Dose Of Rabbit Antithymocyte Globulin Research Articles

Rabbit antithymocyte globulin dose and early subclinical and clinical rejections in kidney transplantation.

Antithymocyte globulin (ATG) is a commonly used induction agent in kidney transplant recipients. However, the optimal dosing has not been well defined. Our protocol aims for a 5-6mg/kg cumulative dose. It is unclear if a dose lower than 5mg/kg is associated with more rejection. We performed a retrospective cohort study of patients who received a kidney transplant at our center between January 1, 2013 and December 31, 2016. Primary outcome was biopsy proven acute rejection (clinical and subclinical) in the first 6months after kidney transplant. CMV viremia in high risk (D+/R-) recipients and BK viremia was compared as a secondary endpoint. Of the 543 patients, the Low Dose (LD) group (n = 56) received <5mg/kg ATG and Regular Dose (RD) group (n = 487) received ≧5mg/kg. Patients in RD were more sensitized (higher PRA and CPRA). LD received a dose of 4 ± 1.1mg/kg ATG whereas RD received 5.6 ± .3mg/kg ATG (P < .001). TCMR (Banff 1A or greater) was present in 34% of patients in LD versus 22% in RD (P = .04) (OR 2.1; 95%CI 1.12-3.81; P = .019). There was no difference in the incidence of CMV or BK viremia. ATG doses lower than 5mg/kg may be associated with a heightened risk of rejection despite a low degree of sensitization.

Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibody detection in lung transplant recipients: A single-center experience.

PurposeInduction immunosuppression has improved the long‐term outcomes after lung transplant. This is the first report exploring the association of induction immunosuppression with the development of de novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) in lung transplant recipients (LTR).MethodsSixty‐seven consecutive primary LTR were followed for 3 years posttransplant. A total of 41/67 (61%) LTR‐received induction immunosuppression using a single dose of rabbit Antithymocyte Globulin (rATG; 1.5 mg/kg) within 24 h of transplant. All recipients had a negative flow cytometry crossmatch on the day of transplant. Serum samples at 1, 3, 6, and 12 months posttransplant were assessed for the presence of de novo HLA DSA.ResultsDe novo HLA DSA were detected in 22/67 (32.8%) LTR within 1‐year posttransplant. Of these, 9/41 (21.9%) occurred in the induction therapy group and 13/26 (50%) in the noninduction group. Class II DSA were detected in 3/41 (7.3%) LTR who received induction compared to 9/26 (34.6%) LTR without induction immunosuppression (p = .005). Differences in overall survival or freedom from chronic lung allograft dysfunction rates between the two groups were not statistically significant.ConclusionInduction immunosuppression utilizing a modified regimen of single‐dose rATG is associated with a significant reduction in de novo DSA production in LTR.

MO982COMPARISON OF BASILIXIMAB AND R-ATG ON ACUTE REJECTION RISK IN HIGH IMMUNOLOGICAL RISK RENAL TRANSPLANT RECIPIENTS

Abstract Background and Aims High Panel Reactive Antibody (PRA) level has been widely accepted as a marker for acute rejection risk following kidney transplantation. PRA&amp;gt;/= 20% is considered a high immunological risk renal transplant. The aim of our study was to assess the risk of acute rejection in kidney transplant recipients (KTR) following Basiliximab induction compared to Rabbit Anti-Thymocyte Globulin (R-ATG) maintained on tacrolimus and mycophenolate mofetil maintenance immunotherapy. Method This was a retrospective observational cohort study using data from the United States Organ Procurement and Transplantation Network, all KTR’s with PRA =/&amp;gt; 20%, who were maintained on tacrolimus and mycophenolate mofetil between September 2017 and September 2019 were included. Follow-up was until September 2020. Data included recipient factors (age, sex, ethnicity, diabetes, body mass index), transplant factors (delayed graft function, cold ischemia time, number of previous transplants, panel reactive antibodies, HLA-mismatches, induction therapy, maintenance immunotherapy and donor factors (donor type, donor age). The cohort were divided into 2 groups; living and deceased donor renal transplants. The groups were further divided by PRA level, each group was divided into 3 subgroups: Group A (low PRA level: PRA range from 20% to 49%), Group B (moderate PRA level: PRA range from 50% to 79%), and Group C (High PRA level: PRA range from 80% to 100%). Multivariable logistic regression models were constructed to assess the effect of induction therapies (Basiliximab versus R-ATG) on acute rejection episodes at 6 months post-transplant. The multivariable model was adjusted for recipient, donor and transplant factors mentioned above. Results Among living donor KTR’s, there was no difference between Basiliximab and R-ATG in acute rejection episodes in any of the three groups, Group A (low PRA level, n=717, OR=1.17, P=0.79, 95%CI:0.34-3.95), Group B (moderate PRA level, n=618, OR=1.51, P=0.58, 95%CI:0.33-6.92) and Group C (high PRA level, n=401, OR=1.17, P=0.85, 95%CI:0.21-6.56) respectively. In contrast, among deceased donor KTR’s R-ATG was associated with lower risk of rejection compared to Basiliximab in all three groups, group A (low PRA level, n=1895, OR=0.52, P=0.03, 95%CI: 0.28-0.94), group B (moderate PRA level, n=1618, OR=0.41, P&amp;lt;0.01, 95%CI: 0.22-0.78) and group C (high PRA level, n=3973, P&amp;lt;0.01, 95%CI: 0.28-0.70). Conclusion This study shows that risk of acute rejection is no different with Basilximab induction compared to R-ATG in high immunological risk living-donor KTR’s at all levels of PRA in the current tacrolimus-mycophenolate mofetil immunosuppression era. However, risk of acute rejection seems to be lower in deceased donor KTR’s having R-ATG induction at all levels of PRA. Delayed graft function is a risk factor for acute rejection, our models did not adjust for dose of R-ATG which may explain the lower risk seen in deceased donor KTR’s, data was not available on donor specific antibodies. In summary, Basiliximab induction has similar acute rejection rates as R-ATG in living donor KTR’s whereas in deceased donor KTR’s R-ATG was found to be better.

The Optimal Cumulative Dose of Rabbit Antithymocyte Globulin Induction in Adult Heart Transplantation

Purpose To determine the optimal cumulative dose of rabbit antithymocyte globulin (rATG) regarding its efficacy and safety and to evaluate the target level of CD3+ T cell count for induction therapy in adult heart transplantation. Methods This retrospective cohort study enrolled adult patients undergoing heart transplantation in a medical center between January 2016 and July 2019. The rATG induction was initiated postoperatively at a dose of 0.75-1 mg/kg/day for 3-5 days to maintain CD3+ counts Results A total of 62 patients with 189 doses of rATG were enrolled. The first dose and the cumulative dose of rATG were 0.67 ± 0.18 mg/kg and 1.44 ± 0.40 mg/kg. The cut-off point for the cumulative dose of rATG in achieving CD3+ count Conclusion A cumulative rATG dose of 1.2 mg/kg may be effective in achieving CD3+ counts

Long-term Efficacy and Safety of Everolimus Versus Mycophenolate in Kidney Transplant Recipients Receiving Tacrolimus.

The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.

Optimization of ATG dose in haploid hematopoietic stem cell transplantation for hematologic malignancies

目的比较含不同剂量兔抗人胸腺细胞球蛋白（rATG）预处理方案单倍型造血干细胞移植（haplo-HSCT）对恶性血液病患者的疗效。方法对2013年3月至2018年12月行haplo-HSCT的恶性血液病患者进行回顾性分析，按预处理方案中rATG总量6、7.5、9 mg/kg分为ATG-6、ATG-7.5、ATG-9三组，比较三组患者急性移植物抗宿主病（GVHD）发生率、感染发生率及生存率。结果①纳入288例患者，男182例，女106例，中位年龄18（6～62）岁。急性髓系白血病（AML）128例，急性淋巴细胞白血病（ALL）110例，慢性髓性白血病（CML）8例，骨髓增生异常综合征（MDS）28例，混合细胞白血病（MAL）14例。ATG-6组159例，ATG-7.5组72例，ATG-9组57例。移植后中位随访时间为14.0（0.2～74.0）个月。②ATG-6、ATG-7.5、ATG-9组粒细胞植入率分别为96.9％、97.2％、96.5％（P＝0.972），血小板植入率分别为92.5％、87.5％、86.0％（P＝0.276），Ⅱ～Ⅳ度急性GVHD发生率分别为14.5％、11.1％、8.8％（P＝0.493），慢性GVHD发生率分别为8.8％、14.3％、12.0％（P＝0.493）。ATG-9组的CMV、EBV感染率（77.2％、12.5％）均高于ATG-6组（43.3％、3.5％）和ATG-7.5组（44.4％、1.5％）（P<0.001，P＝0.033）。③ATG-6、ATG-7.5、ATG-9组移植后3年总生存率分别为68.5％（95％CI 60.3％～77.9％）、60.1％（95％CI 48.3％～74.8％）、64.7％（95％CI 51.9％～80.7％）（P＝0.648），3年累积复发率分别为34.6％（95％CI 34.3％～35.1％）、38.0％（95％CI 37.3％～38.7％）、20.6％（95％CI 20.0％～21.3％）（P＝0.165），3年无病生存率分别为53.3％（95％CI 44.9％～63.4％）、51.9％（95％CI 41.0％～65.8％）、63.9％（95％CI 51.9％～78.7％）（P＝0.486），3年非复发死亡率分别为24.2％（95％CI 23.8％～24.5％）、26.0％（95％CI 25.4％～26.6％）、23.6％（95％CI 26.3％～28.2％）（P＝0.955）。结论低剂量rATG（6 mg/kg）可增加haplo-HSCT后Ⅱ～Ⅳ度急性GVHD的发生率，高剂量rATG（9 mg/kg）使CMV、EBV感染风险增加，中剂量ATG（7.5 mg/kg）可能是兼顾降低中重度急性GVHD和CBV/EBV感染发生率的选择。

Two dose levels of rabbit antithymocyte globulin as graft-versus-host disease prophylaxis in haploidentical stem cell transplantation: a multicenter randomized study

BackgroundThe optimal dose of rabbit antithymocyte globulin (ATG, ImtixSangstat) minimizing infections without increasing graft-versus-host disease (GVHD) is unknown in T cell-replete, G-CSF-primed haploidentical hematopoietic stem cell transplantation (haplo-HSCT).MethodsFour hundred and eight patients were enrolled in this multicenter study to evaluate the effect of 7.5 mg/kg and 10.0 mg/kg rabbit ATG on viral infections and GVHD prophylaxis after haplo-HSCT. The primary endpoint was EBV DNAemia within 1 year posttransplantation.ResultsThe 1-year incidence of EBV DNAemia was 20.7% (95% confidence interval, 15.4–26.5) and 40.0% (33.3–46.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (P < 0.001). The 100-day cumulative incidence of grade II to IV aGVHD was 27.1% (21.1–33.4) and 25.4% (19.6–31.5) in the 7.5 mg/kg and 10.0 mg/kg ATG groups, respectively (P = 0.548). The 2-year incidence of chronic GVHD was 34.6% (27.8–41.4) and 36.2% (29.1–43.2) in the 7.5 mg and 10.0 mg groups (P = 0.814). The 1-year incidence of CMV DNAemia was 73.4% (67.2–79.4) and 83.4% (77.5–87.9) in the 7.5 mg/kg and 10.0 mg/kg groups (P = 0.038). The 3-year overall survival posttransplantation was 69.5% (63.2–75.8) and 63.5% (56.2–70.8), and the disease-free survival was 62.2% (55.3–69.1) and 60.3% (53.0–67.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (OS: P = 0.308; DFS: P = 0.660). The counts of EBV- and CMV-specific cytotoxic T cells (CTLs) were higher in the 7.5 mg/kg group than in the 10.0 mg/kg group early posttransplantation.ConclusionsCompared with 10.0 mg/kg, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in haplo-HSCT, probably by affecting EBV- and CMV-specific CTLs.Trial registrationclinicaltrials.gov, NCT01883180. Registered 14 June 2013.

Prospective randomized trial comparing two doses of rabbit anti‐thymocyte globulin in patients with severe aplastic anaemia

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n=89), China (n=85) and Korea (n=48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5mg/kg and 110 receiving 3·5mg/kg of rabbit ATG for 5days. The primary endpoint was the haematological response at day 180. After 6months, no significant difference in response rates was observed between the 2·5 and 3·5mg/kg groups (49% vs. 48%, P=0·894). Overall survival at 3years was similar between the two groups [85% (95% confidence interval [CI], 76%-91%) vs. 91% (95% CI, 82%-96%); P=0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

Cost-Effectiveness Analysis of Everolimus versus Mycophenolate in Kidney Transplant Recipients Receiving No Pharmacological Prophylaxis for Cytomegalovirus Infection: A Short-Term Pharmacoeconomic Evaluation (12 Months)

BackgroundModern immunosuppressive regimens, although associated with improved 1-year graft survival, are associated with adverse effects, including opportunistic infections, diabetes mellitus after transplantation, cardiovascular complications, and de novo malignancies. ObjectivesTo determine the short-term (12 months) cost-effectiveness of everolimus (EVR) versus mycophenolate sodium (MPS) in kidney transplant recipients receiving induction therapy, tacrolimus, prednisone, and no prophylaxis for cytomegalovirus infection. MethodsA Markov state transition model was designed. Data from a single-center prospective trial were used along with data from the center’s medical bills database. The target population comprised adults with low immunological risk submitted to first ABO-compatible transplantation with kidneys recovered from living or deceased donors. The time horizon was 12 months. The interventions included tacrolimus and prednisone plus a single 3-mg/kg dose of rabbit antithymocyte globulin (ATG) and EVR or basiliximab (BAS) and EVR or BAS and MPS. The clinical outcomes considered for this analysis were cytomegalovirus infection/disease, acute rejection, graft dysfunction, surgical complications, graft loss, and life-years gained. ResultsATG/EVR was cost-saving compared with BAS/MPS on all evaluated outcomes; BAS/EVR outperformed BAS/MPS on most of the evaluated outcomes. Results were confirmed by sensitivity analysis. ConclusionsCompared with MPS, EVR is an alternative immunosuppressive agent that is able to provide resource-saving to the health care provider with effectiveness gains for the patient.

Donor-Specific Anti-Human Leukocyte Antigens Antibodies, Acute Rejection, Renal Function, and Histology in Kidney Transplant Recipients Receiving Tacrolimus and Everolimus

Background: This analysis compared efficacy, renal function, and histology in kidney transplant recipients receiving tacrolimus (TAC) combined with everolimus (EVR) or mycophenolate (MPS). Methods: This was a retrospective analysis from a randomized trial in kidney transplant recipients who received a single 3 mg/kg dose of rabbit antithymocyte globulin (r-ATG), TAC, EVR, and prednisone (PRED; r-ATG/EVR, n = 85), basiliximab (BAS), TAC, EVR, and PRED (BAS/EVR, n = 102) or BAS, TAC, MPS, and PRED (BAS/MPS, n = 101). We evaluated the incidence of de novo donor-specific anti-human leukocyte antigens antibodies (DSA) and histology on protocol biopsies at 12 months, and the incidence of acute rejection, estimated glomerular filtration rate (eGFR) and proteinuria at 36 months. Results: At 12 months, there were no differences in de novo DSA (6.4 vs. 3.4 vs. 5.5%) or in subclinical inflammation (2.0 vs. 4.8 vs. 10.2%), interstitial fibrosis/tubular atrophy (57.1 vs. 58.5 vs. 53.8%) and C4d deposition (2.0 vs. 7.3 vs. 2.6%). At 36 months, there were no differences in the incidence of treatment failure (19.0 vs. 27.7 vs. 27.7%, p = 0.186), first biopsy-proven acute rejection (9.5 vs. 21.8 vs. 16.8%, p = 0.073), and urine protein/creatinine ratios (0.53 ± 1.05 vs. 0.62 ± 0.75 vs. 0.71 ± 1.24). eGFR was lower in the BAS/EVR compared to that in the BAS/MPS group (53.4 ± 20.9 vs. 50.8 ± 19.5 vs. 60.7 ± 21.2 mL/min/1.73 m², p = 0.017) but comparable using a sensitive analysis (49.5 ± 23 vs. 47.5 ± 22.6 vs. 53.6 ± 27.8 mL/min/1.73 m², p = 0.207). Conclusion: In this cohort, the use of EVR and reduced TAC concentrations were associated with comparable efficacy, renal function, and histological parameters compared to the standard-of-care immunosuppressive regimen.

Steroid-free Liver Transplantation Using Rabbit Antithymocyte Globulin Induction in 500 Consecutive Patients.

We have previously documented the efficacy of a steroid-free immunosuppression protocol using rabbit antithymocyte globulin (RATG) induction in orthotopic liver transplantation (OLT) with tacrolimus minimization. The purpose of this report is to demonstrate the benefits of this protocol in a large cohort of patients. We evaluated outcomes of 500 consecutive OLT recipients who received RATG induction and a single dose of solumedrol given before the first dose of RATG. Mycophenolate mofetil was initiated postoperatively with delayed initiation of tacrolimus. Sirolimus replaced tacrolimus if serum creatinine remained above 2.0 mg/dL by day 7. Patients were weaned to tacrolimus or sirolimus monotherapy at 3 months. Mean model for end-stage liver disease (MELD) at transplantation was 22 ± 6. Forty-four percent of patients had hepatitis C. Posttransplant creatinine was highest at 1 month (1.43 ± 0.95 mg/dL) and improved to 1.26 ± 0.60 mg/dL (P < 0.05) at 2.5 years. Glomerular filtration rate was lowest at 1 month (65.6 ± 30.0) and improved by 1 year (72.7 ± 28.2, P < 0.01). Tacrolimus was initiated at 4.79 ± 13.3 days with a level of 4.95 ± 2.45 ng/mL at 1 year. One-year patient and graft survival were 92.8% and 89.6%, respectively, with a 3-year patient survival of 82.9%. Rejection occurred in 114 (22.8%) patients, 33 (6.6%) patients requiring steroids. Univariate and multivariate Cox proportional hazard analyses were performed to evaluate the effects of donor and recipient characteristics on patient and graft survivals. Pretransplant creatinine was consistently a statistically significant predictor for patient and graft survival. This is the largest reported series of OLT recipients using a steroid-free protocol with RATG induction demonstrating excellent outcomes, low complication rates, and preservation of renal function.

Comparison between two different dose of r-ATG combined with CsA for treating children with severe aplastic anemia

This study was purposed to compare the efficacy and safety of two different doses of rabbit anti-thymocyte globulin (r-ATG) combined with cyclosporine (CsA) for treating children with severe aplastic anemia (SAA). From January 2005 to July 2010, a total of 95 children with SAA accepted intensive immunosuppressive therapy (IIST) in our department, out of them 55 cases were treated with r-ATG 2.5 mg/(kg·d) for 5 days in combination with CsA (group I) and other 40 cases were treated with r-ATG 3.5 mg/(kg·d) for 5 days in combination with CsA (group II). The responsive rate, adverse reactions, early mortality, relapse and clonal disease were analyzed retrospectively and results between the two groups were compared. Out of 95 patients 43 were boys and 52 were girls, their ages were from 1 to 16 years. The sex, age, severity and course of the disease were comparable between the two groups. The results showed that after treating for 3 and 6 months, the response of patients in group II was higher than that of patients in group I (50% vs 32.1%, P = 0.08 and 65% vs 45.3%, P = 0.059), at 9 and 12 months the response rate of patients in group II and group I did not show significant difference (70.0% vs 71.1%,P = 0.904 and 82.5% vs 80.8%,P = 0.832); at 12 months of treatment, the complete response rate of patients in group II was significantly higher than that of patients in group I (40.0% vs 23.1%,P = 0.08); at 3, 6, 9 months of treatment, the complete response rate of 2 groups showed no obvious difference. The incidence of serum disease, early infection and early mortality did not show statistical difference between two groups. There was no statistical difference in 2 year overall survival rate of two groups. In group I 39 patients were followed-up for more than 2 years, among them 3 patients relapsed, 1 patient died and 1 patient was diagnosed as acute monocytic leukemia (M5). In group II 15 patients were followed up for more than 2 years, there were no relapse, death and clonal disease. It is concluded that the r-ATG combined with CsA is an effective and safe therapeutic regimen for the SAA children. The effect of r-ATG 3.5 mg/(kg·d) is better than the 2.5 mg/(kg·d). The early safety is comparable between the two groups. However, the long-term effect, complications and survival rate need longer follow-up study to evaluate.

Outcomes of matched sibling donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative conditioning and intermediate-dose of rabbit anti-thymocyte globulin.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5-10% chance of rejection and transplant related mortality (TRM) with 12-23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti-thymocyte globulin (r-ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD. Fifteen patients, median age 5 (range 1.5-18) years, underwent MSD HSCT using busulfan (≥ 12.8 mg/kg with first dose pharmacokinetics), cyclophosphamide (total 200 mg/kg) and r-ATG. Bone marrow was the stem cell source; tacrolimus and methotrexate were given for GVHD prophylaxis. All patients achieved donor engraftment and there was no TRM. One patient rejected donor cells at 2 months post-transplant. Majority of the patients had high and sustained level of donor chimerism. None of the patients developed ≥ Grade II GVHD. Incidence of CMV (10%) and EBV (9%) reactivations was low with rapid immune-reconstitution. Overall survival was 100% with event free survival of 93%. Eliminating the risks of TRM and GVHD by optimizing the regimen may lead to further acceptance of HSCT for SCD.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

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.

Ex Vivo Expansion of Human Tregs by Rabbit ATG Is Dependent on Intact STAT3-Signaling in CD4+ T Cells and Requires the Presence of Monocytes

The addition of low, nondepleting doses of rabbit antithymocyte globulin (ATG) to human peripheral blood mononuclear cells has been shown to expand functional CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in vitro. This report is the first to elucidate the exact cellular mechanisms of ATG-mediated Treg expansion. CD4(+) T cells require monocytes, but not other antigen presenting cell subsets, to be present in coculture to expand Tregs. However, T cells do not require direct cell-cell contact with monocytes, suggesting the importance of soluble factors. Moreover, ATG initially "reprograms" CD4(+) T cells, but not monocytes, and induces STAT3 and STAT5 signaling in CD4(+) cells. These reprogrammed CD4(+) T cells subsequently secrete GM-CSF and IL-10 only in case of intact STAT3 signaling, which in turn promote the generation of tolerogenic CD14(+) CD11c(+) dendritic cells characterized by enhanced IL-10 and decreased IL-12 production. Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM-CSF and Bcl-2, but not TGF-β, in peripheral blood mononuclear cells. These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram CD4(+) T cells in a STAT3-dependent but TGF-β-independent manner, leading to the generation of monocyte-derived dendritic cells with a tolerogenic cytokine profile.

Favorable Outcomes in Patients with High Donor-Derived T Cell Count Following In Vivo T Cell Depleted Reduced Intensity Allogeneic Stem Cell Transplantation

Abstract 3043In patients undergoing T cell depleted stem cell transplantation (SCT) a high rate of mixed chimerism is seen. Further, chimerism analysis does not consistently predict risks of GVHD or relapse upon withdrawal of immunosuppression (IS) in these patients. Thus, a reliable predictor for the expected evolution of mixed T cell chimerism is needed to help in clinical decision-making for withdrawal of IS and donor lymphocyte infusion (DLI). An alternative immune parameter is T cell recovery post-transplant. We combined this measure with T cell chimerism and examined the predictive value of a calculated donor-derived T cell count for clinical outcomes following SCT.Patients were enrolled in a randomized clinical trial examining two different doses of rabbit anti-thymocyte globulin (ATG 2.5 or 1.7 mg/kg/day; Thymoglobulin®, Genzyme, Cambridge, MA) given IV on day –9 through –7, followed by total body irradiation (4.5 Gray), administered in 3 doses on day –1 and 0 (NCT00709592). Donor engraftment was measured by PCR of short tandem repeat alleles in each donor and patient at 4, 8, 12, and 24 weeks following SCT on whole blood, granulocytes, and total T cells. Between 2008 and 2011, 25 patients were enrolled in this trial, and 22 patients were eligible for this analysis. Nine of the 22 patients had mixed T cell chimerism (≥5% recipient DNA) at 8 weeks post-transplant, and of these 33% (n=3) became fully donor T cell chimeric after withdrawal of IS over the ensuing weeks. One of the 9 patients had improved donor chimerism after DLI. Of the 13 patients who were full donor chimeric in T cells, one patient reverted from full donor to mixed chimerism.Donor-derived CD3+ T cell count (dd CD3) was calculated from T cell chimerism and absolute blood CD3+ T cell count. Median dd CD3+ cell count at 8 weeks following SCT was 433 ƒýL (range: 3–2464). After calculating the sum of receiver operating characteristic area under the curves (AUC), a dd CD3 of 110ƒýL was found to be the optimal cut-off value with both the highest AUC sum and the highest AUC for each measure (cumulative acute and chronic GVHD: 0.79, remission: 0.74, whole blood chimerism: 0.88), and was subsequently used to distinguish between low (<110; n=8) and high (>110; n=14) values of dd CD3. A significant correlation was found between this single dd CD3 level discriminator and higher rates of cumulative GVHD (Fishers Exact Test: p = 0.024), remission (p = 0.0524) and full donor whole blood chimerism at ≥12 weeks following SCT (p < 0.0001) in patients with high-dd CD3 cell counts. Furthermore, Bayesian analysis showed higher whole blood mixed chimerism rates (Posterior Probability = 0.99), lower GVHD rates (PP = 0.99), and lower remission rates (PP = 0.99) in the low-dd CD3 group. Both overall survival and time to relapse favored the high-dd CD3 group (vs. low-dd CD3 group). However, while the relationship was significant for relapse (p = 0.028), it was only marginally significant for overall survival (p = 0.07). When measured after withdrawal of IS, declining donor or persistent mixed T cell chimerism was observed in patients who had mixed T cell chimerism and low- dd CD3 at eight weeks post SCT (Fig 1A), whereas those with high- dd CD3 had increasing donor T cell chimerism (Fig 1B). Granulocyte chimerism too was modulated by dd CD3 in patients with mixed chimerism and early DLI arrested the decline of donor hematopoiesis in a patient with low-dd CD3. NK cell counts were significantly higher in the high-dd CD3 group than in the low-dd CD3 group at 8 weeks (p = 0.044; PP = 0.99). No significant relationships were found between dd CD3 levels and donor age, donor type, total ATG dose, and infused graft CD34+ or CD3+ cell dose. [Display omitted] In conclusion, we report the effect of an easily calculable measure of donor T cell reconstitution on clinical outcomes following SCT (particularly GVHD), stability of engraftment and disease relapse. Donor-derived CD3+ cell count may help in the decision-making regarding IS withdrawal and DLI timing in allogeneic SCT recipients. We will be confirming the optimal dd CD3 cell count parameter in larger patient cohorts with comparable disease biology for validation in regimens of varying myeloablative intensities. Disclosures:Toor:Genzyme: Research Funding. Off Label Use: ATG in stem cell transplantation.

Human CD4 +CD25 + Cells in Combination with CD34 + Cells and Thymoglobulin to Prevent Anti-hematopoietic Stem Cell T Cell Alloreactivity

Cotransplantation of human CD34(+) hematopoietic stem cells (HSC) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) could prevent anti-HSC alloreactivity and reduce the risk of rejection in HLA mismatched transplants. To pursue this hypothesis we cocultured CD34(+) cells and CD4(+)CD25(+) cells immunomagnetically isolated (Milteny) from human peripheral blood (unmanipulated or granulocyte-colony stimulating factor [G-CSF] mobilized) or cord blood. Enriched Tregs obtained from the same source (autologous) of CD34(+) cells showed greater inhibitory effect on T cell alloreactivity than third-party (allogeneic) Tregs. The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic CD34(+) cells and Tregs did not modify the clonogenic activity of CD34(+) cells in vitro. Cotransplantation of Tregs with CD34(+) cells at 1:1 or 2:1 ratios in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice resulted in normal hematopoietic stem cell engraftment. Incubation with physiologic doses of rabbit antithymocyte globulin (rATG, thymoglobulin) did not affect the number of Tregs in 6-day culture. Upon exposure to thymoglobulin Tregs maintained their suppressive activity, increased expression of CCR7, and released multiple cytokines, primarily interleukin (IL)10. Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with CD34(+) cells after preparative regimens including thymoglobulin.

Lymphoproliferative Disorders and De Novo Malignancies in Intestinal and Multivisceral Recipients: Improved Outcomes With New Outlooks

Early experience with intestinal and multivisceral transplantation was plagued with high risk of rejection and posttransplant lymphoproliferative disorders (PTLD). To improve outcome, innovative management and immunosuppressant strategies were sequentially evolved. With initiation of the program in 1990, serial monitoring of Epstein-Barr-Viral load was introduced in 1994 with adoption of preemptive antiviral therapy. In 1995, cyclophosphamide or daclizumab induction was added to the tacrolimus-steroid-based multiple drug immunosuppressions. Such a conventional approach was replaced in 2001 with a novel immunosuppressive protocol consisting of recipient pretreatment with a single dose of rabbit antithymocyte globulin or alemtuzumab and posttransplant tacrolimus monotherapy. With a total of 395 consecutive primary recipients, de novo malignancy(s) developed in 61 (15%) patients, with PTLD in 52 (13%), and nonlymphoid cancer (NLC) in 13 (3.2%). Malignancy was donor driven in 3 (4.6%) recipients and associated with graft-versus-host disease in 7 (11.4%). Children were at a significantly higher risk (P<0.001) of PTLD, and adults were more vulnerable (P=0.01) to NLC. With multivariate analyses, type of immunosuppression, recipient age, splenectomy, and treatment of rejection were significant PTLD risk factors. Despite pretransplant lymphoid depletion, preemptive antiviral therapy and minimization of posttransplant immunosuppression significantly reduced PTLD morbidity (P=0.0001) and mortality (P=0.001) with no impact on NLC. Patient survival was also improved (P=0.0001) with 91% at 1 year and 75% at 5 years.

A Randomized Trial of Rabbit Anti-Thymocyte Globulin, Given on Day+7 after Alternative Donor Transplants.

Background. We have shown that the risk of transplant mortality (TRM) can be predicted by using laboratory values, on day+7 after an allogeneic hemopoietic stem cell transplant (HSCT) (Sormani et al, Bone Marrow Transpl.2003). TRM in patients with low, intermediate and high risk on day+7, is 15%, 40% and 69%: increased mortality is mainly, but not exclusively, due to increased acute graft versus host disease (GvHD). In a pilot study we have shown that a small dose of rabbit anti-thymocyte globulin (rATG) (Thymoglobulin, Genzyme), was feasible and reduced GvHD and TRM.Aim of the study. We have therefore opened a randomized trial testing this hypothesis in patient undergoing an unrelated donor HSCT, with rATG (7.5 mg/kg) in the conditioning regimen.Patients. 170 were eligible: all patients received rATG 3.75 mg/kg x2 pre-transplant, and on day+7 they were scored and randomized to receive an additional dose of rATG (1,25 mg/kg day +7 and day+9) (n=84) or to receive no further treatment (n=86) (control arm). The two groups were balanced for age, disease phase and day+7 score.Results. The predictive value of day+7 score on TRM was confirmed in the control arm (18% vs 42% for intermediate and high risk patients, p=0.03), whereas in the day+7 ATG arm, there was no difference (29% vs 29%, p=1.0). TRM was overall reduced from 35% in the control arm to 29% in the ATG day+7 arm (p=0.37) : the difference was more pronounced in patients with early disease and high risk on day 7 (35% vs 15% p=0.08). Acute GvHD grade III–IV was reduced overall from 16% to 6% (p=0.04), and chronic GvHD was reduced 32% to 14% (p=0.02). In multivariate COX analysis TRM and overall survival was predicted by risk score day7 and disease phase.Conclusions. We confirm that patients with different risk of TRM can be identified on day+7 after HSCT. Administration of rATG on day+7 can influence the risk of TRM, by reducing acute and chronic GvHD. Additional intensified supportive care (including anti-infectious therapy) may further reduce TRM in patients with a high risk score on day+7.