Alemtuzumab and Tacrolimus Monotherapy After Renal Transplantation

[okarol]

Alemtuzumab and Tacrolimus Monotherapy After Renal Transplantation

Robert J. Stratta, MD

Medscape Transplantation.  2008; ©2008 Medscape
Posted 08/14/2008
Alemtuzumab (Campath-1H) and Tacrolimus Monotherapy After Renal Transplantation: Results of a Prospective Randomized Trial

Margreiter R, Klempnauer J, Neuhaus P, Muehlbacher F, Boesmueller C, Calne RY
Am J Transplant. 2008;8:1480-1485

From January 2004 through June 2005, the authors performed a prospective trial at 4 European transplant centers and randomized 131 primary adult deceased-donor kidney transplant recipients to either alemtuzumab induction (n = 65, 20 mg intravenous on day 0 and day 1 with methylprednisolone 250 mg intravenous with each dose) followed by tacrolimus (TAC) monotherapy vs a control group receiving no antibody induction with triple therapy (n = 66) consisting of TAC, mycophenolate mofetil (MMF), and corticosteroids. Retransplant and multiorgan transplant recipients, and patients with a panel reactive antibody level > 25% or any crossmatch positivity, were excluded. For patients receiving alemtuzumab, no immunosuppression was given on day 2 and TAC was started on day 3 with target levels of 8-12 ng/mL for the first 6 months and 5-8 ng/mL thereafter. For patients not receiving any antibody induction, TAC was begun either preoperatively or immediately post transplantation with the same target levels as above. In addition, these patients received MMF 1-1.5 g twice daily with dose adjustments based on toxicity and corticosteroids according to local standards, with a stepwise reduction to 20-25 mg/day prednisone by day 10 and 5 mg/day at 1 year.

The alemtuzumab group included more female recipients (P =.04) and somewhat older donors (P =.06), but had better human leukocyte antigen matching (P =.06) compared with the triple-therapy control group. The 6-month rate of biopsy-proven acute rejection (BPAR), which was the primary endpoint for the study, was 15% in the alemtuzumab group and 29% (P =.05) in the control group. At 12 months, the rates of BPAR were 20% in the alemtuzumab group and 32% (P =.09) in the control group. Time to first BPAR was 4.9 months in the alemtuzumab group and 0.4 months in the control group. The control group also had more grade II (Banff criteria) rejection episodes (7 vs 1), whereas Banff I (10 vs 11) and III (1 in each group) rejection episodes were evenly distributed between the 2 groups. Patient survival and renal function were similar between groups. One-year kidney graft survival rates were 96% and 90% in the alemtuzumab and control groups, respectively (hazard ratio = 0.33). At 1 year, 71% of patients in the alemtuzumab group were on TAC monotherapy (82% were corticosteroid-free), whereas 74% of patients in the control group remained on their initial immunosuppressive regimen. Adverse events were similar, although the incidence of cytomegalovirus (CMV) infection (28% in alemtuzumab group vs 12% in control group, relative risk =2.28) was higher with alemtuzumab. However, none of the alemtuzumab patients developed tissue-invasive CMV disease compared with 3 patients in the study group. Two cases of polyomavirus nephropathy occurred in the alemtuzumab group compared with 1 in the control group. On the basis of these results, the authors concluded that alemtuzumab induction followed by TAC monotherapy is at least as effective short-term as a TAC/MMF-based triple-drug regimen without antibody induction in low-risk kidney transplant recipients.

Viewpoint

Immunosuppressive regimens strive to achieve effective control of rejection while minimizing injury to the allograft, specific drug toxicities, and risks to the patient. Immunosuppressive strategies are generally employed in 3 clinical settings: (1) induction, primary, or consolidation therapy; (2) maintenance or chronic therapy; and (3) treatment of rejection. Calcineurin inhibitors (cyclosporine and TAC) have been the cornerstone of maintenance immunosuppression for over 20 years. Strategies for induction therapy consist of using either relatively high doses of conventional immunosuppressive agents or biologic agents such as polyclonal or monoclonal antibodies in combination with lower doses of conventional immunosuppressants. The major strategy for maintenance therapy has been to employ multiple agents (usually double or triple therapy) with differing mechanisms of action at lower individual dosages to achieve adequate cumulative immunosuppression, while minimizing specific drug toxicities. However, adverse effects associated with conventional immunosuppressants, even at relatively low dosages, have fueled the quest for new agents or regimens that minimize toxicities and maximize efficacy.

Alemtuzumab is a humanized monoclonal antibody directed against the CD52 cell surface receptor that is expressed on most T and B lymphocytes, eosinophils, and on some populations of monocytes, macrophages, and dendritic cells. Alemtuzumab has been shown to be a powerful depleting antibody that appears to confer long-lasting immunosuppression. At present, TAC appears to be the single most effective maintenance immunosuppressive agent in solid organ transplantation. Single-center nonrandomized retrospective studies have suggested that depleting antibody induction and TAC monotherapy (with or without subsequent "spaced weaning" of tacrolimus) may be a safe and effective regimen in selected patients.

The above study is the first multicenter, prospective, randomized trial to compare alemtuzumab induction plus tacrolimus monotherapy with conventional triple induction plus maintenance therapy in low-risk kidney transplant recipients. The control arm of this study would generally be considered to be the "standard of care" with respect to maintenance immunosuppression in renal transplantation, although the absence of antibody induction in the control group probably accounts for the differences reported in the incidence, timing, and perhaps severity of BPAR episodes in the 2 groups. This limitation in study design notwithstanding, the above preliminary results are impressive and certainly suggest that TAC monotherapy is feasible in selected kidney transplant recipients. Whether this novel and bold protocol is applicable to higher-immunologic-risk subgroups (ie, black patients, retransplants, highly-sensitized patients, positive crossmatch) is a matter of conjecture. Moreover, long-term data on patients receiving TAC monotherapy, particularly in regard to chronic allograft nephropathy, are needed before widespread application of this innovative protocol should be considered.

Abstract

Robert J. Stratta, MD, Professor of Surgery, Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Director of Transplantation, North Carolina Baptist Hospital, Winston-Salem, North Carolina

Disclosure: Robert J. Stratta, MD, has disclosed that he has received grants for clinical research from Astellas, Wyeth, Novartis, and Roche. Dr. Stratta has also disclosed that he has received grants for educational activities from Astellas, Genzyme, Wyeth, Novartis, and Roche, and that he has served as an advisor or consultant to Astellas, Genzyme, Novartis, and Roche.

http://www.medscape.com/viewarticle/578052

[Chris]

Gonna need to look up a couple words used in this one. Some words just make me go    What does that mean.

[pelagia]

This one took me awhile, but here is my "translation" of what it says.  I have to do this with challenging material otherwise I can't make heads or tails of what they are saying:

1. This is Dr. Stratta's synopsis and critique of a paper published by Margrieter et al. 2008.

2. The study by Margrieter and colleagues compares two groups of transplant recipients - they all received deceased donor kidneys and were similar in other ways (e.g. 1st transplant).

3. The first group received a monoclonal antibody (Alemtuzumab - helps to keep the body from making antibodies) + methylprednisolone (a intravenous prednisone type drug) on days 0 and 1.  After that they were given only tacrolimus (prograf, abbreviated as TAC).  The second group had a more traditional therapy of tacrolimus, mycophenolate mofetil (cellcept, abbreviated as MMF) and corticosteroids (e.g. prednisone).

4.The 6-month rate of biopsy-proven acute rejection (BPAR), which was the primary endpoint for the study, was 15% in Group 1 and almost double (29%) in Group 2.  That difference was significant.  At 12 months, the rates of BPAR were 20% in the Group 1 and 32% in Group 2, but the difference was less significant with the statistical test they used.

5. Adverse events were similar, although the incidence of cytomegalovirus (CMV) infection was higher in Group 1 (28%) relative to Group 2 (12%). However, none of the Group 1 patients developed tissue-invasive CMV disease compared with 3 patients in the Group 2.

Some of the highlights of what Dr. Stratta says about the use of new approaches and this particular study are quite interesting:

"Immunosuppressive regimens strive to achieve effective control of rejection while minimizing injury to the allograft, specific drug toxicities, and risks to the patient.

Immunosuppressive strategies are generally employed in 3 clinical settings:
(1) induction, primary, or consolidation therapy;
(2) maintenance or chronic therapy; and
(3) treatment of rejection.

Calcineurin inhibitors (cyclosporine and TAC) have been the cornerstone of maintenance immunosuppression for over 20 years.

Strategies for induction therapy consist of using either relatively high doses of conventional immunosuppressive agents or biologic agents such as polyclonal or monoclonal antibodies in combination with lower doses of conventional immunosuppressants.

The major strategy for maintenance therapy has been to employ multiple agents (usually double or triple therapy) with differing mechanisms of action at lower individual dosages to achieve adequate cumulative immunosuppression, while minimizing specific drug toxicities. However, adverse effects associated with conventional immunosuppressants, even at relatively low dosages, have fueled the quest for new agents or regimens that minimize toxicities and maximize efficacy."

He basically concludes that "the above preliminary results are impressive and certainly suggest that TAC monotherapy is feasible in selected kidney transplant recipients."

Thanks for posting this Okarol.  I was quite interested because my husband received Zenapax (similar to Alemtuzumab) on Day 0 (transplant day) and did not receive prograf until the end of Day 2, although he did receive cellcept on Day 0.  He is getting what Stratta characterizes as a "the standard or care" now - with a regime of prograf, cellcept and prednisone.  The part about CMV is a little troublesome, however, as my husband is just a few days from going off Valcyte!

[Chris]

Well I was going to look this up later to better understand it, but thanks pelagia.