Costimulation Blockade with Belatacept in Renal Transplantation
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The recent trial of belatacept in renal transplantation (Aug. 25 issue)1 reveals three cases of post-transplantation lymphoproliferative disorder. Two of the patients with the disorder had a primary Epstein–Barr virus (EBV) infection. The promise of belatacept is greater specificity in the suppression of the immune response.2 Theoretically, therefore, the use of belatacept should not prevent the development of primary immunity against EBV if the virus is introduced in patients with an allograft. It would be interesting to know from the authors whether the primary infection in these two patients was secondary to an EBV seromismatch at transplantation or was subsequently acquired in the community. The simultaneous use of basiliximab, mycophenolate mofetil, and glucocorticoids with belatacept may have been counterproductive, since these are nonselective immunosuppressive agents that could have hindered the development of primary immunity to EBV. Basiliximab, which was initially touted as being selective for activated T cells, may also increase the risk of post-transplantation lymphoproliferative disorder.3 The true value of belatacept in relation to this disorder may thus be evident only in trials that do not incorporate the use of nonselective immunosuppressive agents.
Vikas R. Dharnidharka, M.D.
University of Florida College of Medicine
Gainesville, FL 32610
vikasmd@ufl.edu
References
Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770-781.
Ingelfinger JR, Schwartz RS. Immunosuppression -- the promise of specificity. N Engl J Med 2005;353:836-839.
Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4:87-93.
Dr. Vincenti replies: Dr. Dharnidharka makes a valid point about the value of using belatacept without concomitant nonselective immunosuppressive drugs in order to avoid side effects, such as post-transplantation lymphoproliferative disorder, that are related to excessive immunosuppression. However, in the early clinical development of a new drug or biologic agent, it is important to provide a safety net in the form of an effective immunosuppressive regimen (in this case, basiliximab, mycophenolate mofetil, and corticosteroids). The anti–interleukin-2 monoclonal antibodies have not been associated with post-transplantation lymphoproliferative disorder either in phase 3 trials or in large-registry data.1 The two cases of the disorder that were associated with EBV infection in our study occurred in EBV-negative recipients. One case was clearly the result of an EBV seromismatch involving an allograft from a living donor who was retrospectively found to be EBV-positive. The second case probably involved an EBV seromismatch or a primary EBV infection; serologic data from the cadaveric donor were not available. The exact risk, if any, of post-transplantation lymphoproliferative disorder with the use of belatacept will become clearer in the course of the ongoing phase 3 trials. In addition, belatacept will be investigated in a pilot study at the University of California, San Francisco, and Emory University, in collaboration with the Immune Tolerance Network, of monotherapy after withdrawal of sirolimus for the induction of tolerance in recipients of kidneys from living donors.
Flavio Vincenti, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222-230.
Vikas R. Dharnidharka, M.D.
University of Florida College of Medicine
Gainesville, FL 32610
vikasmd@ufl.edu
References
Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770-781.
Ingelfinger JR, Schwartz RS. Immunosuppression -- the promise of specificity. N Engl J Med 2005;353:836-839.
Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4:87-93.
Dr. Vincenti replies: Dr. Dharnidharka makes a valid point about the value of using belatacept without concomitant nonselective immunosuppressive drugs in order to avoid side effects, such as post-transplantation lymphoproliferative disorder, that are related to excessive immunosuppression. However, in the early clinical development of a new drug or biologic agent, it is important to provide a safety net in the form of an effective immunosuppressive regimen (in this case, basiliximab, mycophenolate mofetil, and corticosteroids). The anti–interleukin-2 monoclonal antibodies have not been associated with post-transplantation lymphoproliferative disorder either in phase 3 trials or in large-registry data.1 The two cases of the disorder that were associated with EBV infection in our study occurred in EBV-negative recipients. One case was clearly the result of an EBV seromismatch involving an allograft from a living donor who was retrospectively found to be EBV-positive. The second case probably involved an EBV seromismatch or a primary EBV infection; serologic data from the cadaveric donor were not available. The exact risk, if any, of post-transplantation lymphoproliferative disorder with the use of belatacept will become clearer in the course of the ongoing phase 3 trials. In addition, belatacept will be investigated in a pilot study at the University of California, San Francisco, and Emory University, in collaboration with the Immune Tolerance Network, of monotherapy after withdrawal of sirolimus for the induction of tolerance in recipients of kidneys from living donors.
Flavio Vincenti, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222-230.