Optimal Dose Of Antithymocyte Globulin Research Articles

Optimal dose of anti-thymocyte globulin to improve allograft and patient survival after kidney transplantation: analysis from Korean Organ Transplantation Registry data

Optimal dose of anti-thymocyte globulin to improve allograft and patient survival after kidney transplantation: analysis from Korean Organ Transplantation Registry data

Antithymocyte globulin for graft-versus-host disease prophylaxis, past, present and future

Antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis has been demonstrated for chronic GVHD inhibition by a series of randomized control trials. The optimal dose of ATG remained unestablished; however, the recommended dose of ATG by the European Group for Blood and Marrow Transplantation has recently decreased. While a lower ATG dose has been used in Japan, ATG usage is recommended in peripheral blood stem cell transplantation or human leukocyte antigens (HLA) 1-locus mismatched bone marrow transplantation with myeloablative conditioning from the nation-wide retrospective studies showing that ATG inhibited chronic GVHD and improved GVHD-free, relapse-free survival. The association of absolute lymphocyte counts (ALC) before ATG administration with transplant outcomes has been reported, which suggests a possible strategy to individualize the ATG dose according to ALC before ATG. Recent studies compared the transplant outcomes using ATG and post-transplant cyclophosphamide, which has rapidly spread in haploidentical transplantation; however, further studies are needed to establish those positioning in HLA-matched/mismatched transplantation.

Graft-Versus-Host Disease Prophylaxis Using Low-Dose Antithymocyte Globulin in Peripheral Blood Stem Cell Transplantation—A Matched-Pair Analysis

Antithymocyte globulin (ATG) decreases chronic graft-versus-host disease (cGVHD) in peripheral blood stem cell transplantation (PBSCT); however, the optimal ATG dose has not been elucidated. We conducted a matched-pair analysis to evaluate whether low-dose ATG could inhibit cGVHD in HLA-matched PBSCT after myeloablative conditioning. A total of 70 patients who were enrolled in the JSCT-ATG15 study, a multicenter phase II clinical trial of 2 mg/kg of ATG (thymoglobulin) given on days −2 and −1, were compared with 210 patients not receiving ATG, who were matched for age, sex, disease, and calcineurin inhibitor selected from the database in Japan. The primary endpoint, cumulative incidence of extensive cGVHD at 2 years was significantly less in the ATG group than that in the non-ATG group (8.7% [95% CI, 3.5%-16.8%] versus 26.2% [95% CI, 20.3%-32.5%], P = .002). ATG significantly reduced the incidence of overall cGVHD and inhibited multiple organ involvement. The ATG group had favorable outcome compared to the non-ATG group in GVHD-free, and relapse-free survival at 2 years. In conclusion, low-dose ATG effectively inhibits chronic GVHD in PBSCT.

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation.

Antithymocyte globulin is extensively used for prophylaxis of graft-versus-host disease in patients undergoing haploidentical hematopoietic stem cell transplantation. However, different doses of antithymocyte globulin are administered in clinical practice. This study aimed to identify the optimal dose of antithymocyte globulin (thymoglobulin) in haploidentical hematopoietic stem cell transplantation. We retrospectively analyzed the effects of 10 mg/kg (2.5 mg/kg on days -5 to -2) versus 7.5 mg/kg thymoglobulin (2.5 mg/kg on days -4 to -2) on patients receiving haploidentical hematopoietic stem cell transplantation with myeloablative conditioning. We observed significant differences between the 2 treatment groups with regard to cumulative incidence of grade II to IV acute graft-versus-host disease (15.3% vs 14.6%; P = .93) and 3-year chronic graft-versus-host disease (12.1% vs 14.3%; P = .77). The probabilities of 3-year overall survival (68.9% vs 73.5%; P = .98) and graft-versus-host disease-free/relapse-free survival (66.7% vs 53.1%; P = .14) were comparable between the 2 groups. However, there was a trend for lower cumulative incidence of hemorrhagic cystitis in the 7.5 mg/kg treatment group compared with the 10 mg/kg treatment group (40.7% vs 24.4%; P = .07). For patients who received a reduced dose of antithymocyte globulin (7.5 vs 10 mg/kg), there was no impaired effect on prophylaxis of graft-versus-host disease, with a trend of reduced incidence of hemorrhagic cystitis. Further studies of the 7.5 mg/kg dose of antithymocyte globulin are warranted for patients receiving haploidentical hematopoietic stem cell transplantation.

Safety of Cumulative Dose Anti-Thymocyte Globulin in Lung Transplant

<h3>Purpose</h3> The optimal dose of anti-thymocyte globulin (ATG) in kidney transplant is well established, however, dosing of ATG in lung transplant (LTx) is not well defined. LTx patients have a more delicate balance between infection and rejection given higher immunosuppression goals and constant exposure of the graft to the external environment. We sought to evaluate the optimal dose (mg/kg) of ATG in LTx patients. <h3>Methods</h3> LTx patients who received ≥1 dose of ATG between 6/2016 and 9/2019 were categorized based on indication (induction, treatment of rejection, or treatment of chronic allograft dysfunction (CLAD)). Cumulative dose (mg/kg) was calculated using actual weight at time of ATG. Safety endpoints following the last ATG dose included infection ≤1 year and malignancy until last follow-up. <h3>Results</h3> ATG indications were induction (n=11, 24%), rejection (n=21, 47%), and CLAD (n=13, 29%). Median doses (mg/kg) were: 3.2 for induction, 4.9 for rejection, and 4.2 for CLAD. Bacterial infections occurred in 23 patients (51%) (1 clinically significant urinary tract infection requiring intravenous antibiotics, 12 blood stream, and 19 respiratory) at a median of 38 days (d) after last ATG dose; viral infections occurred in 11 patients (24%) with cytomegalovirus viremia being the most common; fungal infections occurred in 27 patients (60%). The most common organisms identified were Pseudomonas and Aspergillus species. Four patients (9%) developed malignancy at a median of 339d, including 3 cases of cutaneous malignancy and 1 case of small cell lung cancer. <h3>Conclusion</h3> Safety concerns with ATG in LTx include infection and malignancy with a possible dose-correlated risk. We found a >50% incidence of both bacterial and fungal infections following ATG; those who received ATG for induction experienced the highest rates (64% bacterial, 73% fungal). The high incidence of infections supports using lower cumulative doses, however, further evaluation into the ideal dosing threshold to balance safety and efficacy within each ATG indication is warranted.

Efficacy of low dose antithymocyte globulin on overall survival, relapse rate, and infectious complications following allogeneic peripheral blood stem cell transplantation for leukemia in children

Antithymocyte globulin (ATG) and anti-T lymphocyte globulin (ATLG) have been widely used to prevent graft-versus-host disease (GvHD), each with distinct properties and noninterchangeable doses. However, the optimal dose of ATG in children undergoing allo-PBSCT for leukemia has not yet been established. Therefore, the impact of ATG dose on overall survival (OS), relapse, GvHD, and infectious complications was investigated. Patients administered high dose (unrelated: 7.5 mg/kg, haploidentical: 10.0 mg/kg) and low dose (unrelated: 3.75 mg/kg, haploidentical: 5.0 mg/kg) ATG during two consecutive time periods were compared. There were 78 (39.8%) patients in the low dose group and 118 (60.2%) in the high dose group. OS was superior in the low dose group compared to the high dose group (P = 0.017), and relapse incidence was significantly lower in the low dose group (P = 0.022). Cumulative incidences of acute and chronic GvHD were similar between the groups (P = 0.095 and P = 0.672, respectively). Cytomegalovirus reactivation (70.3% vs. 51.3%, P = 0.007), Epstein-Barr virus reactivation (81.4% vs. 39.7%, P < 0.001), and invasive bacterial infections (12.7% vs. 0%, P = 0.001) post transplant were more frequent in the high dose group compared to the low dose group. Therefore, low dose ATG is more optimal in pediatric allo-PBSCT providing better OS while lowering the risk of relapse and infectious complications.

Long-Term Follow-up of a Randomized Trial of Two Dose Levels of Antithymocyte Globulin in Haploidentical Hematopoietic Stem Cell Transplantation

Background The optimal dose of antithymocyte globulin (ATG) with respect to the prevention of graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is under investigation. In our previous single-center randomized study, as compared with 6 mg/kg ATG, 10 mg/kg ATG was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection-related deaths. Later on, in our multi-center randomized trial, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in comparison with 10.0 mg/kg ATG in haplo-HSCT. Methods We reanalyzed and updated the prospective, randomized trial (clinicaltrials.gov, NCT01883180) identifying the influence of 7.5mg/kg versus 10.0 mg/kg of ATG on clinical outcomes in haplo-HSCT with extended follow-up (N=145. Seventy-six patients received 7.5 mg/kg ATG (ATG-7.5), whereas the remaining patients received 10 mg/kg ATG (ATG-10). Results The median follow-up period was 1702 days (range, 23-2036 days). The rate of infection-related deaths in ATG-10 arm was double that of the ATG-7.5 arm (20.0% vs 11.8%; P=0.024). The 5 year cumulative incidence of relapse was not significantly different between the ATG-7.5 and ATG-10 groups (16.8% vs. 5.7%, P = 0.053). The 5 year cumulative incidence of non-relapse mortality was comparable between the ATG-7.5 and ATG-10 groups (27.6% vs. 28.7%, P = 0.938). The 5 year cumulative incidence of chronic GVHD (46.7% vs. 48.3%, P = 0.913), moderate-to-severe chronic GVHD (32.8% vs. 25.3%, P = 0.248), and severe chronic GVHD (17.1% vs. 13.3%, P = 0.505) were comparable between the ATG-7.5 and ATG-10 groups. The 5 year probabilities of disease-free survival (DFS) in the ATG-7.5 and ATG-10 groups were 55.6% and 65.7%, respectively (P = 0.281). The 5 year probability of GVHD-free/relapse-free survival (GRFS) in the ATG-10 group was significantly higher than that in the ATG-7.5 group (48.1% vs. 29.5%, P = 0.020). The 5 year cumulative incidence of late effects of grades 1-5 (67.2% vs. 71.2%, P = 0.695) and multiple late effects (26.2% vs. 25.4%, P = 0.920) were comparable between the ATG-7.5 and ATG-10 groups. In multivariate analysis, ATG-7.5 was associated with a significantly lower GRFS compared to ATG-10 (hazard ratio, 1.819; 95% confidence interval, 1.106-2.994; p=0.019). Conclusion it appears that 10 mg/kg ATG was found to be associated with superior GRFS and comparable GVHD and late effects, but an increase in infection-related deaths as compared with 7.5 mg/kg ATG for haplo-HSCT. Figure Disclosures No relevant conflicts of interest to declare.

Personalizing rabbit anti-thymocyte globulin therapy for prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation: is there an optimal dose?

The efficacy of anti-thymocyte globulin (ATG) as prophylaxis for graft-versus-host disease (GVHD) has been investigated by many clinical studies over the past decade, including some randomized controlled trials. Intriguingly, although ATG is commonly used as prophylaxis for GVHD, there is still controversy about the optimal dose of ATG for prophylaxis of GVHD after allogeneic hematopoietic cell transplantation (allo-HCT). Indeed, the dose and formulation of ATG, as well as the degree of clinical benefit, has varied among studies, which makes it difficult to fully determine the clinical benefit of ATG. The aim of this review is to summarize the information regarding the optimal ATG dose of each formulation according to stem cell source, and to discuss how best to determine the personalized optimal dose of ATG in each allo-HCT recipient.

PF762 EFFECTS OF TWO DOSES OF ANTITHYMOCYTE GLOBULIN IN CONDITIONING REGIMENS FOR HAPLOIDENTICAL PERIPHERAL BLOOD STEM CELL TRANSPLANTATION

Background:Antithymocyte globulin (ATG), an important in vivo T‐cell depletion strategy, has been used for graft‐versus‐host disease (GVHD) prophylaxis and shown significant clinical benefit. However, the optimal ATG dose remains unclear.Aims:To assess the effectiveness of ATG at a total dose of 10.0 mg/kg and 7.5 mg/kg for haploidentical peripheral blood stem cell transplantation (PBSCT).Methods:We retrospectively analyzed patients who underwent haploidentical PBSCT, receiving myeloablative conditioning and standard GVHD prophylaxis. ATG (rabbit thymoglobulin) at a total dose of 10.0 mg/kg (2.5 mg/kg on days −5 to −2) and 7.5 mg/kg (2.5 mg/kg on days −4 to −2) were used in the two groups.Results:40 and 35 patients were enrolled in the ATG‐10 and ATG‐7.5 groups, respectively. No significant difference was observed regarding the cumulative incidence of 100‐day grade II‐IV acute GVHD (20.0% vs 14.3%; p = 0.53) and 3‐year chronic GVHD (13.7% vs 15.7%; p = 0.83). The 3‐year probability of overall survival (OS) was 72.6% vs 74.4% (p = 0.81) and the 3‐year probability of GVHD‐free/relapse‐free survival (GRFS) was 69.0% vs 53.0% (p = 0.16). The incidence of relapse in the ATG‐7.5 group (30.9%) was higher compared with the ATG‐10.0 group (17.1%), but this difference was not statistically significant (p = 0.20). In multivariate analysis, the ATG dose was not associated with relapse, while no further respond to therapy (NR) before PBSCT predicted relapse (HR 1.19, p = 0.04). There were 5 patients (12.5%) and 8 patients (22.9%) in NR in the ATG‐10 and ATG‐7.5 groups, respectively (p = 0.19). Additionally, the ATG‐7.5 group had a trend for lower 300‐day incidence of EBV reactivation (92.5% vs 80.0%; p = 0.14) and CMV reactivation (90.5% vs 80.0%; p = 0.16), and lower 100‐day incidence of hemorrhagic cystitis (42.5% vs 28.6%; p = 0.15).Summary/Conclusion:7.5 mg/kg ATG led to lower incidence of EBV reactivation, CMV reactivation and hemorrhagic cystitis without compromising control of grade II‐IV acute GVHD, chronic GVHD and OS when compared with 10.0 mg/kg ATG. Therefore, ATG at a dose of 7.5 mg/kg could be considered for further study.

Antithymocyte globulin improves GVHD-free and relapse-free survival in unrelated hematopoietic stem cell transplantation.

Antithymocyte globulin (ATG) is an important component of conditioning regimens to prevent graft-versus-host disease (GVHD) in unrelated hematopoietic stem cell transplantation (HSCT), but the optimal dose of ATG remains unknown. We prospectively analyzed 205 unrelated HSCTs in patients with malignant hematological disorders. HSCTs were classified as follows: HLA-matched transplant without ATG (n = 53, group A), HLA-mismatched transplant treated with 6.0 mg/kg thymoglobulin (n = 77, group B), and HLA-matched transplant treated with 4.5 mg/kg thymoglobulin (n = 75, group C). For groups A and B, the 5-year moderate/severe chronic GVHD rates were 31.9% and 24.2%, the 5-year GVHD-free and relapse-free survival (GRFS) rates were 28.3 and 47%, and the 2-year immunosuppressive therapy (IST)-free survival rates were 8.6% and 40.2% (p = 0.0016), respectively. Furthermore, group C had lower incidences of grade II-IV acute GVHD (18.7%) and 5-year moderate/severe chronic GVHD (16.6%) than group A did. Group C had higher 5-year GRFS (52.1% vs 28.3%, p = 0.002), 2-year IST-free survival (51.7% vs 8.6%, p = 0.00004), and 5-year overall survival (OS) (68.3% vs 41.5%, p = 0.007) rates than group A did. Thus, ATG was associated with better GVHD prevention, a higher rate of IST-free survival, lower transplant-related mortality (TRM), and superior OS and GRFS in unrelated HSCTs.

Effect of antithymocyte globulin on HLA-mismatched unrelated transplantation.

HLA 1-locus-mismatched unrelated donors (1MMUD) are often considered as alternative donors in allogeneic hematopoietic stem-cell transplantation (allo-HCT) when an HLA-matched related or unrelated donor is unavailable. However, HLA mismatch remains a major risk factor for acute and chronic graft-versus-host disease (GVHD). Antithymocyte globulin (ATG) has been used to prevent acute and chronic GVHD, and multiple studies have shown that use of ATG is associated with decreased acute and chronic GVHD, which is associated with improved QOL. However, at high doses, ATG may lead to an increase in fatal infection, relapse, or delayed engraftment. The optimal ATG dose for MMUD remains unclear. The optimal ATG dose should be determined based on a fine balance between the reduction of GVHD and the risk of relapse, fatal infection, and/or delayed engraftment. Interestingly, promising results from some recent Asian studies suggest that a low dose of ATG may improve non-relapse mortality and overall survival without increasing relapse or fatal infection in allo-HCT from an HLA-mismatched unrelated donor. A randomized control trial is expected to confirm these results in Japan. In addition, pharmacokinetic/pharmacodynamic studies may help to identify the personalized optimal ATG dose.

Role of thymoglobulin in matched sibling allogeneic hematopoietic stem cell transplantation with busulfan and fludarabine conditioning in myeloid malignanicies.

In vivo T-cell depletion using anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis of GvHD. We investigated the influence of thymoglobulin dose (an ATG) on GvHD following matched sibling donor (MSD) HSCT with a busulfan and fludarabine preparative regimen. Medical records of 180 patients who received MSD HSCT with a conditioning regimen of busulfan, fludarabine, and ATG (BuFluATG) were reviewed retrospectively. The median age was 53 years (range 18-68). Initial diagnoses were acute myeloid leukemia (73.3%) and myelodysplastic syndrome (26.7%). Forty-four and 68 patients (24.4 and 37.7%) experienced acute and chronic GvHD of any grade, respectively. High-dose (⩾4.5 mg/kg) ATG was independently associated with decreased risk of acute GvHD (hazard ratio=0.36, 95% confidence interval (CI): 0.15-0.84, P=0.019) compared to low-dose ATG (<4.5 mg/kg). Although ATG dose was associated with the risk of acute GvHD, it was not associated with the risk of chronic GvHD in our study. A higher dose (⩾4.5 mg/kg) of ATG decreases the risk of acute GvHD but had no significant impact on disease-free survival in MSD HSCT patients conditioned with BuFluATG. The optimal dose of ATG should be further investigated in a large prospective study context.

Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: Long-term outcomes of a prospective randomized trial.

Antithymocyte globulin (ATG) is an important component of conditioning regimens to prevent severe graft-versus-host disease (GVHD) in patients undergoing unmanipulated, haploidentical stem cell transplantation (haplo-SCT). However, to the authors' knowledge, the optimal dose of ATG is unknown. In this prospective, randomized trial, the authors compared the long-term outcomes of 2 ATG doses (rabbit thymoglobulin) used in myeloablative conditioning before unmanipulated haplo-HSCT. Patients were randomly assigned (1:1) to received 10 mg/kg (ATG-10) or 6 mg/kg (ATG-6) of ATG. Analysis of disease-free survival, GVHD-free/recurrence-free survival (GRFS), disease recurrence, nonrecurrence mortality, and chronic GVHD (cGVHD) included the entire population. Late effects were assessed in disease-free patients who had survived for at least 6 months and had received regular follow-up evaluations. A total of 224 patients were recruited. The median follow-up period was 1614 days (range, 28-1929 days). The rate of infection-related deaths in ATG-10 arm was double that of the ATG-6 arm (14.3% vs 7.1%; P = .084). The 5-year cumulative incidence was comparable between the ATG-6 and ATG-10 groups for disease recurrence (12.8% vs 13.4%; P = .832) and nonrecurrence mortality (11.6% vs 17.0%; P = .263). The 5-year probability of disease-free survival was comparable between the groups (75.6% vs 69.6%; P = .283). The 5-year cumulative incidence of cGVHD was found to be higher with ATG-6 (75.0% vs 56.3% [P = .007] and moderate-to-severe cGVHD: 56.3% vs 30.4% [P<.0001]) as well as that for late effects (71.2% vs 56.9%; P = .043). The 5-year probability of GRFS was higher in the ATG-10 group (41.0% vs 26.8%; P = .008). In the multivariate analysis, ATG-10 was found to be associated with a lower risk of cGVHD and improved GRFS. ATG-10 was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection-related deaths. Cancer 2017;123:2881-92. © 2017 American Cancer Society.

Optimal Dose of Antithymocyte Globulin in Conditioning Regimens for Unmanipulated Haploidentical Haematopoietic Stem Cell Transplantation: Long-Term Outcomes of a Prospective Randomised Trial

Background: Antithymocyte globulin (ATG) is an important component of conditioning regimens to prevent severe GVHD in patients undergoing unmanipulated haploidentical stem cell transplantation (haplo-SCT). However, the optimal dose of ATG is unknown.Methods: In this open-label extension of a prospective, randomised trial, we compared the long-term outcomes of two ATG doses used in myeloablative conditioning before unmanipulated haplo-HSCT. Patients were randomly assigned (1:1) to 10 mg/kg (ATG-10) or 6 mg/kg (ATG-6) ATG. Patients and individuals assessing outcomes were masked to treatment allocation. Analysis of disease-free survival (DFS), GVHD-free/relapse-free survival (GRFS), relapse, non-relapse mortality (NRM), and chronic GVHD (cGVHD) included the entire population. Late effects were assessed in disease-free patients who had survived for at least 6 months and had received regular follow-up evaluations.Results: Between December 2010 and May 2012, 224 patients were recruited. The median follow-up period was 1614 days (28-1929 days). The 5-year cumulative incidence was comparable between the ATG-6 and ATG-10 groups for relapse (12·8% vs. 13·4%, p=0·832) and NRM (11·6% vs. 17·0%, p=0·263). The 5-year probability of DFS was comparable between groups (75·6% vs. 69·6%, p=0·283). The 5-year cumulative incidence was higher with ATG-6 for cGVHD (75·0% vs. 56·3%, p=0·007; moderate-to-severe cGVHD: 56·3% vs. 30·4%, p<0·0001) and late effects (71·2% vs. 56·9%, p=0·043). The 5-year probability of GRFS was higher with ATG-10 (41·0% vs. 26·8%, p=0·008). In the multivariate analysis, ATG-10 was associated with lower cGVHD risk and improved GRFS.Conclusions: ATG 10 mg/kg may be the optimal dose for conditioning regimens before unmanipulated haplo-SCT. DisclosuresNo relevant conflicts of interest to declare.

Dose Study of Antithymocyteglobulin in Haploidentical Allogeneic Stem Cell Transplantation

Backgroud:Graft-versus-host diseases (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially in recipients with HLA-mismatched or unrelated donors. Antithymocyteglobulin (ATG) has been widely used to prevent acute GVHD (aGVHD) in haploidentical and unrelated donor transplantation The use of ATG may increase the risk of opportunistic infections and primary disease relapse, which is associated with the dose of ATG. Till now, the optimal dose of ATG is not known for haploidentical and unrelated donor transplantation. Here, we compared the outcome of patients undergoing haploidentical HSCT who were treated with two different doses of ATG.Methods: Between January 2013 and June 2014, 40 consecutive patients with hematological malignancies undergoing haploidentical HSCT were enrolled in this prospective study. Of the 40 patiens, 19 received allo-HSCT from sibling donors, 18 lineal relatives donors (i.e. father, mother or child) and 3 collateral relatives donors (i.e. uncle or aunt). Five patients received 1 locus HLA-A, -B, -DRB1, -C, -DQ-mismatched donor transplantation, 6 received 2 locus mismatched, 9 received 3 locus mismatched, 6 received 4 locus mismatched and 14 received 5 locus mismatched transplantation. All the patients received GVHD prophylaxis including cyclosporine A, short-term methotrexate (on day +1, +3, and +6) and mycophenolate mofetil (0.5 g twice a day on day 0 to +28) as well as ATG ( a total dosage of 7.5mg/kg or 10mg/kg according to randomization). Epstein-Barr virus (EBV) -DNA and cytomegalovirus (CMV) -DNA levels of blood were monitored weekly for the first 3 months after transplantation, every two weeks during the 4 to 9 month after HSCT, and then once a month during 10 to 12 month. The primary endpoint was the cumulative incidence of aGVHD within day +100 after allo-HSCT.Results:Nineteen of the 40 patients were randomized to receive a total dosage of 7.5 mg/kg ATG and 21 were randomized to receive 10 mg/kg ATG. One patient was withdrawn from transplantation because of infection during conditioning and did not receive ATG. Of the 39 evaluable patients, 38 achieved engraftment except for one died of infection on day +32. The median time to neutrophil engraftment was 13 days (range, 9 to 19 days), and the median time to platelet engraftment was 14 days (range, 10 to 73 days). Patients with 7.5 mg/kg ATG achieved neutrophil engraftment earlier than those with 10 mg/kg (P=0.011). Time to platelet engraftment was comparable in the 2 arms with different dosage of ATG (P=0.063). The cumulative incidence of aGVHD grades II to IV and III to IV within day 100 post-transplantation was 26.5±7.2% and 10.6±5.0%, respectively. Acute GVHD grade II to IV developed in 35.5±11.8% of the patients with 7.5 mg/kg ATG and 19.3±8.7% of those with 10 mg/kg ATG (P=0.273). The incidence of aGVHD grade III to IV within day 100 were 11.9±7.9% in 7.5 mg/kg arm and 9.8±6.6% in 10 mg/kg arm (P=0.831). The cumulative incidence of chronic GVHD (cGVHD) 50.0%±25.0% and 59.6%±21.1% in the patients with 7.5 mg/kg and 10mg/kg ATG, respectively (P=0.819). The 1-year cumulative incidence of CMV reactivation were similar in the two arms (7.5 mg/kg arm : 82.8±10.5% vs 10 mg/kg arm: 66.7±10.3%, P=0.600). The incidence of EBV reactivation were 49.6±12.5% in 7.5 mg/kg arm and 67.2±12.7% in 10 mg/kg arm (P=0.729).Six patients relapsed, including 3 receiving 7.5 mg/kg ATG and 3 receiving 10 mg/kg ATG. The median follow up was 247 days (range, 32 to 569 days). The 1-year cumulative overall survival were 62.8±12.6% in 7.5 mg/kg arm and 68.2±10.9% in 10 mg/kg arm (P=0.536). The 1-year cumulative non-relapse mortality (NRM) rates were 23.4±10.3% and 23.3±10.5% in 7.5 mg/kg and 10 mg/kg arm, respectively (P=0.609).Conclusion:This trial suggests that 7.5 mg/kg ATG might have similar efficacy in preventing aGVHD after haploidentical HSCT compared with 10 mg/kg.Whether patients with 7.5 mg/kg ATG have lower risk for viral infections than those with 10 mg/kg needs further studies. DisclosuresLiu:National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding.

Higher Doses of Antithymocyte Globulin (ATG) Increase the Risk of Relapse in Acute Myeloid Leukemia (AML) Patients Undergoing Matched Related Donor Allogeneic Transplantation in First Complete Remission (CR1): An Analysis from the Acute Leukemia Working Party of EBMT

The use of ATG as part of the reduced-intensity conditioning regimen for AML is still controversial especially in the setting of matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (alloHSCT). A previous study suggested that the use of ATG reduced the incidence of graft versus host disease (GVHD) but increased the risk of relapse when a MRD is used, leading to worse outcome compared to patients who did not receive any in vivo T-cell depletion (CIBMTR data, Soiffer et al., Blood 2011). In contrast, the EBMT series, focused on AML patients undergoing alloHSCT from MRD in CR1, showed that the use of ATG reduced the incidence of GVHD without increasing the risk of relapse (Baron et al., BMT 2014). These discordant conclusions could be explained by the different median doses of ATG used, 7 and 5 mg/kg in the CIBMTR and EBMT studies, respectively. Thus, we hypothesized that the dose and the type of ATG are critical issues and could be a major determinant of outcome after alloHSCT. Here, we investigated the impact of ATG (Thymoglobulin) dose on cumulative incidences of GVHD, non-relapse mortality (NRM), relapse (CIR), leukemia-free (LFS) and overall survival (OS).Data of patients with the following criteria were collected from the EBMT registry: alloHSCT between January 2000 and February 2013; AML in CR1; peripheral blood stem cells from MRD as graft source; RIC regimen; use of ATG (Thymoglobulin) as part of the RIC regimen.We analyzed 334 consecutive patients with a median age of 56 years (range, 19-70). Fifty-eight (17%) patients had unfavorable cytogenetics and 238 (71%) received a busulfan-based RIC regimen. Most patients (95%) received cyclosporine A as GVHD prophylaxis, while mycophenolate mophetil (MMF) was added to 99 patients (30%). ATG was given at the dose of 6 mg/kg or more (high dose group, median dose: 7.5 mg/kg, range: 6-10.5) in 71 patients (21%) while 263 patients (79%) received less than 6 mg/kg total dose (low dose group, median dose: 5 mg/kg, range: 2-5.5). Patients in the higher dose group were more frequently transplanted before 2009, received more frequently a RIC regimen without busulfan and were more frequently given MMF in GVHD prophylaxis. Age, time from diagnosis to alloHSCT and cytogenetic risk groups were equally distributed according to both high and low ATG dose groups.In multivariate analysis after adjustment for age (<=55 vs. >55 years), transplant period (2000-08 vs. 2009-13), cytogenetics (unfavorable vs. other), RIC regimen (busulfan-based vs. other) and GVHD prophylaxis (MMF vs. no MMF) showed no significant impact of high ATG dose (low dose was considered as the reference group) on the incidence of both grade II-IV acute (OR=0.996 [95%CI, 0.561-1.767]; p=0.989) and chronic GVHD (HR=0.977 [95%CI, 0.543-1.759]; p=0.939). Similarly, ATG dose did not influence the cumulative incidence of NRM (HR=1.202 [95%CI, 0.467-3.093]; p=0.703). With a median follow up of 36 months, high ATG dose significantly increased the CIR (HR=2.298 [95%CI, 1.328-3.977]; p=0.003, Figure A), leading to significantly shorter both leukemia-free (HR=1.904 [95%CI, 1.186-3.058]; p=0.008) and overall survival (HR=1.711 [95%CI, 1.030-2.844]; p=0.038, Figure B).In conclusion, these results suggest that ATG dose is a determinant factor for outcome. ATG total dose below 6 mg/kg is likely sufficient for GVHD prophylaxis, with no additional benefit for using the higher ATG doses. In contrast, a higher ATG dose (6 mg/kg and more) will likely impair outcome of patients due to a significant increase of the relapse risk. Therefore, in the setting of CR1 AML patients undergoing RIC alloHSCT from MRD, lower ATG doses (<6 mg/kg total dose) could be safely used and can allow for better GVHD control without impairing the overall outcome. These results may differ in patients transplanted for other diseases than CR1 AML. Further comparative prospective studies could be helpful to better identify the optimal ATG dose in different setting of AML. [Display omitted] DisclosuresBaron:sanofi: Honoraria. Blaise:Sanofi: Honoraria, Research Funding. Mohty:Sanofi: Honoraria, Research Funding.

Efficacy of Early Steroid Withdrawal with Anti-Thymocyte Globulin Induction -Optimal Dose of Anti-Thymocyte Globulin in Korean Kidney Transplantation -

Efficacy of Early Steroid Withdrawal with Anti-Thymocyte Globulin Induction -Optimal Dose of Anti-Thymocyte Globulin in Korean Kidney Transplantation -

Use of antithymocyte globulin for treatment of steroid-refractory acute graft-versus-host disease: an international practice survey.

Antithymocyte globulin (ATG) is accepted as a treatment option for steroid-refractory acute graft-versus-host disease (GVHD). We conducted an international survey to determine how steroid refractoriness is defined and how ATG is used in clinical practice. Responses were received from 153 centers in 36 countries. The most common threshold steroid dose to define steroid refractoriness was 2 mg/kg/day (67% of respondents), and the median duration of treatment before failure was declared varied from 3 to 5.5 days, depending on whether failure was defined as 'progressed', 'not improved' or 'not resolved'. The threshold corticosteroid dose was significantly higher in pediatric centers than in adult or combined programs (P = 0.003). ATG was used routinely for treatment of steroid-refractory GVHD by 67% of the respondents. Horse ATG was used more frequently than rabbit ATG overall (50% vs 24%, P < 0.001), and predominance of horse ATG was most evident in the western hemisphere, in small- to medium-sized centers, and in pediatric centers. A wide variety of dose schedules for both drugs was reported. We conclude that there is some degree of variation in the definition of steroid refractoriness, especially between pediatric and nonpediatric programs, and no consensus has emerged in identifying the optimal ATG dose schedule in this setting.