- Email: [email protected]
Alemtuzumab Induction With Tacrolimus Monotherapy in De Novo Renal Transplantation
Alemtuzumab Induction With Tacrolimus Monotherapy in De Novo Renal Transplantation M.E. Villanueva, A.S. Muñoz, C.C. Casasola, J.B. Africa, R.A. Danguilan, and E.T. Ona ABSTRACT Objectives. Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. Methods. This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. Results. At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 ⫾ 0.65 mg/dL at 3 months, 1.56 ⫾ 0.84 at 6 months, 1.45 ⫾ 0.37 at 12 months, and 1.74 ⫾ 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and ⬎6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. Conclusion. Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.
L
YMPHOCYTE DEPLETION at the time of transplantation facilitates graft acceptance and prevents kidney transplant rejection.1 Alemtuzumab is being increasingly used as induction therapy for kidney transplantation, because of its powerful lymphocyte-depleting property. This humanized monoclonal antibody is directed against CD52 antigens located on T and B lymphocytes, natural killer cells, but less densely, on monocytes and macrophages.2,3 It has shown promise in tolerogenic induction protocols requiring minimal maintenance immunosuppression, such as steroid-free regimens with low doses of a calcineurin inhibitor (Ona et al, unpublished data, NKT1 proceedings, 2006).4 –14 This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients.
METHODS Study Design This single-center, retrospective study of primary renal transplant recipients at standard immunologic risk utilized alemtuzumab induction therapy and low-dose tacrolimus as the maintenance immunosuppressive regimen. The protocol was approved by the institution’s ethics committee. All patients were informed that alemtuzumab was not approved by the Bureau of Food and Drugs for use in kidney transplantation and that its use would be in a pilot
From the National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr Marlene E. Villanueva, National Kidney and Transplant Institute, East Avenue, Quezon City, Philippines. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.037
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2222
Transplantation Proceedings, 40, 2222–2225 (2008)
ALEMTUZUMAB INDUCTION study fashion and “off label”. All patients were informed that the recommendation to use alemtuzumab for their transplant was based on physicians’ judgment and not part of an investigation. All participating patients gave written informed consent after a full explanation of the treatment options, including the conventional methods of treatment. The right of the patient to refuse to participate without giving reasons was respected. The patient remained free to withdraw from the protocol treatment at any time without giving reasons and without prejudicing further treatment.
Inclusion Criteria Patients aged 16 to 65 years who were primary transplant recipients from living or deceased donors, had a panel reactive antibody (PRA) ⬎10% but ⬍50% were included.
Exclusion Criteria We excluded patients with a positive T-cell cross-match, who were pregnant or nursing women, or showed active systemic infection, or received multiple organ transplants, or were positive for the hepatitis B surface antigen and/or anti-hepatitis C antibody, from the study.
Population Data were collected for renal transplants performed between September 2005 and February 2007. We reviewed patient charts and the hospital computer database for demographic data, nature of kidney disease, donor source, number of HLA mismatches, and PRA level. Serum creatinine levels were noted at week 1, as well as months 3, 6, and 18. Episodes of elevated creatinine were noted and biopsy findings were reviewed. If acute rejection was noted, data were collected on the type and Banff grade, timing, and response to treatment. The causes of death were recorded.
Immunosuppressive Protocol The first 20 patients received two 20-mg doses of alemtuzumab intravenously; the first dose was given within 2 hours of transplantation, and the second was administered 24 hours later. Subsequent patients received a single dose of 30 mg alemtuzumab before surgery, due to a revised protocol based on new data showing equivalent efficacy of two doses of 20 mg and a single dose of 30 mg alemtuzumab administration, in addition to economic issues. The patients received methylprednisolone (500 mg IV), paracetamol (300 mg IV), and diphenhydramine (50 mg IV) before the alemtuzumab dose. For recipients of grafts from living kidney donors, tacrolimus was started at 0.05 to 0.07 mg/kg per day in two divided doses within 48 hours after transplant surgery. The tacrolimus dose was adjusted to achieve a 12-hour trough of 7 to 10 ng/mL for the first 6 months posttransplant and 5 to 7 ng/mL thereafter. For deceased donor recipients with immediate graft function, tacrolimus was given at 0.07 mg/kg per day in two divided doses within 24 hours after the first dose of alemtuzumab. Tacrolimus dose was adjusted to achieve the same trough level as living donor recipients. However, for patients with delayed graft function, mycophenolate was immediately started at 1 g BID and tacrolimus given at 48 hours after the first alemtuzumab dose. Tacrolimus was started at 0.04 mg/kg per day in two divided doses and adjusted to
2223 achieve the same trough level as the living donor recipients once the urine output was ⬎60 mL/hr and/or the serum creatinine was ⱕ3 mg/dL without the need for dialysis. Mycophenolate was discontinued once the target tacrolimus trough level was achieved.
Definition of Terms Delayed graft function (DGF) was a requirement for dialysis within the first week posttransplantation or urine output ⬍60 mL/hr without diuretics Immediate graft function was the production of urine ⱖ100 mL/hr without diuretics. Acute rejection was a ⬎25% rise in serum creatinine from baseline or other graft dysfunction confirmed by histologic findings of rejection on allograft biopsy, or clinical response to methylprednisolone pulse therapy Steroidresponsive acute rejection was a serum creatinine that returned to within 25% of the baseline within 1 week after initiation of treatment for rejection. Steroid-resistant acute rejection was a serum creatinine that continued to increase or failed to return to within 25% of baseline within 1 week after initiation of rejection treatment, or a second rejection episode occurring within 1 month after the initial episode, with apparent initial steroid responsiveness. Graft survival was the presence of renal function adequate to prevent the patient from resuming maintenance dialysis. Graft loss was a return to dialysis owing to a failed graft. Cytomegalovirus (CMV) infection was either CMV antigenemia or a threefold rise in CMV antibody titer with or without persistent fever, pneumonia, hepatitis, gastrointestinal ulceration, or chorioretinitis.
Statistical Analysis Serum creatinine concentrations were reported as mean values (⫹) standard deviations. We computed acute rejection, graft survival, and patient survival rates.
RESULTS
Between September 2005 and February 2007, 47 standardrisk patients underwent the study protocol. These patients showed a mean age of 36.8 ⫾ 11.9 years. They were mostly men and had chronic glomerulonephritis as their native kidney disease (Table 1). Recipients of deceased kidney donors comprised 45% of patients. Fifty-five percent of patients had an HLA mismatch of ⬎3. Most patients had a PRA of 0% to 10%. The mean follow-up time was 12.53 months (range, 6 to 23). At the time of study, all patients were at least 6 months from transplant; 28 patients were at least 12 months and 6 patients, at least 18 months. The mean serum creatinine values were 1.47 ⫾ 0.65 at 3 months, 1.56 ⫾ 0.84 at 6 months, 1.45 ⫾ 0.37 at 12 months, and 1.74 ⫾ 0.35 at 18 months posttransplant. Among the deceased donor renal transplants, eight (36%) showed delayed graft function. The serum creatinine of recipients from deceased vs living donors was comparable at 1 year posttransplantation. The 1-year clinically diagnosed acute rejection rate was 21%; however, the biopsy-proven acute rejection (BPAR) rate was only 14%. The majority of rejection episodes occurred at ⬎6 months posttransplantation. Among the BPAR, all showed pure acute cellular rejections except one
2224
VILLANUEVA, MUÑOZ, CASASOLA ET AL Table 1. Patient Characteristics (N ⴝ 47) Characteristics
Age (yrs, mean ⫾ SD) Gender (male) Follow-up (mos, mean [range]) Nature of kidney disease Chronic glomerulonephritis DM nephropathy Hypertensive nephrosclerosis Polycystic kidney disease Others Type of dialysis Hemodialysis Peritoneal dialysis Preemptive Length of time on RRT before KT (mos) Donor source Living Deceased Cold ischemia time (min) HLA mismatches 0–3 ⬎3 Panel reactive antibody Class 1 Mean 0–10% ⬎10% No data Class 2 Mean 0–10% ⬎10% No data
n
%
33
36.8 ⫾ 11.9 70 12.53 (6–23)
33 7 3 1 3
71 15 6 2 6
38 5 4 17.422 25 22 850.727
80 11 9 ⫾15.8 53 47 ⫾774
20 27
43 57
3.69 44 4 1
⫾5.77 90 8 2
3.19 46 2 1
⫾4.56 94 4 2
Abbreviations: DM, diabetes mellitus; HLA, human leukocyte antigen; KT, kidney transplantation; RRT, renal replacement therapy; SD, standard deviation.
who had concomitant acute humoral rejection. Most patients with cellular rejection had Banff grade ⱖ IIA and half responded to steroid pulses (Table 2). Among the four patients who had rejection, only one was due to medication nonadherence. No “lymphocyte-sparse” or monocytemediated rejection (CD68 stain) was noted. The 6-month and 1-year patient survival rates were 91.5% and 90%, respectively. All deaths were related to infection (pneumonia and CMV infection) with the majority occurring after-steroid pulse therapy. The 6-month and 1-year death-censored graft survival rates were 98%. Graft loss was owing to humoral rejection despite plasmapheresis and rituximab treatment. DISCUSSION
Our Institute was part of a pilot study of alemtuzumab in Asia (CampAsia).9 The study that followed used alemtuzumab induction with tacrolimus/cyclosporine monotherapy in moderate immunologic risk primary renal transplants. A historical control group used interleukin-2 receptor antagonists as induction followed by a triple
immunosuppressive regimen. This study showed satisfactory renal graft function at 6 months with creatinine clearances of 59 ⫾ 26 mL/min, an acute rejection rate of 18%, and patient and graft survivals both at 96%.15 Because of these promising results, we explored an immunosuppressive protocol using alemtuzumab with low-dose tacrolimus. This present study followed a cohort of patients with standard immunologic risk who were given alemtuzumab induction and low-dose tacrolimus monotherapy. Although we were not able to determine the creatinine clearances, the serum creatinine remained acceptable at 18 months from transplant. The 1-year serum creatinine level was comparable with the studies of Kaufman et al14 and Cianco et al,6 both of whom used tacrolimus and mycophenolate dual therapy. In studies using tacrolimus monotherapy maintenance immunosuppression, our results were a little better than those of Knechtle et al1 (1-year creatinine 1.8 ⫾ 0.8), or of Shapiro et al12 (1-year creatinine 1.59 ⫾ 0.75). The 1-year acute rejection rate in our study was high if clinical rejection is included; however, only 14.6% were BPARs, which was comparable with the study by Kaufmann et al14 using dual therapy with tacrolimus and mycophenolate. The high rate of late rejection (⬎6 months) may reflect inadequate maintenance immunosuppression during lymphocyte repopulation. The effective tacrolimus trough level to prevent rejection should be explored. There were six mortalities in this study. The majority died from infections after treatment of acute rejection. This observation suggested to us that alemtuzumab alone does not cause severe immunosuppression to produce mortality in the first 6 months after transplantation. However, the addition of methylprednisolone as treatment for rejection causes severe, life-threatening infection in these patients. Thus, a biopsy should be done to confirm rejection and lower doses of steroid pulsing may be recommended for treatment. In conclusion, alemtuzumab induction with steroid-free, low-dose tacrolimus monotherapy is an acceptable option for primary renal transplant patients with standard immuTable 2. One-Year Acute Rejection Episodes (N ⴝ 28)
Clinically diagnosed acute rejection episodes At 0–3 mos At 4–6 mos At ⬎6 mos Biopsy-proven acute rejection ACR AHR Banff grade for ACR ⬍IIA ⱖIIA Response to steroid pulsing Complete Partial None
n
Percent
6 2 1 3 4 4 1
21 33 17 50 14 100 25
1 3
25 75
3 2 1
50 33 17
Abbreviations: ACR, acute cellular rejection; AHR, acute humoral rejection.
ALEMTUZUMAB INDUCTION
nologic risk. BPAR was 14%, but renal function remained good at 18 months posttransplantation. REFERENCES 1. Knechtle SJ, Fernandez LA, Pirsch JD, et al: Campath-1H in renal transplantation: the University of Wisconsin experience. Surgery 136:754, 2004 2. Hale G: CD52 antigen as target for immunotherapy. Transplant Rev 17(suppl):S8, 2003 3. Bindon Cl, Hale G, Waldmann H: Importance of antigen specificity for complement-mediated lysis by monoclonal antibodies. Eur J Immunol 18:1507, 1988 4. Kirk AD, Hale DA, Mannon RB, et al: Results from a human renal allograft tolerance trial evaluating the humanized CD52specific monoclonal antibody alemtuzumab (campath-1H). Transplantation 76:120, 2003 5. Tzakis AG, Tryphonopouos P, Kato T, et al: Preliminary experience with alemtuzumab (campath-1H) and low dose tacrolimus immunosuppression in adult liver transplantation. Transplantation 77:1209, 2004 6. Ciancio G, Burke GW, Gaynor JJ, et al: The use of campath1H as induction therapy in renal transplantation: preliminary results. Transplantation 78:426, 2004 7. Watson CJ, Bradley JA, Firth J, et al: Campath-1H (alemtuzumab) in renal transplantation: 5 year comparative follow-up. Am J Transplant 4:404, 2004
2225 8. Watson CJ, Bradley JA, Friend PJ, et al: Alemtuzumab (campath-1H) induction therapy in cadaveric kidney transplantation— efficacy and safety at 5 years. Am J Transplant 5:1347, 2005 9. Vathsala A, Ona ET, Tan SY, et al: CampAsia: a pilot randomized controlled trial of the effectiveness of campath-1H (MabCampath) as an induction agent for prevention of graft rejection and preservation of renal function in patients receiving kidney transplants. Am J Transplant 4:406, 2004 10. Cianco G, Burke GW, Gaynor JJ, et al: A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 80:457, 2005 11. Tan H, Kaczorowski D, Basu A, et al: Steroid-free tacrolimus monotherapy after pretransplantation thymob\globulin or campath-1H, and laparoscopy in living donor renal transplantation. Transplant Proc 37:4235, 2005 12. Shapiro R, Ellis D, Tan HP, et al: Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediat 148:813, 2006 13. Thomas PG, Woodside KJ, Lappin JA, et al: Alemtuzumab (campath-1H induction with tacrolimus monotherapy is safe for high immunological risk renal transplantation. Transplantation 83:1509, 2007 14. Kauffmann DB, Leventhal JR, Axelrod D, et al: Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction-long term results. Am J Transplant 5:2539, 2005
L
YMPHOCYTE DEPLETION at the time of transplantation facilitates graft acceptance and prevents kidney transplant rejection.1 Alemtuzumab is being increasingly used as induction therapy for kidney transplantation, because of its powerful lymphocyte-depleting property. This humanized monoclonal antibody is directed against CD52 antigens located on T and B lymphocytes, natural killer cells, but less densely, on monocytes and macrophages.2,3 It has shown promise in tolerogenic induction protocols requiring minimal maintenance immunosuppression, such as steroid-free regimens with low doses of a calcineurin inhibitor (Ona et al, unpublished data, NKT1 proceedings, 2006).4 –14 This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients.
METHODS Study Design This single-center, retrospective study of primary renal transplant recipients at standard immunologic risk utilized alemtuzumab induction therapy and low-dose tacrolimus as the maintenance immunosuppressive regimen. The protocol was approved by the institution’s ethics committee. All patients were informed that alemtuzumab was not approved by the Bureau of Food and Drugs for use in kidney transplantation and that its use would be in a pilot
From the National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr Marlene E. Villanueva, National Kidney and Transplant Institute, East Avenue, Quezon City, Philippines. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.037
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2222
Transplantation Proceedings, 40, 2222–2225 (2008)
ALEMTUZUMAB INDUCTION study fashion and “off label”. All patients were informed that the recommendation to use alemtuzumab for their transplant was based on physicians’ judgment and not part of an investigation. All participating patients gave written informed consent after a full explanation of the treatment options, including the conventional methods of treatment. The right of the patient to refuse to participate without giving reasons was respected. The patient remained free to withdraw from the protocol treatment at any time without giving reasons and without prejudicing further treatment.
Inclusion Criteria Patients aged 16 to 65 years who were primary transplant recipients from living or deceased donors, had a panel reactive antibody (PRA) ⬎10% but ⬍50% were included.
Exclusion Criteria We excluded patients with a positive T-cell cross-match, who were pregnant or nursing women, or showed active systemic infection, or received multiple organ transplants, or were positive for the hepatitis B surface antigen and/or anti-hepatitis C antibody, from the study.
Population Data were collected for renal transplants performed between September 2005 and February 2007. We reviewed patient charts and the hospital computer database for demographic data, nature of kidney disease, donor source, number of HLA mismatches, and PRA level. Serum creatinine levels were noted at week 1, as well as months 3, 6, and 18. Episodes of elevated creatinine were noted and biopsy findings were reviewed. If acute rejection was noted, data were collected on the type and Banff grade, timing, and response to treatment. The causes of death were recorded.
Immunosuppressive Protocol The first 20 patients received two 20-mg doses of alemtuzumab intravenously; the first dose was given within 2 hours of transplantation, and the second was administered 24 hours later. Subsequent patients received a single dose of 30 mg alemtuzumab before surgery, due to a revised protocol based on new data showing equivalent efficacy of two doses of 20 mg and a single dose of 30 mg alemtuzumab administration, in addition to economic issues. The patients received methylprednisolone (500 mg IV), paracetamol (300 mg IV), and diphenhydramine (50 mg IV) before the alemtuzumab dose. For recipients of grafts from living kidney donors, tacrolimus was started at 0.05 to 0.07 mg/kg per day in two divided doses within 48 hours after transplant surgery. The tacrolimus dose was adjusted to achieve a 12-hour trough of 7 to 10 ng/mL for the first 6 months posttransplant and 5 to 7 ng/mL thereafter. For deceased donor recipients with immediate graft function, tacrolimus was given at 0.07 mg/kg per day in two divided doses within 24 hours after the first dose of alemtuzumab. Tacrolimus dose was adjusted to achieve the same trough level as living donor recipients. However, for patients with delayed graft function, mycophenolate was immediately started at 1 g BID and tacrolimus given at 48 hours after the first alemtuzumab dose. Tacrolimus was started at 0.04 mg/kg per day in two divided doses and adjusted to
2223 achieve the same trough level as the living donor recipients once the urine output was ⬎60 mL/hr and/or the serum creatinine was ⱕ3 mg/dL without the need for dialysis. Mycophenolate was discontinued once the target tacrolimus trough level was achieved.
Definition of Terms Delayed graft function (DGF) was a requirement for dialysis within the first week posttransplantation or urine output ⬍60 mL/hr without diuretics Immediate graft function was the production of urine ⱖ100 mL/hr without diuretics. Acute rejection was a ⬎25% rise in serum creatinine from baseline or other graft dysfunction confirmed by histologic findings of rejection on allograft biopsy, or clinical response to methylprednisolone pulse therapy Steroidresponsive acute rejection was a serum creatinine that returned to within 25% of the baseline within 1 week after initiation of treatment for rejection. Steroid-resistant acute rejection was a serum creatinine that continued to increase or failed to return to within 25% of baseline within 1 week after initiation of rejection treatment, or a second rejection episode occurring within 1 month after the initial episode, with apparent initial steroid responsiveness. Graft survival was the presence of renal function adequate to prevent the patient from resuming maintenance dialysis. Graft loss was a return to dialysis owing to a failed graft. Cytomegalovirus (CMV) infection was either CMV antigenemia or a threefold rise in CMV antibody titer with or without persistent fever, pneumonia, hepatitis, gastrointestinal ulceration, or chorioretinitis.
Statistical Analysis Serum creatinine concentrations were reported as mean values (⫹) standard deviations. We computed acute rejection, graft survival, and patient survival rates.
RESULTS
Between September 2005 and February 2007, 47 standardrisk patients underwent the study protocol. These patients showed a mean age of 36.8 ⫾ 11.9 years. They were mostly men and had chronic glomerulonephritis as their native kidney disease (Table 1). Recipients of deceased kidney donors comprised 45% of patients. Fifty-five percent of patients had an HLA mismatch of ⬎3. Most patients had a PRA of 0% to 10%. The mean follow-up time was 12.53 months (range, 6 to 23). At the time of study, all patients were at least 6 months from transplant; 28 patients were at least 12 months and 6 patients, at least 18 months. The mean serum creatinine values were 1.47 ⫾ 0.65 at 3 months, 1.56 ⫾ 0.84 at 6 months, 1.45 ⫾ 0.37 at 12 months, and 1.74 ⫾ 0.35 at 18 months posttransplant. Among the deceased donor renal transplants, eight (36%) showed delayed graft function. The serum creatinine of recipients from deceased vs living donors was comparable at 1 year posttransplantation. The 1-year clinically diagnosed acute rejection rate was 21%; however, the biopsy-proven acute rejection (BPAR) rate was only 14%. The majority of rejection episodes occurred at ⬎6 months posttransplantation. Among the BPAR, all showed pure acute cellular rejections except one
2224
VILLANUEVA, MUÑOZ, CASASOLA ET AL Table 1. Patient Characteristics (N ⴝ 47) Characteristics
Age (yrs, mean ⫾ SD) Gender (male) Follow-up (mos, mean [range]) Nature of kidney disease Chronic glomerulonephritis DM nephropathy Hypertensive nephrosclerosis Polycystic kidney disease Others Type of dialysis Hemodialysis Peritoneal dialysis Preemptive Length of time on RRT before KT (mos) Donor source Living Deceased Cold ischemia time (min) HLA mismatches 0–3 ⬎3 Panel reactive antibody Class 1 Mean 0–10% ⬎10% No data Class 2 Mean 0–10% ⬎10% No data
n
%
33
36.8 ⫾ 11.9 70 12.53 (6–23)
33 7 3 1 3
71 15 6 2 6
38 5 4 17.422 25 22 850.727
80 11 9 ⫾15.8 53 47 ⫾774
20 27
43 57
3.69 44 4 1
⫾5.77 90 8 2
3.19 46 2 1
⫾4.56 94 4 2
Abbreviations: DM, diabetes mellitus; HLA, human leukocyte antigen; KT, kidney transplantation; RRT, renal replacement therapy; SD, standard deviation.
who had concomitant acute humoral rejection. Most patients with cellular rejection had Banff grade ⱖ IIA and half responded to steroid pulses (Table 2). Among the four patients who had rejection, only one was due to medication nonadherence. No “lymphocyte-sparse” or monocytemediated rejection (CD68 stain) was noted. The 6-month and 1-year patient survival rates were 91.5% and 90%, respectively. All deaths were related to infection (pneumonia and CMV infection) with the majority occurring after-steroid pulse therapy. The 6-month and 1-year death-censored graft survival rates were 98%. Graft loss was owing to humoral rejection despite plasmapheresis and rituximab treatment. DISCUSSION
Our Institute was part of a pilot study of alemtuzumab in Asia (CampAsia).9 The study that followed used alemtuzumab induction with tacrolimus/cyclosporine monotherapy in moderate immunologic risk primary renal transplants. A historical control group used interleukin-2 receptor antagonists as induction followed by a triple
immunosuppressive regimen. This study showed satisfactory renal graft function at 6 months with creatinine clearances of 59 ⫾ 26 mL/min, an acute rejection rate of 18%, and patient and graft survivals both at 96%.15 Because of these promising results, we explored an immunosuppressive protocol using alemtuzumab with low-dose tacrolimus. This present study followed a cohort of patients with standard immunologic risk who were given alemtuzumab induction and low-dose tacrolimus monotherapy. Although we were not able to determine the creatinine clearances, the serum creatinine remained acceptable at 18 months from transplant. The 1-year serum creatinine level was comparable with the studies of Kaufman et al14 and Cianco et al,6 both of whom used tacrolimus and mycophenolate dual therapy. In studies using tacrolimus monotherapy maintenance immunosuppression, our results were a little better than those of Knechtle et al1 (1-year creatinine 1.8 ⫾ 0.8), or of Shapiro et al12 (1-year creatinine 1.59 ⫾ 0.75). The 1-year acute rejection rate in our study was high if clinical rejection is included; however, only 14.6% were BPARs, which was comparable with the study by Kaufmann et al14 using dual therapy with tacrolimus and mycophenolate. The high rate of late rejection (⬎6 months) may reflect inadequate maintenance immunosuppression during lymphocyte repopulation. The effective tacrolimus trough level to prevent rejection should be explored. There were six mortalities in this study. The majority died from infections after treatment of acute rejection. This observation suggested to us that alemtuzumab alone does not cause severe immunosuppression to produce mortality in the first 6 months after transplantation. However, the addition of methylprednisolone as treatment for rejection causes severe, life-threatening infection in these patients. Thus, a biopsy should be done to confirm rejection and lower doses of steroid pulsing may be recommended for treatment. In conclusion, alemtuzumab induction with steroid-free, low-dose tacrolimus monotherapy is an acceptable option for primary renal transplant patients with standard immuTable 2. One-Year Acute Rejection Episodes (N ⴝ 28)
Clinically diagnosed acute rejection episodes At 0–3 mos At 4–6 mos At ⬎6 mos Biopsy-proven acute rejection ACR AHR Banff grade for ACR ⬍IIA ⱖIIA Response to steroid pulsing Complete Partial None
n
Percent
6 2 1 3 4 4 1
21 33 17 50 14 100 25
1 3
25 75
3 2 1
50 33 17
Abbreviations: ACR, acute cellular rejection; AHR, acute humoral rejection.
ALEMTUZUMAB INDUCTION
nologic risk. BPAR was 14%, but renal function remained good at 18 months posttransplantation. REFERENCES 1. Knechtle SJ, Fernandez LA, Pirsch JD, et al: Campath-1H in renal transplantation: the University of Wisconsin experience. Surgery 136:754, 2004 2. Hale G: CD52 antigen as target for immunotherapy. Transplant Rev 17(suppl):S8, 2003 3. Bindon Cl, Hale G, Waldmann H: Importance of antigen specificity for complement-mediated lysis by monoclonal antibodies. Eur J Immunol 18:1507, 1988 4. Kirk AD, Hale DA, Mannon RB, et al: Results from a human renal allograft tolerance trial evaluating the humanized CD52specific monoclonal antibody alemtuzumab (campath-1H). Transplantation 76:120, 2003 5. Tzakis AG, Tryphonopouos P, Kato T, et al: Preliminary experience with alemtuzumab (campath-1H) and low dose tacrolimus immunosuppression in adult liver transplantation. Transplantation 77:1209, 2004 6. Ciancio G, Burke GW, Gaynor JJ, et al: The use of campath1H as induction therapy in renal transplantation: preliminary results. Transplantation 78:426, 2004 7. Watson CJ, Bradley JA, Firth J, et al: Campath-1H (alemtuzumab) in renal transplantation: 5 year comparative follow-up. Am J Transplant 4:404, 2004
2225 8. Watson CJ, Bradley JA, Friend PJ, et al: Alemtuzumab (campath-1H) induction therapy in cadaveric kidney transplantation— efficacy and safety at 5 years. Am J Transplant 5:1347, 2005 9. Vathsala A, Ona ET, Tan SY, et al: CampAsia: a pilot randomized controlled trial of the effectiveness of campath-1H (MabCampath) as an induction agent for prevention of graft rejection and preservation of renal function in patients receiving kidney transplants. Am J Transplant 4:406, 2004 10. Cianco G, Burke GW, Gaynor JJ, et al: A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 80:457, 2005 11. Tan H, Kaczorowski D, Basu A, et al: Steroid-free tacrolimus monotherapy after pretransplantation thymob\globulin or campath-1H, and laparoscopy in living donor renal transplantation. Transplant Proc 37:4235, 2005 12. Shapiro R, Ellis D, Tan HP, et al: Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediat 148:813, 2006 13. Thomas PG, Woodside KJ, Lappin JA, et al: Alemtuzumab (campath-1H induction with tacrolimus monotherapy is safe for high immunological risk renal transplantation. Transplantation 83:1509, 2007 14. Kauffmann DB, Leventhal JR, Axelrod D, et al: Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction-long term results. Am J Transplant 5:2539, 2005