Transcript Thymoglobulin: An Overview of Its Performance in Clinical

Thymoglobulin: An Overview of Its
Performance in Clinical Trials as an
Agent for the Induction Therapy
Reference: Osama Gaber A, Knight RJ, Patel S,
et al. A review of the evidence for use of
thymoglobulin induction in renal
transplantation. Transplant Proc. 2010;42:1395–
1400.
Introduction
• Prevention of early acute rejection in posttransplantation period can be
achieved through the use of biological agents/monoclonals that deplete T
or B cells or regularize the cellular/antibody response.
• This therapy is termed as an induction therapy. Presently, monoclonal
antibody (IL2RA) blockers and lymphocyte-depleting antibodies are used
in the induction therapy in kidney transplantation.
• Depleting antibodies such as thymoglobulin-activated cytokines, which are
attributed with an increased chance of postinfusion reaction.
• Rabbit antihuman thymocyte globulin (rATG; thymoglobulin) is the most
commonly used agent in the induction therapy, but has yet to be approved
by the Food and Drug Administration (FDA).
• The delay in the approval has become a barrier in the assessment of rATG
in large scale clinical induction trials, and its clinical performance as an
induction therapy agent through registry data, a single-center trial and
randomized trials.
• Osama Gaber et al. in a recent review compiled the various evidences of
rATG for its use as an induction agent in renal transplantation.
Registry Analysis rATG vs. IL2RA vs.
No Antibody Induction
• The safety and the effi cacy results of rATG obtained from
the registry analysis have so far been promising.
• Results have been encouraging particularly in the high
immunological risk and Afro-American renal transplant
recipients.
• One of the analyses carried out by Willoughby et al., report
rATG with signifi cant reduction in the incidence of triple
end point, graft loss and patient death compared to
tacrolimus and mycophenolate mofetil (MMF).
• The authors conclude that from studies carried out so far,
rATG is as safe as IL2RA and provides better outcomes in
high immunological risk patients and in a steroidminimization regimen.
Performance of rATG in Randomized,
Controlled Clinical Trials
Effi cacy of rATG over eATG in Renal Transplant Recipients
• Comparison of rATG and equine antithymocyte globulin (eATG) in relation to safety
and effi cacy was initially carried out in living adults and deceased donor kidney
recipients in a study.
• Patients were randomized to receive rATG or eATG, which was administered
intraoperatively and then up to 6 days.
• Cyclosporine (CysA), azathioprine/ MMF and prednisolone were administered as
maintenance immunosuppressants to patients.
– At 1 year, there was no difference in the groups in terms of survival rates (rATG-98%; eATG-96%).
However, rATG treatment was associated signifi cantly with lesser episodes of acute rejections
(4.2 vs. 25%).
– Higher proportions of incident-free survival were observed with rATG treatment compared to
eATG at the end of 5-year posttransplantation.
– The actual advantages of rATG were observed at the 10- year posttransplantation follow-up.
Compared to eATG, rATG was associated with higher event-free survival (48 vs. 29%) and lower
10-year cumulative acute rejection (11 vs. 42%; see Fig. 1).
– Rabbit antihuman thymocyte globulin was associated with no posttransplant
lymphoproliferative disorder.
Effi cacy of rATG over Basiliximab and Daclizumab in HighRisk Renal Transplant Recipients
• The safety and effi cacy of rATG was compared against
basiliximab in a multicentered, international study in
deceased donor kidney transplant recipients at a risk of
acute rejection episodes or delayed graft function (DGF).
• Patients were randomized to receive either rATG or
basiliximab. At the end of the study,
– At 1 year follow-up, comparisons of various parameters were;
biopsy-proven acute rejection (BPAR) (15.6 vs. 25.5%), graft
survival (90.8 vs. 89.8%) and patient survival (95.7 vs. 95.6%).
– At 5-year follow-up, rATG was associated with lower incidences
of a composite endpoint of BPAR, graft loss and death compared
to basiliximab (37 vs. 51%), incidences of BPAR was also found
to be signifi cantly less with rATG (15 vs. 27%).
• Another study, which was a multicenter
investigatorsponsored study, compared the safety and
the effi cacy of rATG against daclizumab in high
immunological risk renal transplant patients.
• Patients were randomized to receive either rATG or
daclizumab.
• The maintenance immunosuppressants included
tacrolimus, MMF and steroids.
• In the rATG group, tacrolimus was delayed up to day 5.
– The rATG treatment was found to be equally effective in
terms of overall graft survival (82.3 vs. 89.5%) and patient
survival (95.6 vs. 96.5%).
– The rATG showed a higher bacterial incidence (18.6 vs.
10.5%).
• The overall outcomes of the study favored rATG, which
was suggested to be better than daclizumab in high
immunity risk kidney transplant recipients through
BPAR.
• Rabbit antihuman thymocyte globulin also fi nds a
mention in the Kidney Disease Quality Outcomes
Initiative (KDQOI) clinical guidelines for the care of
transplant recipients.
• They recommend its use in adult kidney recipients who
are at risk for acute rejection episodes.
• The guidelines also suggest that leukocyte-depleting
antibodies provide beneficial effects.
rATG vs. IL2RA in Low Immunological Risk Patients
• Investigations carried out so far with rATG in low immunological risk
patients are summarized in Table 1.
• Four studies compared rATG with IL2RA, in which they were found
to be equally effective in preventing BPAR in low immunological
risk, primary kidney transplant patients.
Thymoglobulin vs. No Induction Therapy
• An induction therapy containing rATG has been compared against
tacrolimus vs. CysA maintenance therapy in two prospective,
multicenter European studies (see Table 2).
• The rATG treatment has been observed with delayed initiation of
tacrolimus administration. The rATG group was associated with a
low rate of BPAR (15.2 vs. 30.4%).
• When compared to no antibody induction, rATG had lower
incidences of acute rejection episodes and delayed the introduction
of a calcineurin inhibitor.
• This is anticipated to be advantageous in patients with a risk of DGF
or other adverse clinical conditions.
Summary
• The induction antibody therapy is used to reduce the incidence of early
acute rejection episodes and minimize the use of immunosuppressants in
early posttransplantation stage.
• This helps in the recovery of renal function before the use of calcineurin
inhibitor-based immunosuppression.
• Despite not being approved by the FDA as an induction therapy, rATG
therapy is evidenced to reduce incidences of acute rejection episodes
after kidney transplantation in high-risk patients when compared against
no antibody induction or interleukin-2 receptor blockers.
• Benefi ts of rATG treatment have given it a place in the KDQOI clinical
guidelines.
• The advantage of delayed use of calcineurin inhibitors have also been
evidenced in different clinical studies.
• However, its reactions such as cytokine activation, hematological
abnormalities and increased risk of viral infections have rendered it to be
used with caution against low immunological risk patients.