly recipient group was not increased in our study.
Kidney/Pancreas Tx
Acute rejection incidence among high risk kidney/pancreas recipients was 8% (one case). This grade IIA rejection episode which occurred at post-transplant day 109 responded to pulse methylprednisolone therapy. Unfortunately, four patients died during the follow-up period due to septic complications, resulting in a surprisingly low patient and graft survival of 67%. Although the immunosuppression was excessive, no cases of PTLD were observed. The data are summarized in Table 1.
REFERENCES 1. Vincenti F: BioDrugs 11:333, 1999 2. Meier-Kriesche HU, Kaza H, et al: Clin Transplant 14:509, 2000 3. Fulton B, Markham A: Drugs 51:278, 1996 4. Ekberg H, Backman L, Tufveson G, et al: Transplant Proc 31:267, 1999 5. Vincenti F, Kirkman R, Light SG, et al: N Engl J Med 338:161, 1998
Use of Daclizumab in the Immunosuppression of High-Risk Kidney and Kidney/Pancreas Recipients: Warsaw Transplantation Center Experience T. Ba˛czkowska, K. Kukula, E. Nowacka-Cieciura, T. Cieciura, D. Lewandowska, R. Ciecierski, T. Grochowiecki, W. Rowinski, J. Szmidt, M. Durlik, and M. Lao
D
ACLIZUMAB is a humanized monoclonal antibody directed against the alpha (CD-25) subunit of the interleukin-2 receptor (IL-2R), a receptor that is expressed solely on activated T lymphocytes. The antibody may therefore induce a selective CDR immunosuppressive effect without increasing the risk of infection and malignancy. The humanization process results in the production of a virtually human antibody with mouse complementarity determining regions (CDRs) only. Plasma half-life of the drug is therefore extended to 20 days. Addition of daclizumab to cyclosporine-based immunosuppression significantly reduces acute rejection incidence.1 Little is known, however, about the efficacy of daclizumab for the treatment of allograft recipients at high risk for rejection;2 the subject of this report which assesses the frequency of acute rejection episodes, side-effect incidence, and long-term outcomes among kidney (group 1) and kidney/pancreas (group 2) recipients treated with a quadruple immunosuppressive protocol.
PATIENTS AND METHODS We examined a population of 31 patients, 14 men and 17 women, undergoing kidney or kidney/pancreas transplantation, deemed to be at high risk for rejection episodes by virtue of a combined kidney/pancreas transplant, PRA above 80%, living unrelated donor kidney recipient, and/or second kidney allograft recipient. The immunosuppressive protocol consisted of daclizumab, cyclosporine (CyA) (or tacrolimus in case of one patient), mycophenolate mofetil (MMF), and prednisone. Daclizumab was administered three times at a dose of 1.07 ⫾ 0.12 mg/kg on the day of procedure and thereafter on days 14 and 28. Cyclosporine was administered at the dose of 8.03 ⫾ 1.85 mg/kg per 24 hours. The dose of mycophenolate mofetil was 2 g/24 h; in the single case of © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 551–552 (2002)
Table 1. Demographic Data and Rejection Rates in the Studied Groups of Patients Kidney Tx
Kidney/ Pancreas Tx
F/M 8/11 9/3 Age (y) 42.7 ⫾ 13.5 38 ⫾ 5.3 Duration of HD treatment 63.7 ⫾ 50.2 37.5 ⫾ 13.3* (mo) First kidney Tx 14 (4 living unrelated donors) — Second kidney Tx 5 — A 1.27 ⫾ 0.5 1.83 ⫾ 0.4* No. of B 1.18 ⫾ 0.8 1.5 ⫾ 0.5 HLA DR 1.0 ⫾ 0.6 1.33 ⫾ 0.8 mismatches GS ⫹ MMF ⫹ CyA 18 12 GS ⫹ MMF ⫹ FK506 1 0 CIT (h) 28.3 ⫾ 10.1 7.6 ⫾ 3.4* ATN (d) 5.5 ⫾ 9.5 2.0 ⫾ 6* Acute rejection episodes 3 (16%) 1 (8%) Treatment of rejection 3 ⫻ 0.5g MP 3 ⫻ 0.5 MP Time to rejection 38 ⫾ 52 109 episodes (d) Graft loss/death 1/1 4/4 *P ⬍ .05.
patient receiving tacrolimus, the mycofenolate dose was 1 g/24 h. The target dose of prednisone was 0.5 mg/kg per 24 hours. The demographic details are presented in Table 1. From the Transplantation Institute, Department of Transplantation and Vascular Surgery; Medical University of Warsaw, Warsaw, Poland Address reprint requests to Teresa Ba˛czkowska, Transplantation Institute, Medical University of Warsaw, 59 Nowogrodzka Street, 02-006 Warsaw, Poland. 0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02842-1 551
552 The study was performed according to the 1964 Helsinki Declaration and its protocol was accepted by the Ethics Committee of the Warsaw Medical University. All patients participating in the study gave their informed consent. Statistical analysis was performed using the Statistica software.
RESULTS Kidney Tx
Acute rejection incidence among high risk kidney recipients was 16% (three cases). Since no steroid resistant episodes were observed, there was no indication for treatment with anti-lymphocyte immunoglobulin. The one grade IIB rejection episode responded to pulse methylprednisolone therapy. The other two rejection episodes were grade IA (1997 modification of Banff classification). Graft and patient survival were both equal to 94.8% (1 patient died with a functioning graft due to an aneurysm rupture). None of the patients experienced more than one rejection episode. Mean time to rejection was 38 ⫾ 52 days. Mean creatinine concentrations at 1 month, 3 months, 6 months, and 12 months were comparable: 1.35 ⫾ 0.37 mg/dL (n ⫽ 19); 1.35 ⫾ 0.36 mg/dL (n ⫽ 19); 1.27 ⫾ 0.27 mg/dL (n ⫽ 14); 1.15 ⫾ 0.24 mg/dL (n ⫽ 12), respectively. None of the patients have yet completed the full follow-up period.
BA˛ CZKOWSKA, KUKULA, NOWACKA-CIECIURA ET AL
DISCUSSION AND CONCLUSIONS
Addition of daclizumab to the triple immunosuppressive regimen of steroids, CyA, and MMF for high-risk allograft recipients yield a low acute rejection rate in our study, namely 13.8% overall including 16% among kidney and 8% for kidney/pancreas recipients. The frequency of acute rejection episodes has been using a regimen of MMF (2 g/24 h), CyA, steroids estimated in other centers to be around 30%. Interestingly, for a normal rejection risk population3 using a protocol of daclizumab, azathioprine, CyA and steroids the incidence of rejection was 22%.4,5 Despite the small number of patients, our data suggest that adding daclizumab to an immunosuppressive protocol with MMF results in a low acute rejection incidence, even among high rejection risk population. The safety assessment of this protocol is difficult to perform, as there was an exceedingly high mortality rate recorded for kidney/pancreas recipients—solely due to fatal sepsis syndromes. However, this seems to be an unfortunate coincidence in this small group of patients since other studies suggest that daclizumab does not increase infection rate in allograft recipients and since the infection rate in the larger kidneyonly recipient group was not increased in our study.
Kidney/Pancreas Tx
Acute rejection incidence among high risk kidney/pancreas recipients was 8% (one case). This grade IIA rejection episode which occurred at post-transplant day 109 responded to pulse methylprednisolone therapy. Unfortunately, four patients died during the follow-up period due to septic complications, resulting in a surprisingly low patient and graft survival of 67%. Although the immunosuppression was excessive, no cases of PTLD were observed. The data are summarized in Table 1.
REFERENCES 1. Vincenti F: BioDrugs 11:333, 1999 2. Meier-Kriesche HU, Kaza H, et al: Clin Transplant 14:509, 2000 3. Fulton B, Markham A: Drugs 51:278, 1996 4. Ekberg H, Backman L, Tufveson G, et al: Transplant Proc 31:267, 1999 5. Vincenti F, Kirkman R, Light SG, et al: N Engl J Med 338:161, 1998