Administration Of Rabbit Antithymocyte Globulin Research Articles

Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation.

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

Combination of umbilical cord mesenchymal stem cells and standard immunosuppressive regimen for pediatric patients with severe aplastic anemia

BackgroundDefects of bone marrow mesenchymal stem cells (BM-MSCs) in proliferation and differentiation are involved in the pathophysiology of aplastic anemia (AA). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) may improve the efficacy of immunosuppressive therapy (IST) in childhood severe aplastic anemia (SAA).MethodsWe conducted an investigator-initiated, open-label, and prospective phase IV trial to evaluate the safety and efficacy of combination of allogenic UC-MSCs and standard IST for pediatric patients with newly diagnosed SAA. In mesenchymal stem cells (MSC) group, UC-MSCs were injected intravenously at a dose of 1 × 106/kg per week starting on the 14th day after administration of rabbit antithymocyte globulin (ATG), for a total of 3 weeks. The clinical outcomes and adverse events of patients with UC-MSCs infusion were assessed when compared with a concurrent control group in which patients received standard IST alone.ResultsNine patients with a median age of 4 years were enrolled as the group with MSC, while the data of another 9 childhood SAA were analysed as the controls. Four (44%) patients in MSC group developed anaphylactic reactions which were associated with rabbit ATG. When compared with the controls, neither the improvement of blood cell counts, nor the change of T-lymphocytes after IST reached statistical significance in MSC group (both p > 0.05) and there were one (11%) patient in MSC group and two (22%) patients in the controls achieved partial response (PR) at 90 days after IST. After a median follow-up of 48 months, there was no clone evolution occurring in both groups. The 4-year estimated overall survival (OS) rate in two groups were both 88.9% ± 10.5%, while the 4-year estimated failure-free survival (FFS) rate in MSC group was lower than that in the controls (38.1% ± 17.2% vs. 66.7% ± 15.7%, p = 0.153).ConclusionsConcomitant use of IST and UC-MSCs in SAA children is safe but may not necessarily improve the early response rate and long-term outcomes. This clinical trial was registered at ClinicalTrials.gov, identifier: NCT02218437 (registered October 2013).

Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates

Adeno-associated virus (AAV) vector gene therapy is a promising treatment for a variety of genetic diseases, including hemophilia. Systemic administration of AAV vectors is associated with a cytotoxic immune response triggered against AAV capsid proteins, which if untreated can result in loss of transgene expression. Immunosuppression (IS) with corticosteroids has limited transgene loss in some AAV gene therapy clinical trials, but was insufficient to prevent loss in other studies. We used a nonhuman primate model to evaluate intensive T cell-directed IS combined with AAV-mediated transfer of the human factor IX (FIX) gene. Early administration of rabbit anti-thymocyte globulin (ATG) concomitant with AAV administration resulted in the development of anti-FIX antibodies, whereas delayed ATG by 5 weeks administration did not. The anti-FIX immune response was associated with increases in inflammatory cytokines, as well as a skewed Th17/regulatory T cell (Treg) ratio. We conclude that the timing of T cell-directed IS is critical in determining transgene-product immunogenicity or tolerance. These data have implications for systemically administered AAV gene therapy being evaluated for hemophilia A and B, as well as other genetic diseases.

Safety and Feasibility of Outpatient Rabbit Antithymocyte Globulin Induction Therapy Administration in Kidney Transplant Recipients.

Kidney transplant induction therapy often includes inpatient administration of rabbit antithymocyte globulin (rATG) over multiple days. To reduce hospital length of stay (LOS) and drug expenditures, the rATG induction course was completed in the outpatient setting via peripheral intravenous administration. The present study assesses early readmission trends ascribable to an outpatient rATG administration protocol to ensure initial reduction in hospital LOS is sustained early after discharge. This was a retrospective study of kidney recipient outcomes for patients transplanted between January 1, 2008, and February 29, 2016, immediately following implementation of an outpatient rATG protocol. Readmission data within 7days of outpatient rATG administration were collected. The relatedness of rATG administration to an adverse drug reaction resulting in readmission was determined by the World Health Organization-Uppsala Monitoring Centre Causality Assessment Scale and the Naranjo Adverse Drug Reaction Probability Scale. A total of 1104 patients received outpatient doses of rATG and were included. An upward trend in kidney transplant volume and outpatient rATG administrations per year was found from 2008-2015. Following protocol implementation, the percentage of overall readmissions ranged from 9% to just over 12% from 2008-2014 and remained less than 10% for 2014 through 2016. The percentage of outpatient rATG infusions that potentially led to rATG-related readmissions was less than 4% per year over the study period. A total of 1124 hospital days were saved, 125days per year on average. Outpatient administration of rATG is feasible, safe, and did not increase readmissions in the period directly following administration. The findings of this analysis support our continued use of the outpatient rATG protocol at our institution.

386 - Relationship of CMV Reactivation and Rabbit Antithymocyte Globulin Administration in Allogeneic Stem Cell Transplant Patients

386 - Relationship of CMV Reactivation and Rabbit Antithymocyte Globulin Administration in Allogeneic Stem Cell Transplant Patients

Administration of Rabbit Anti-Thymocyte Globulin: Slowing Infusion Rate over a 4 Day Course with Aggressive Use of Pre-Medications May Decrease ATG Related Infusion Reactions

Administration of Rabbit Anti-Thymocyte Globulin: Slowing Infusion Rate over a 4 Day Course with Aggressive Use of Pre-Medications May Decrease ATG Related Infusion Reactions

Clinical and Economic Analysis of Delayed Administration of Antithymocyte Globulin for Induction Therapy in Kidney Transplantation

The increasing number of marginal deceased kidney donors and an aging recipient population, prolonged hospitalization, and increased costs have destabilized the economic viability of kidney transplants. To determine if a delay in the administration of the day-of-discharge dose of rabbit antithymocyte globulin would result in equivalent clinical outcomes with cost savings. Single-center, prospective, observational before-and-after study of adult kidney transplant recipients who received induction with rabbit antithymocyte globulin.Intervention-Patients who received a transplant between June 2006 and February 2009 and received rabbit antithymocyte globulin served as the control group. Patients who received a transplant between March 2009 and August 2010 and received rabbit antithymocyte globulin had the day-of-discharge dose delayed to the following day and administered in the clinic. A total of 231 patients (146 in the control group, 85 in the study group) were included. Baseline demographic and clinical characteristics were similar in the 2 groups. Patients who had delayed administration of rabbit antithymocyte globulin had shorter stays (3.9 vs 3.1 days, P< .001) and reduced inpatient costs for rabbit antithymocyte globulin (mean $860/patient); these changes were achieved without affecting acute rejection rates (5% vs 5%, P> .99) or readmission rates. In conclusion, delayed inpatient administration of rabbit antithymocyte globulin provided identical clinical outcomes while helping to reduce inpatient costs and increase timely discharges.

Severe Acute Hepatitis Following Administration of Rabbit Antithymocyte Globulin in Reduced Intensity Conditioning Regimen Before Allo-SCT. A Single Center Experience

Abstract 4135Antithymocyte globulin (ATG) can be used in reduced intensity conditioning regimen before allogeneic stem cell transplantation (RIC allo) with the aim of reducing the incidence and severity of graft-versus-host disease (GVHD). The liver toxicity of ATG in this setting does exist, but its knowledge is limited by the scarcity of available data. Thus, in an effort to explore the incidence, the characteristics and the potential consequences of severe acute liver toxicity of ATG administered in RIC regimen, we undertook a retrospective analysis in our center between January 1, 2008 and April 30, 2012.During this period, 186 RIC allo were performed with the same regimen of fludarabine (30 mg/m2/day from d-5 to d-1), IV busulfan (0.8 mg/kg × 4/day at d-4 and d-3) and rabbit ATG (Thymoglobulines,® 2.5 mg/kg/day at d-2 and d-1). After reviewing all records, 27 patients (pts, 14%) developed a severe acute hepatitis (SAH) defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 10 × ULN shortly after the administration of ATG. Their median age was 57 years (22–65). There were 15 females. Diagnoses were AML (n=7), ALL (n=2), T cell lymphoma (n=4), Hodgkin’s disease (n=4), high-grade B cell lymphoma (n=1), multiple myeloma (n=5), myelodysplastic syndrome (n=3) and CLL (n=1). Status at transplant were CR1 (n=13), ≥ CR2 (n=6), PR1 (n=1), ≥ PR2 (n=5), SD (n=1) and untreated (n=1). The median number of lines of treatment before allo was 1 (0–5). Donors were matched related (n=15), matched unrelated (n=7) or mismatched unrelated (n=5, all C mismatch). The source of stem cells was peripheral blood in all cases with a median number of 7.5 × 106 CD34+ cells/kg (2.8–21.6).No patient had evidence of hepatic involvement by the hematological malignancy before allo. One patient had a chronic C hepatitis before allo while none had a history of B hepatitis. Twenty-six patients had transaminases < 2 × ULN before the administration of ATG, while 1 had ALT at 3 × ULN with normal AST. All pts had a normal renal function. All developed fever the 1st day of ATG and received acetaminophen. Of note, they also received acetaminophen afterwards, during aplasia, without recurrence of hepatitis. No patient was receiving azoles at the time of hepatitis. No bacterium was isolated from blood cultures during fever except Enterococcus sp. in 1 patient. No virus was detected in blood by PCR (EBV, CMV, B and C hepatitis). The maximum median levels of AST and ALT were 22 × ULN (4–113) and 26 × ULN (9–109), respectively. The second day of ATG was cancelled in 8 patients when SAH was noted immediately after the 1st day. No patient died of liver failure and the liver function tests improved in all cases with a median time to reach transaminases <5 × ULN and <2 × ULN of 7 days (4–19) and 14 days (4–22), respectively. The prothrombin test was below normal in 15 pts with a median of 40% (19%-68%) but rapidly went back to normal in less than 1 week. No patient developed VOD or acute GVHD of the liver. One patient developed chronic GVHD of the liver 11 months after transplant.The median times to reach ANC > 500/mm3, platelets > 20,000/mm3 and > 50,000/mm3 were 18 days (13–31), 11 days (8–15) and 13 days (9–20), respectively. One patient transplanted for a CLL did not engraft, relapsed at 14 months and died of disease at 29 months. Prophylaxis of GVHD consisting of cyclosporine (CsA) in 14 pts and CsA+mycophenolate mofetil (MMF) in 2 pts were unchanged during SAH. Eleven pts were planned to receive CsA+methotrexate (at days +1, +3, +6). Methotrexate was replaced by MMF in 7 of them because of significant persistent hepatitis at day+1. With a median follow-up of 20 months (3–44), the 2-year OS, EFS, NRM, and relapse incidence were 75% ± 10%, 61% ± 11%, 6% ± 6%, and 32% ± 10%, respectively. The cumulative incidences of acute GVHD II-IV and extensive chronic GVHD were 15% ± 7% and 15% ± 8%, respectively. All these results (survival, NRM, relapse, GVHD) were similar in pts receiving 1 or 2 days of ATG.We conclude that the incidence of SAH following ATG in RIC regimen is 14%. We also report that transaminases rapidly normalized in all patients, that no patient developed severe liver failure, VOD, or acute GVHD of the liver. Finally, our study does not provide any evidence that SAH following ATG might favor NRM and thus adversely affect the outcome of RIC allo. However, a comparative study is warranted to draw firm conclusions and delineate risk factors of SAH following ATG. Disclosures:No relevant conflicts of interest to declare.

Serum Sickness After Treatment With Rabbit Antithymocyte Globulin in Kidney Transplant Recipients With Previous Rabbit Exposure

Serum sickness after rabbit antithymocyte globulin administration has a reported incidence of 7% to 27% in kidney transplant recipients. We describe 4 patients with previous exposure to rabbits who developed serum sickness after primary rabbit antithymocyte globulin induction. All patients presented with jaw pain. Three of 4 patients treated with plasmapheresis and steroids had prompt recovery, and 1 patient treated with steroids had slower recovery. We performed a telephone interview of 214 patients who contemporaneously underwent transplantation between November 2006 and July 2008 regarding rabbit exposure. More than half the patients had some type of previous rabbit exposure. There was a suggestion that patients with serum sickness were exposed more frequently to rabbits than those without. Jaw pain appears to be a hallmark symptom, and treatment with plasmapheresis and steroids relieves symptoms more rapidly than steroids alone.

Basiliximab and Rabbit Anti-thymocyte Globulin for Prophylaxis of Acute Rejection After Heart Transplantation: A Non-inferiority Trial

Induction of immunosuppression with antibodies after heart transplantation decreases early acute rejection rate compared with placebo. We tested the non-inferiority of basiliximab vs rabbit anti-thymocyte globulin (RATG) on the incidence of acute rejection 6 months after transplantation. From July 2002 to April 2004, 35 patients were enrolled in a multicenter, parallel group, open-label, non-inferiority trial. Patients were randomized to receive induction treatment with basiliximab (20 mg on Day 0 and 4) or RATG (125 mg on Day 0, 1, and 2). Standard maintenance therapy with cyclosporine, mycophenolate mofetil, and prednisone was used. Seventeen patients (aged 54 +/- 9 years old) received basiliximab, and 18 patients (aged 54 +/- 12 years old) received RATG. The freedom rate of rejection at 6 months (grade 3A or more) averaged 65% (11/17) with basiliximab and 83% (15/18) with RATG. The upper limit of the 1-sided 90% confidence interval for the difference RATG-basiliximab was 37.2%, exceeding the 22.5% non-inferiority margin. CD3 and CD4 levels were higher (p < 0.0001 for both), whereas CD25/CD4 and CD25/CD8 levels were lower (p < 0.0001 and p = 0.0462, respectively) in patients treated with basiliximab. One of the 14 basiliximab patients showed detectable cytomegalovirus viral load during the first 3 months after transplantation, whereas cytomegalovirus was detected by quantitative polymerase chain reaction in the plasma of 5 of the 13 RATG patients (p = 0.0505). Non-inferiority of basiliximab treatment for prophylaxis of acute rejection after heart transplantation could not be shown. RATG administration is associated with a higher rate of asymptomatic cytomegalovirus viral load detection in the plasma.

Deep vein thrombosis during rabbit antithymocyte globulin administration

Introduction Rabbit antithymocyte globulin (RATG) is recommended for central administration, and no evidence justifies the common practice of adding heparin to the bag, but the evaluation of thrombocytopenia may be complicated by coadministration. We recently phased out the use of heparin in RATG in our kidney and kidney-pancreas transplant recipients but subsequently observed several episodes of deep vein thrombosis (DVT), so we sought to determine the factors linked to DVT during RATG therapy. Methods A search of billing and diagnosis codes for RATG and DVT in one hospital revealed relevant admissions from January 2000 to April 2004. Results Patients ( n = 288) received 330 courses of RATG (central or peripheral), and nine were diagnosed with DVT. Four patients were excluded because the diagnosis was not confirmed by Doppler ultrasound ( n = 1), DVT occurred more than 10 days after RATG discontinuation ( n = 2), or DVT occurred after switching to equine antithymocyte globulin ( n = 1). All patients ( n = 5) who developed DVT related to RATG exhibited prior infusion-related reactions, received peripherally administered RATG with premedication (methylprednisolone, diphenhydramine, and acetaminophen), and did not receive heparin. The DVT occurred near the site of the infusion in 60% of cases. Four of the patients were male, and 80% had diabetes (one developed posttransplant), and all included patients received infusions over at least 6 hours for the first dose, and at least 4 hours for subsequent doses. Conclusions These results provide justification for adding heparin to the RATG bag, especially when administered peripherally.

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23–61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2–60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/μL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/μL; P = .001; Mann-Whitney ranked sum test). Although the numbers are limited, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study.

Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory renal-transplant patients.

Antilymphocyte globulins have been used for the treatment and prevention of acute rejection in renal-allograft recipients. Thymoglobulin, rabbit antithymocyte globulin (RATG), has been shown to be effective for these indications and has been used primarily on an inpatient basis because of the recommendation that it be administered through a central line. We retrospectively reviewed the charts of all patients treated with RATG since its first use in 1999. After premedication, the dose of RATG was administered over 4 to 6 hours, with 1,000 units of heparin and 20 mg of hydrocortisone to reduce the incidence of thrombosis and local tissue reaction. All adverse reactions were recorded. Eighteen patients underwent a total of 57 outpatient infusions. Of the 57 infusions, 52 (91%) were without complication. Five infusions (9%) were complicated by infiltrates. No serious reactions were noted. These data confirm that peripheral, outpatient administration of RATG is safe.

SUPPRESSOR CELLS IN RHESUS MONKEYS TREATED WITH ANTITHYMOCYTE GLOBULIN

Treatment of rhesus monkey skin allograft recipients with a brief course of rabbit antithymocyte globulin (ATG) produces an enduring immunosuppressive effect on the cellular immune system. Despite early recovery of circulating T cells, in vitro mitogen-induced lymphoproliferative responses of peripheral blood mononuclear cells (PBMCs) remain abnormally depressed for months. In this study we show that depressed mitogen-induced lymphoproliferative responses in these animals are attributable to regulatory effects of adherent PBMCs. Removal of the adherent fraction of PBMCs on Sephadex G-10 produced a significant restoration of the mitogen-induced lymphoproliferative responses in ATG-treated monkeys. Addition of the prostaglandin synthetase inhibitor indomethacin to cultures of unfractionated PBMCs from these animals also caused a significant recovery of the lymphoproliferative response. Indomethacin did not enhance the response of control animals or the response of the nonadherent PBMC fraction of ATG-treated animals. These data suggest that a prostaglandin-dependent mechanism is involved in the suppressive action of the adherent cells. PBMCs from ATG-treated monkeys cocultured with normal cryopreserved autologous cells induced a dose-dependent suppression in the response to both concanavalin A (Con A) and phytohemagglutinin (PHA). The suppressive activity depended upon the adherent cell fraction and was found to be resistant to low-dose gamma irradiation. These data indicate that administration of rabbit ATG induces nonspecific suppressor cells in the rhesus monkey. Preliminary characterization studies suggest the involvement of suppressor monocytes. The possible role of this suppressor cell system in the immunosuppressive action of rabbit ATG is discussed.