Anti-thymocyte globulin (Thymoglobuline) for renal transplant rejection and aplastic anaemia. Australian Prescriber review

From Australian Prescriber:

Anti-thymocyte globulin

Thymoglobuline (Genzyme)
vials containing 25 mg freeze-dried powder
Approved indication: renal transplant rejection and aplastic anaemia
Australian Medicines Handbook section 14.5.3

Anti-thymocyte globulin is indicated for the prophylaxis of renal graft rejection as well as the treatment of steroid-resistant renal transplant rejection. Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. However, 15−35% of transplant recipients will experience one episode of acute rejection in the first year. Giving antibody to deplete thymocytes (T cells) is one way to suppress the immune system to prevent or reverse graft rejection.

Anti-thymocyte globulin is a polyclonal antibody against human T cells. It is a gamma immunoglobulin produced by immunising rabbits. As well as depleting T cells in the circulation, anti-thymocyte globulin is also thought to reduce T cell proliferation, homing and cytotoxic effects within the body. Depletion of T cells occurs within a day of starting intravenous treatment.

This immunoglobulin has been compared to other treatments in renal transplant patients who are also receiving other immunosuppressant drugs. In a randomised trial of 72 patients, anti-thymocyte globulin was more effective at preventing acute rejection during the first year after transplantation than a similar polyclonal antibody derived from horses (4% vs 25% patients had acute rejection).1 Five years after surgery, patient survival was similar for both treatments, but graft survival was significantly better in patients treated with anti-thymocyte globulin (77%) compared to those treated with the horse antibody (54%).2

The rabbit polyclonal has also been compared to basiliximab (an antibody directed towards the interleukin-2 receptor) for the prevention of acute rejection in 278 renal transplant patients. Although there was a lower incidence of biopsy-proven acute rejection with anti-thymocyte globulin compared to basiliximab (16% vs 26% of patients), approximately half of the patients in both groups had acute rejection, delayed graft function, graft loss or had died after one year.3

In another trial, the rabbit antibody was found to be as effective as a horse antibody at reversing acute rejection episodes (return of serum creatinine to baseline levels). After one year, there was no significant difference in overall graft survival between the two treatments (83% vs 75% of patients). Response to treatment depended on the severity of the initial rejection episode.4

Anti-thymocyte globulin is also indicated for refractory or relapsing aplastic anaemia. This is an autoimmune disease resulting from the destruction of pluripotent stem cells in the bone marrow. Depletion of these stem cells reduces the number of red and white blood cells and platelets. Anti-thymocyte globulin is thought to benefit these patients by preventing activation and clonal expansion of cytotoxic T cells which are involved in mediating the disease.

The approval of anti-thymocyte globulin for the treatment of aplastic anaemia is based on an uncontrolled trial of 30 adults and children who had not responded to a course of immunosuppressive therapy (which included a horse anti-lymphocyte antibody). These patients were given a second course of treatment consisting of rabbit anti-thymocyte globulin for 1−5 days plus cyclosporin for 1−180 days and in addition most received granulocyte colony stimulating factor for 1−90 days. After a median of 95 days, 23 of the 30 patients had responded to treatment, which was defined as transfusion not required for at least one month. (Women were less likely to respond than men.) After two and a half years, 93% of the patients were still alive. One patient had died early during treatment from sepsis.5

Following intravenous administration of this drug, fever, chills, dyspnoea, nausea, diarrhoea, changes in blood pressure, malaise, rash and headache consistent with cytokine release syndrome have been reported. Anaphylaxis has also occurred. Reducing the infusion rate may help to reduce the incidence and severity of these adverse events. Premedication with paracetamol, corticosteroids and/or antihistamines is also recommended. This antibody is contraindicated in patients with hypersensitivity to rabbit proteins.

Leucopenia and thrombocytopenia are common with anti-thymocyte globulin treatment but can be reversed by decreasing the dose. White blood cell and platelet counts should be monitored. Not surprisingly, infections or reactivation of infections (such as cytomegalovirus) are very common so careful patient monitoring and appropriate prophylaxis are recommended. Immunisation with live vaccines should be avoided. In one of the trials, 19% of patients developed acne.1

Some patients have developed cancer, in particular lymphoma and post-transplant lymphoproliferative disease, after receiving anti-thymocyte globulin as part of their immunosuppression therapy.

Around two-thirds of renal transplant patients developed anti-rabbit antibodies to the anti-thymocyte globulin. It is not clear if these antibodies would affect the efficacy of this drug if it is used again. Monitoring the patient’s T cell count to ensure depletion is recommended for all patients receiving treatment.

This polyclonal antibody seems to be effective in preventing or reversing rejection in renal transplant patients when given with other drugs to induce immunosuppression. Patients with aplastic anaemia may also benefit from this drug. However, because of the profound depletion in T cells, patients must be monitored closely for serious adverse events.

manufacturer provided clinical evaluation

References

Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, et al. A randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 1999;67:1011-18.
Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, Koch MJ, et al. Five-year follow up of thymoglobulin versus Atgam induction in adult renal transplantation. Transplantation 2004;78:136-41.
Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D; Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-77
Gaber AO, First MR, Tesi RJ, Gaston RS, Mendez R, Mulloy LL, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998;66:29-37.
Di Bona E, Rodeghiero F, Bruno B, Gabbas A, Foa P, Locasciulli A, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Br J Haematol 1999;107:330-4.

Source. Aust Prescr 2008;31:136-9

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