Anti-thymocyte Globulin Prophylaxis Research Articles

Posttransplant cyclophosphamide versus anti-thymocyte globulin versus combination for graft-versus-host disease prevention in haploidentical transplantation for adult acute myeloid leukemia: A report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

The optimal choice for graft-versus-host disease (GVHD) prophylaxis in haploidentical stem cell transplantation (haplo-SCT) remains debatable. Posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are two common strategies, but little is known about their combination. Using the European Society for Blood and Marrow Transplantation (EBMT) registry, the authors identified 3649 adult patients with acute myeloid leukemia (AML) who underwent haplo-SCT in complete remission between 2007 and 2021 at 260 EBMT-participating centers who received either PTCy (n=2999), ATG (n=358), or combination prophylaxis (n=292). Cord blood transplants, combined bone marrow and peripheral grafts, and transplants with ex vivo graft manipulation were excluded. Median follow-up was 31.8 months. On multivariate analysis, adjusting for patient age and performance status, disease status at transplant, cytogenetic risk, conditioning intensity, stem cell source, female-to-male graft, and donor and patient CMV status, we present the following. Compared to PTCy, ATG had a higher risk of nonrelapse mortality (hazard ratio [HR], 1.6; p=.003), worse leukemia-free survival (HR, 1.4; p=.002), overall survival (HR,1.49; p=.0009), and GVHD-free and relapse-free survival (HR,1.29; p=.012). The combination of PTCy and ATG, however, led to significantly reduced rates of grade 2-4 (HR, 0.51; p=.0003) and grade 3-4 (HR, 0.5; p=.018) acute GVHD and did not affect any transplant outcomes compared to PTCy without ATG. The authors conclude that ATG alone is a less effective prophylaxis strategy compared to PTCy, however, the combination of PTCy and ATG is superior to either monotherapy. They propose that this combination could be considered a potential new standard of care for GVHD prophylaxis in haplo-SCT for AML.

Graft-Versus-Host-Disease Prophylaxis with ATG or Ptcy in Patients with Lymphoproliferative Disorders Undergoing Reduced Intensity Conditioning Regimen 9/10 Mmud HCT

Introduction: Post-transplant cyclophosphamide (PTCY) has been introduced as a graft-versus-host disease (GvHD) prophylaxis in haploidentical setting with successful results. As a result, PTCY has been applied to other settings such as in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, T-cell depletion with anti-thymocyte globulin (ATG) remains the main strategy in one antigen HLA-mismatched unrelated donor (9/10 MMUD). Data comparing the two GvHD prophylaxis strategies in patients undergoing MMUD 9/10 for lymphoproliferative disease are limited. Methods: We compared PTCY versus ATG as GvHD prophylaxis in patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Adult patients in all disease status for which high-resolution HLA-allele typing was available in the European Society for Blood and Marrow Transplantation (EBMT) data registry were included. Patients receiving PTCY were matched to patients receiving ATG according to the following variables: age, disease status at transplant, female to male donor status, stem cell source and CMV serology. Results: A total of 411 patients were identified (n=341 for ATG group and n=70 for PTCY group). According to the above mentioned variables, 106 patients receiving ATG were identified and matched with 58 patients receiving PTCY. Among the group of 164 patients paired up, diagnosis was Hodgkin Lymphoma in most of the cases (19% and 38% in the ATG and PTCY group, respectively). The median age was 54 (range 21-69) and 52 (range 22-69) years old in the ATG and PTCY group, respectively (p= NS). The majority of patients underwent a previous autologous HCT (72% in the ATG and 68% in the PTCY group, respectively). Disease state at HCT was complete remission in 71% of the patients in both ATG and PTCY group. The most frequent GvHD prophylaxis in the ATG group was cyclosporine A (CsA) and methotrexate (MTX) (n=51; 48%), followed by CsA and mycophenolate mofetil (MMF) (n=31; 29%). In the PTCY group, the majority of patients (n=30; 52%) received CsA and MMF, while tacrolimus and MMF (n=27; 46%) represented the second most used associated immunosuppressive agents. The median follow-up was 5.1 (CI: 3.8-6.7) years for the ATG group and 1.7 (CI 0.9-2.4) years in the PTCY group. The cumulative incidence of neutrophil engraftment was 97% (CI:90.5-99.1) and 100% in ATG and PTCY groups, respectively (p=0.08). Grade III-IV acute GVHD at 100 day was not significantly different between the two groups 11.3% (CI:6-18.6) versus 17.4% (CI: 8.1-29.7) in the ATG and PTCY group, respectively; p=0.60). No differences were observed in 1-y relapse incidence (22.3% (CI: 11.5-27.6) versus 17.3% (CI: 7.4-30.5), p=0.32) and non-relapse mortality (19% versus 32%, p=0.20). GvHD-free, relapse-free survival was not different across the two groups (43.5% (CI: 33.2-53.3) in ATG and 46.9% (CI: 31.2-61.2) in PTCY, p=0.88). The cumulative incidence of 1-year extensive chronic GvHD was 14.4% (CI: 7.8-22.9) in the ATG group and 5.3% (CI: 0.9-15.9) in the PTCY group, respectively (p=0.21). The 1 year-progression free survival was 58.9% (CI: 47.9-68.3) in patients receiving ATG and 50.7% (CI: 34.3-65) in those receiving PTCY (p=0.74) and 1-year overall survival was 65.9% (CI: 55.4-74.4) in the ATG group versus 55.2% (CI: 38.8-68.9) in the PTCY group (p=0.69). Forty-seven patients died in the ATG group, 20 died in the PTCY group. The main cause of death was transplant related complications (n=27 in ATG and n=14 in PTCY patients, respectively) followed by relapse of disease (n=13 in ATG and n=4 in PTCY group). Conclusions: In patients with lymphoproliferative diseases undergoing 9/10 MMUD HSCT, PTCY as GVHD prophylaxis might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed to allow better understand the effectiveness of adding PTCY into different platforms, including MMUD 9/10 HSCT.

Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia.

Graft-versus-host disease (GvHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation includes posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing data in the European Society for Blood and Marrow Transplantation registry, we compared ATG- versus PTCy-based GvHD prophylaxis in 434 adults with acute lymphoblastic leukemia undergoing haploidentical hematopoietic cell transplantation. Of the 434 patients included in this study, ATG was used in 98 and PTCy in 336.. The median follow-up was approximately 2 years. The baseline characteristics of the patients were similar between the groups except that the ATG group was more likely to have had relapsed/refractory acute lymphoblastic leukemia (P=0.008), had conditioning not including total body irradiation (P<0.001), have had peripheral blood as the source of their grafts (P≤0.001) and to have been transplanted in an earlier timeperiod (median year of transplantation: 2011 vs. 2015). The 100-day rates of grade II-IV and III-IV acute GvHD were similar in the ATG and PTCy groups, as were 2-year chronic GvHD rates. On multivariate analysis, leukemia-free survival and overall survival were better with PTCy than with ATG prophylaxis. Relapse incidence was lower in the PTCy group (P=0.03), while non-relapse mortality was not different. Advanced disease and lower performance score were associated with poorer leukemia-free survival and overall survival and advanced disease was associated with inferior GvHD-free/relapse-free survival. Compared to bone marrow grafts, peripheral grafts were associated with higher rates of GvHD. In patients with acute lymphoblastic leukemia undergoing unmanipulated haploidentical hematopoietic cell transplantation, PTCy for GvHD prevention resulted in a lower incidence of relapse and improved leukemia-free survival and overall survival, compared to ATG.

Anti-Thymocyte Globulin Prophylaxis Induces a Decrease in Naive Th Cells to Inhibit the Onset of Chronic Graft-versus-Host Disease: Results from the Canadian Bone Marrow Transplant Group (CBMTG) 0801 Study.

Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21low B cells, CD56bright NKreg cells, and Treg cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56bright NKreg cells (P < .0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.

Risk Factors for Graft-Versus-Host Disease After Transplantation of Hematopoietic Stem Cells from Unrelated Donors in the China Marrow Donor Program.

BackgroundWe identified risk factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) in recipients after hematopoietic stem cell transplantation (HSCT) from unrelated donors in the China Marrow Donor Program (CMDP).Material/MethodsWe analyzed follow-up clinical information from 1824 patients who underwent HSCT between 2001 and 2010.ResultsThe incidence of aGVHD and cGVHD after transplantation was 49.29% and 27.3%, respectively. aGVHD incidence decreased as HLA matching increased (p<0.001). Incidence of aGVHD and cGVHD was higher in 2 HLA-A locus donor/recipient groups (02: 01/02: 06 and 02: 01/02: 07; p≤0.022). aGVHD incidence was associated with patient age, absence of rabbit anti-thymocyte globulin (ATG) pretreatment, and disease status (p≤0.040). aGVHD appeared to be a risk factor for cGVHD, and total body irradiation (TBI) was also associated with cGVHD. Patients with cGVHD after transplantation had a higher survival rate than patients without cGVHD (p<0.001), which may be due to reduced relapse rates. Survival was also associated with ATG prophylaxis and disease status.ConclusionsThe incidence of GVHD after HSCT from unrelated donors in the Chinese population is similar to the results reported from other countries. A high degree of HLA matching, a conditioning regimen without TBI, and the use of ATG may reduce the incidence of aGVHD.

Anti-Thymocyte Globulin for Graft-Versus-Host Disease Prophylaxis in Patients with Acute Myeloid Leukemia Undergoing Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation in First Complete Remission: A Survey on Behalf of the EBMT Acute Leukemia Working Party

Introduction: Anti-thymocyte globulin (ATG) prophylaxis was shown to be effective in reducing both acute and chronic graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (allo-SCT). In previously published studies, the addition of ATG to the pre-allo-SCT conditioning regimen resulted in substantial reduction in GVHD incidence, but theoretically ATG could be associated with increased relapse rate, especially if administered at high doses (> 6 mg/kg of ATG Thymoglobulin or >15mg/kg of ATG Fresenius) to patients with high-risk acute myeloid leukemia (AML). To further address this question, we assessed transplantation outcome in adult AML patients who underwent reduced intensity conditioning (RIC) allo-SCT from a matched sibling donor (MSD) while in complete remission (CR1), with or without ATG. We used the registry data of the Acute Leukemia Working Party of the European Society forBlood and Marrow Transplantation (EBMT).Patients and Methods: Inclusion criteria were adult patients with AML (de novo or secondary) who underwent RIC allo-SCT from an MSD in CR1 between the years 2000 and 2014. RIC conditioning was defined as per the EBMT criteria. Only patients presenting with intermediate- or poor-risk cytogenetics or secondary AML were included in the analysis. Patients who received any kind of T cell depletion including Campath were excluded. Patients were considered to receive high-dose ATG if they received > 6mg/kg of ATG-Thymoglobulin or >15mg/kg of ATG-Fresenius. All other patients were considered as a control.Results: Two hundred and five of the 1750 patients, included in the analysis, received high-dose ATG. The median patient age at diagnosis was 56 years and the median donor age was 55 years for both groups. Fifty four percent of the patients were males. The graft properties were similar in the high-dose ATG and control groups, with female-to-male transplants in 48/205 (23.4%) and 378/1545 (24.6%) patients, respectively. Peripheral blood was the source of grafts in 193/205 (94.1%) and 1413/1545 (91.5%) patients, respectively (p=NS). Poor cytogenetics was reported in 28/205 (13.7%) patients who were given high-dose ATG and in 247/1545 (16%) patients from the control group. Secondary AML was more prevalent among patients from the high-dose ATG group compared to the control group [84/205 (41%) vs 425/1545 (27.5%; p=0.0003]. The median follow-up was 44.6 (0-177) months.The 3-year overall survival (OS) and leukemia-free survival (LFS) were almost identical in both groups, amounting to 54.9 and 46.3 months, respectively for patients who received high-dose ATG and to 54 and 49.5 months, respectively for patients in the control group (p=0.978 and 0.376 ). Differences in relapse incidence (RI) (40.9% vs 34.4%; p=0.1) and non-relapse mortality (NRM) (11.7% vs 16%; p=0.152) were insignificant. The composite endpoint of GVHD-free/relapse-free survival (GRFS) was similar in the groups after one and three years of follow-up (42.9 vs 49.7 and 31.1 vs 36 months, respectively; p=0.152 and p=0.124). In multivariate analysis, the use of ATG prophylaxis was not found to be associated with any of the evaluated parameters. In contrast, OS, LFS, RI, NRM and GRFS were all affected by patient age and presence of secondary AML. Poor cytogenetics correlated with inferior OS, LFS, RI and GRFS. Donor CMV positivity was associated with lower OS, LFS and GRFS and a higher rate of NRM.Conclusions: In AML patients presenting with intermediate- or poor-risk cytogenetics who are referred to RIC allo-SCT from an MSD in CR1, the addition of ATG to conditioning regimens does not influence the outcome. The composite GRFS endpoint is mainly affected by AML risk factors (hazard ratio of 1.43 for secondary AML and 1.37 for poor-risk cytogenetics; p=0.0001). The role of ATG prophylaxis in AML patients undergoing RIC allo-SCT should be prospectively evaluated. DisclosuresMaertens:Gilead: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy; Astellas: Consultancy, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups.

Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial

Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87-9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died-the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG. ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. The Canadian Institutes of Health Research and Sanofi.

Low-Dose Antithymocyte Globulin, Post-Transplant Cyclophosphamide and Sirolimus As Graft-Versus-Host Disease Prophylaxis in Unrelated Donor Transplants

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for several patients with high-risk hematological malignancies. Recent advances in supportive therapies have significantly reduced the treatment-related mortality over the last decades. Nevertheless graft-versus-host disease (GvHD) still represents a major complication, and research is needed to achieve further progress in this area of transplantation. Moreover, although initial studies suggested relative equivalence, recent and large prospective studies showed higher rates of acute and chronic GvHD, and worse survival in allo-HSCT from unrelated donors (URD) compared with HLA-identical sibling donors. Following our encouraging results in haplodentical setting with the more recently post-transplantation cyclophosphamide (PTCy) and sirolimus as GvHD prophylaxis (Cieri et al, 2015), in this study we investigated whether the incorporation of low dose anti-thymocyte globulin (ATG) to PTCy and sirolimus GvHD prophylactic approach, may alleviate some of the increased alloreactivity associated with URD transplants.We retrospectively evaluated a cohort of 21 haematological patients receiving URD allo-HSCT in the San Raffaele Haematology and BMT Unit, from 2013 to 2015.All subjects had high-risk hematologic malignancies, with the most common diagnosis being myeloid diseases (52%). A total of 11 patients had active disease at HSCT, while 9 were in hematologic remission. Nine patients scored high according to disease risk index defined by Armand et al, 10 scored intermediate, while only 2 had a low disease score.Myeloablative conditioning consisted of treosulfan (14 g/m2/day) on days -6 to -4, fludarabine (30 mg/m2/day) on days -6 to -2, and melphalan (70 mg/m2/day) on days -2 and -1, followed by T-replete G-CSF-mobilized PBSCs (n=19) or BM grafts (n=2). Whether 12 patients received stem cells from HLA- matched URD (fully 10/10 HLA matched), the remaining 9 had one-locus HLA-mismatched from their donors. During conditioning patients received ATG-Fresenius 5 mg/kg per day IV on day -4 to -2. In vivo B-cell depletion was obtained by rituximab (i.v. 375mg/m2 given as a single dose on day -1). Postgrafting immunosuppression consisted of PTCy (50 mg/kg/day) on days 3 and 4. Sirolimus was given orally from day 5, and monitored to maintain a target therapeutic plasma level of 5-14 ng/ml. According to chimeric status and evidence of GVHD, the dosage of sirolimus was tapered during the second month post-transplantation, ending in complete withdrawal within the sixth month after HSCT. Mycophenolate mofetil (MMF) was initiated orally at 10 mg/kg t.i.d. on day 5 after HSCT, and withdrawn on day 30.Median follow up was 247 days (range 29-486) from HSCT. All patients were engrafted in a median time of 17 days (range, 14-51 days), with full donor chimerism achieved by day 30. Poor graft function was observed in 11 patients. Post-HSCT recovery of lymphocyte subsets was lengthy as compared to other unmanipulated HSCT, with a median time to CD3>100/ml of 41 days (range, 22-389 days) by flow-cytometry, while 5 patients never reached immune reconstitution.All except one developed febrile neutropenia during aplasia. We observed a high rate of serious infections: severe pneumonia in 7 cases (5 required NIV, 4 were admitted to ICU), CMV reactivation in 13 (3 CMV disease), HHV6 reactivation in 10, BK virus haemorrhagic cystitis in 2 patients. Although the overall mortality associated with these complications was limited, as evidenced by a favourable NRM, it caused significant morbidity in patients and often required aggressive therapies, potentially contributing to poor graft function.The incidences of acute and chronic GVHD were low. A grade II-IV acute GvHD was reported in 10% patients, while five patients developed chronic GvHD (mild in 4 cases, only one moderate).Non-relapse mortality (NRM) at 100 days and 1 year was 4.8% and 20.7%, respectively. The estimated 1-year overall survival (OS) and relapse incidence were 51% and 22.5% respectively.Although limited by a small number of patients with relatively short follow-up, our study suggests that URD allo-HSCT with ATG, PTCy and sirolimus-based GvHD prophylaxis, can be very effective in preventing GvHD, but at the expense of delayed immune reconstitution and high rate of infectious complications, while warranting acceptable NRM and relapse incidence. DisclosuresBonini:MolMed S.p.A: Consultancy.

Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation.

In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched-related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II-IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival.

Pretransplantation GAD-Autoantibody Status to Guide Prophylactic Antibody Induction Therapy in Simultaneous Pancreas and Kidney Transplantation

Daclizumab and antithymocyte globulin (ATG) have been shown to reduce allograft rejection. We assessed the safety and efficacy of daclizumab or ATG prophylaxis in combination with triple immunotherapy in simultaneous pancreas-kidney transplant (SPKT) recipients. Thirty-nine type 1 diabetic patients scheduled for primary SPKT were randomized to receive prophylactic therapy with either daclizumab or ATG. A group of 27 patients without prophylactic antibodies was used for retrospective comparison. All patients received cyclosporine and mycophenolate mofetil and gradually tapered prednisone. Autoantibodies and cellular autoreactivity were measured to assess recurrent autoreactive responses. Baseline and transplant characteristics were comparable among groups. Both daclizumab and ATG therapy resulted in a significant reduction in acute rejection episodes. The incidence of rejection episodes was significantly higher in pretransplantation GAD autoantibody-positive daclizumab-treated recipients compared with GAD autoantibody-negative or ATG-treated recipients. IA-2 islet autoantibodies showed no association with rejection. There were no significant differences between the groups for in vitro autoreactivity, clinical outcome, or functional parameters. Daclizumab or ATG combined with a maintenance immunosuppressive regime consisting of cyclosporine, mycophenolate mofetil, and prednisolone were well tolerated and equally effective in reducing the incidence of acute rejection episodes in SPKT recipients. Up to 3 years, no adverse sequelae of the immunoprophylaxis or clinical and ex vivo recurrent autoimmunity were observed. We propose that the pretransplantation existence of GAD65 autoantibodies serves as a marker guiding the choice for prophylactic therapy in pancreas transplantation.

Effect of Antithymocyte Globulin Dosage for Prophylactic Gvhd On Epstein-Barr Virus Reactivation and Diseases in Allogeneic Hematopoietic Stem Cell Transplantation

Abstract 4486 Background:Antithymocyte globulin (ATG) is one of the main risk factors for Epstein-Barr virus (EBV) reactivation and disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, whether there is a correlation between ATG dose and EBV reactivation is unsure. Aim of this single-center prospective study is to explore the relationship between ATG dose and EBV reactivation in allo-HSCT. Methods:Ninety-nine patients with hematologic malignancies underwent allo-HSCT and administration of ATG for graft versus host disease (GVHD) prophylaxis were enrolled in this study in Nanfang hospital from February 2008 to February 2012. Sixty-one patients were unrelated donor transplants, thirty-eight were HLA-mismatched related donor transplants. GVHD prophylactic regimen was cyclosporine A+Methotrexate+ATG. According to donors’ HLA matching, we chose three dosage groups of prophylactic ATG: low dose group with ATG dose of 5.0∼6.0mg/kg (n=28), medium dose group with ATG dose of 7.0∼8.0mg/kg (n=55), and high dose group with ATG doses of ≥10mg/kg (n=16). The levels EBV-DNA in plasma were regularly monitored by quantitative real-time polymerase chain reaction (RQ-PCR). Results:With a median follow-up of 21 (range, 1–50) months post allo-HSCT, the cumulative incidence of EBV viremia and EBV-associated diseases was 17.6% (5/28) and 17.6% (5/28) in low dose group, respectively, with 32.7% (18/55) and 29.1% (16/55) in medium dose group, respectively, with 50.0% (8/16) and 31.3% (5/16) in high dose group, respectively. There were statistical significances of the incidence (χ2□□9.555, P=0.008). Logistic regression models showed that ATG prophylaxis was one of the main risk factors for EBV infection (RR=16.728, P=0.000) while bivariate correlation analysis presented that the incidence of EBV reactivation was positively correlated with ATG prophylaxis dosage (rpearman = 0.452, P = 0.000). The cumulative incidence of high degree (II∼IV°) aGVHD was 35.7% (10/28) in low dose group, with 39.6% (21/53) in total and 50.0% (6/12) in relapsed leukemia with HLA-mismatched related transplantation in medium dose group, with 68.8% (11/16) in high dose group. There were not statistical significances of the incidence (χ2□□6.971, P=0.137). Conclusion:EBV reactivation might be positively correlated with ATG prophylaxis dosage. According to donors' HLA matching, reducing ATG prophylaxis dose appropriately could prevent EBV reactivation in allo-HSCT without increasing high degree aGVHD. Disclosures:No relevant conflicts of interest to declare.

Effect of Prophylaxis With Low-Dose Anti-Thymocyte Globulin on Prevention of Acute Kidney Allograft Rejection

Introduction During kidney transplantation, the first contact between the recipient’s immune system and the donor organ takes place immediately following the arterial anastomosis. The aim of this study was to evaluate the efficacy of a single, low-dose anti-thymocyte globulin (ATG) prophylaxis in the reduction of early acute rejection in renal allograft recipients. Methods In a randomized, controlled clinical trial, we studied the rate of acute rejection within the first month of kidney transplantation in patients who had received their transplant at a single center between the years 2004 and 2007. The patients were divided into 2 groups: group 1 (n = 37) received cyclosporine, mycophenolate mofetil or azathioprine, and prednisolone; group 2 (n = 31) received the above-mentioned agents plus a single ATG bolus (Thymoglobulin; SangStat, Lyon, France; 4–5 mg/kg) the night before the transplantation (∼12 hours before the operation). Blood urea and serum creatinine levels were measured regularly in the posttransplantation period. Acute allograft rejection was justified clinically and/or pathologically. Statistical analysis was performed by SPSS 13.0 using Student t test and Fisher exact test. A P value ≤ .05 was considered to indicate statistical significance. Results There were no significant differences regarding the age and gender ratio between the 2 groups. Acute allograft rejection was found in 32.4% (n = 12) of group 1 patients, and was reduced to 12.9% (n = 4) in group 2 ( P = .05). Hence, the first-month acute rejection episodes decreased by ∼60% with ATG prophylaxis in renal transplant recipients. Conclusion Prophylactic administration of a single and low-dose ATG the night before kidney transplantation could reduce the risk of acute allograft rejection in renal transplant recipients. However, further studies with a greater number of patients should be conducted to confirm these results.

Single-bolus high-dose ATG for prophylaxis of rejection in renal transplantation - a prospective, randomized study

Abstract Currently, most centers use antithymocyte globulin (ATG) for induction or treatment of acute rejection. In the literature, postponement of introduction of cyclosporin or delay in acute rejection following ATG induction are well documented [1-4]. In contrast, data are very scant on the reduction of incidence of rejection or improvement of graft survival following ATG prophylaxis [5, 6]. The objective of this study was to compare the efficacy and safety of ATG high-dose single-bolus therapy with that of a standard cyclosporine-based protocol in prophylaxis of acute rejection in renal transplantation in an adult population. Rabbit ATG (Fresenius, Oberursel) was administered intraoperatively (before revascularization) to 19 renal transplant recipients as a single intravenous injection in a dose of 9 mg/kg body weight (high dose, single bolus). Treatment results were compared with those of a control group comprising 19 recipients receiving the same cyclosporin-Neoral-based protocol as the study group. In all patients concomitant medication consisted of steroids and azathioprine. The incidence of acute rejection in the high-dose ATG bolus group was 26%, compared with 58% in controls (P < 0.05). In the ATG treated group no grafts were lost to acute rejection in both high-and low-risk recipients, versus compared with a loss of 37% of rejecting grafts in controls. Though the observed difference in 1-year graft survival between study and control groups (84.2% vs 73.6%) did not reach statistical significance, the same trend was also observed in patients (n = 9 and n = 12 respectively) who, at he time of this report, had completed a 2nd post-transplantation year. The bolus and control groups had a similar incidence of complications and comparable renal function. We conclude that a single-bolus high-ATG protocol is efficient and safe in prophylaxis of renal allograft rejection.