Alemtuzumab - Specific Agents Used In Solid Organ Transplant

Alemtuzumab

Recently, alemtuzumab was introduced into solid organ transplantation. Alemtuzumab is a recombinant DNA-derived, humanized, rat IgG1k monoclonal antibody targeting the 21 to 28 kDa cell surface protein glycoprotein CD52, which is produced in a Chinese hamster ovary suspension medium (Genzyme Corporation, 2005; Kneuchtle et al., 2004). Initially, the first anti-CD52 antibodies were developed from rat hybrid antibodies that were produced to lyse lymphocytes in the presence of complement (Morris, 2006). Campath-1M was the first agent developed. This molecule was a rat IgM antibody which produced little biological effect. In contrast, the rat IgG (Campath-1G) produced profound lymphopenia (Morris, 2006). In order to prevent the formation of antibodies against the rat IgG the molecule was humanized and called alemtuzumab or Campath-1H (Morris, 2006). The biologic effects of alemtuzumab are the same as Campath-1G, and include comple-ment-mediated cell lysis, antibody-mediated cytotoxi-city, and target cell apoptosis (Magliocca, 2006). The CD52 receptors accounts for 5% of lymphocytesurface antigens (Morris, 2006). Cells which express the CD52 antigen include T- and B-lymphocytes, natural killer cells, monocytes, and dendritic cells (Genzyme Corporation, 2005; Bloom et al., 2006). Following administration a marked decrease in circulating lymphocytes is observed. Use in the hematology population indicates that this effect is dose-dependent . However, single doses of 30 mg or two doses of 20 mg are currently used in the solid organ transplant population.

The plasma elimination half life after single doses is reported to be around 12 days and the molecule may be removed by post-transplant plasmapheresis  (Magliocca, 2006). The biological activity of alemtuzumab, however, may last up to several months. One in vivo study of kidney transplant recipients aimed to observe the recovery and function of lymphocytes following administration of 40 mg of alemtuzumab (Bloom et al., 2006). Authors reported a 2 Log reduction in peripheral lymphocytes following administration. Absolute lymphocyte counts at 12 months remained marketly depleted, falling below 50% of their original baseline. Monocytes and B-lymphocytes were the first cell lines to recover at 3 to 12 months post-administration. T-lymphocytes re-turned to 50% of their baseline value by 36 months (Bloom et al., 2006).

Currently, alemtuzumab is only FDA approved for the treatment of B-cell chronic lymphocytic leukemia. The first report of alemtuzumab use in solid organ transplantation appeared in 1991. Friend et al. (1991) published a case series on the use of alemtuzumab to reverse acute rejection in renal transplant recipients. Shortly thereafter, Calne et al. (1999) issued the first report of alemtuzumab use as an induction agent. The authors reported the results of 31 consecutive renal transplant recipients. Patients received two 20 mg doses of alemtuzumab, the first dose was given in the operating room and the second dose was given on post-operative day 1. Patients were initiated on low dose cyclosporine monotherapy, with a goal trough range of 75 to 125 ng/mL. Three patients experienced corticosteroid responsive rejection (20%) and were maintained on corticosteroids and azathioprine following rejection. Allografts remained functional in 94% (29/31) of patients at 15 to 28 months post transplant (Calne et al., 1999).

Alemtuzumab is currently being used for induc-tion and for treatment of rejection (Morris, 2006). In a recent review of immunosuppression trends in the United States, alemtuzumab use has markedly increase in the past 3 years, with use primarily limited to induction (Table 2). In 2004, alemtuzumab was the predominant agent used for induction in both pancreas and intestinal transplant recipients (Meier-Kriesche et al., 2006). Use in liver transplant has been limited, buthas appeared in a couple of published trials. Specific findings from these trials indicate that patients without hepatitis C were able to tolerate lower levels of calcineurin inhibitors which corresponded to lower serum creatinine levels at one year post transplant (Tzakis et al., 2004). In contrast, administration of alemtuzumab positively correlated with early recur-rence of hepatitis C viral replication (Marcos et al., 2004). Alemtuzumab induction has allowed for early withdrawal of corticosteroids in several clinical trials, thereby decreasing long-term exposure which has been correlated with an increased incidence of cardiovas-cular disease, endocrine and metabolic side effects. However, early trials in which calcineurin inhibitor avoidance was initiated, the rate of early acute anti-body-mediated rejection was 17% compared to 10% under traditional immunosuppression which included calcineurin inhibitors (Magliocca, 2006).

The infusion of alemtuzumab is well tolerated. In general, induction doses are administered imme-diately preceeding reperfusion of the transplanted allograft. Pre-treatment with corticosteroids, diphen-hydramine and acetaminophen is generally advised to prevent sequelae from cellular apotosis. However, cytokine release associated with alemtuzumab is insignificant in comparison to other agents (Morris, 2006).

Currently, there are few published experiences detailing long-term outcomes in patients who re-ceived alemtuzumab induction (Magliocca, 2006). Initially clinicians were concerned that the profound lymphodepletion that was observed following admin-istration would lead to a significant increase in the number of severe infections. Therefore, lymphocyte response to donor antigens following alemtuzumab administration was also evaluated in vitro (Bloom et al., 2006). Lymphocytes from patients treated with alemtuzumab were able to respond to donor antigens and cytokines. A small subset of patients, however, were hyporesponsive which is similar to the control patients observed in this study (Bloom et al., 2006). In addition, several reports detailing the use of alemtu-zumab thus far suggest that both infection and malignancy rates are minimal when compared to other agents used for the same indication (Morris, 2006; Magliocca, 2006). At present, the most signifi-cant concern associated with alemtuzumab adminis-tration is an increased incidence of autoimmune diseases. The exact incidence and etiology of auto-immune diseases following alemtuzumab administra-tion in solid organ transplant is currently unknown. Initial reports of autoimmune diseases associated with alemtuzumab administration came from the multiple sclerosis population. A single center observed the development of Grave’s disease in 9 out of 27 patients who received alemtuzumab (Coles et al., 1999).

Thyroid function in all patients was normal prior to alemtuzumab and the mean time to development of autoimmune hyperthyroidism was 19 months (range 9 to 31 months) (Coles et al., 1999). Autoimmune hyperthyroidism was first reported in a kidney transplant recipient who received alemtuzumab in-duction 4 years earlier (Kirk et al., 2006). Watson et al. (2005) recently published a 5 years experience with alemtuzumab induction, in which they reported a 6% (2/33) incidence of autoimmune disease development following administration. One patient developed hyperthyroidism in the early post-transplant period and one patient developed hemolytic anemia which was refractory to corticosteroids. With the increased use of alemtuzumab in solid organ transplant the actual risk of autoimmune disease development may be more accurately assessed in the next decade.