Dissociation of Depletional Induction and Posttransplant Lymphoproliferative Disease in Kidney Recipients Treated With Alemtuzumab

Abstract

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B-and T-cell depletion may be more relevant determinants of PTLD risk.

Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

“…The highest risk was limited to EBV-seronegative recipients with the clinical implication that sirolimus should probably be avoided in this population, especially in those who are already at higher risk for PTLD. (Kirk et al, 2007) Nee et al also noted the same higher risk of PTLD with sirolimus, in a retrospective cohort of 53,719 kidney transplant recipients. (Nee et al, 2011) It seems that antimetabolites such as azathioprine and mycophenolate mofetil used primarily as adjunct therapy alongside calcineurin inhibitors for preventing allograft rejection, are associated with a lower or not increased risk of PTLD.…”

“…The use of antibody preparations that deplete T cells has been identified as a risk factor for PTLD in early studies by both univariate and multivariate analyses. ( Faull et al, 2005;Kirk et al, 2007;Opelz & Dohler, 2004;Yang et al, 2008) However, data from multiple transplant registries have demonstrated mixed results regarding a direct association between the use of Thymoglobulin and the risk of developing PTLD. (Marks et al, 2011) Quinlan et al in a retrospective cohort study among 156,740 kidney transplant recipients reported that the use of antibody induction or antirejection therapies was not associated with PTLD risk, even when restricted to T-cell-based therapies, in contrast to earlier reports where there was an association between antibody induction therapy and risk of early onset PTLD.…”

“…Induction with alemtuzumab (anti-CD52 antibody), which depletes both T and B lymphocytes, was also not found to be associated with PTLD. (Caillard et al, 2005;Kirk et al, 2007;Opelz &Dohler, 2004) Shapiro et al reported a small series using alemtuzumab as pre-conditioning with tacrolimus monotherapy in pediatric renal transplantation, with no cases of PTLD after a median time of follow up of 25 months. (Shapiro et al, 2007) There are some controversies regarding the risk with the use of calcineurin inhibitors, which at this point in time continue as the pillars of maintenance regimens.…”

Low Dose Rabbit Anti-Thymocyte Globulin as an Induction immunosuppression in High-Risk Renal Transplant Recipients

“…However, the studies that reported lower incidence of malignancies including PTLD in patients who had induction therapy with rabbit ATG may be blighted by inadequate sample size, non-standardization of doses maintenance immunosuppression and inadequate follow-up period [78][79][80][81][82][83][84][85].…”

No Increased Risk of Posttransplant Lymphoproliferative Disorder Following Alemtuzumab Induction in Kidney Transplant

“…1,2 Most occurrences of PTLD originate from uncontrolled Epstein-Barr virus (EBV) activation, which causes an unregulated transformation and proliferation of nodal and extranodal lymphocytes. 2 Within populations of transplant patients, the disorder usually has an incidence rate that ranges between 1% and 2%; however, it can have a higher incidence in pediatric populations.…”