Type Of Anti-thymocyte Globulin Research Articles

Similar Event-Free Survival but Higher Incidence of Mixed T Cell Chimerism after Hematopoietic Cell Transplantation for Sickle Cell Disease Using Rabbit Versus Horse ATG: a Study from the Sickle Transplant Alliance for Research (STAR)

▪Background: Myeloablative HLA-matched sibling donor hematopoietic cell transplantation (HCT) is highly curative for children and young adults with sickle cell disease (SCD). The most common regimen used worldwide has been Busulfan, Cyclophosphamide and anti-thymocyte globulin (ATG). The optimal type of ATG for this approach remains unclear.Objective: To compare HCT outcomes of horse ATG (hATG) versus rabbit ATG (rATG) in patients with SCD undergoing HCT.Methods: Multicenter retrospective data from patients with SCD undergoing HCT were abstracted from the Sickle Transplant Alliance for Research (STAR) database. Patients undergoing myeloablative and reduced intensity conditioning HCT with matched related donors where the conditioning regimen included ATG were included in the analysis. Baseline characteristics were compared between the groups using chi-square and Wilcoxon Rank-Sum tests. Kaplan-Meier curves were used to assess time-to-event outcomes, such as overall and event free survival (EFS), and compared with log-rank tests. Death, disease recurrence (acute sickle cell symptoms/HbS >50%) and graft failure (whole blood or myeloid chimerism < 5%) were considered events for EFS. Full donor chimerism was defined as ≥95% donor. P-values less than 0.05 were considered statistically significant.Results: 103 patients (hATG = 78, rATG = 25) from 7 U.S. centers and one Canadian site were available in the database for analysis. Median age at HCT (8.1 years vs 7.6 years, p = 0.866) and gender distribution (55.1% vs 56.0% male, p = 0.939) was similar between the cohorts. Sickle cell genotype was 97.4% vs. 84% HbSS, 1.3% vs. 12.0% HbSBetazero, 1.3% vs. 0% HbSC, and 0% vs.4% other. Pre-transplant disease acute symptoms were similar between the groups. Myeloablative conditioning was used in 92.3% and 96.0% in the hATG group versus the rATG group (p=1) and the most common conditioning regimen was Busulfan and Cyclophosphamide +/- Fludarabine in both groups (93.2%). Donor age and source of graft were similar between the two groups. Median follow-up for hATG and rATG groups were 3.0 and 3.6 years respectively. The year of transplant for the two groups ranged from 1993 to 2015 (hATG) and 2003 to 2014 (rATG). Three-year OS for the entire group was 92.6% (95% CI: 87.4-98.0), with 90.1% (95% CI: 83.4-97.4) in the hATG group and 100% (95% CI: 100-100) in the rATG group (p = 0.122) (Figure 1). Three-year EFS was 90% vs. 96% (p=0.415) in hATG vs. rATG group with 2-year graft failure incidence of 0% vs. 4% (p =0.085) respectively. Limiting the analysis to transplants performed after 2000 did not materially alter the analyses for OS and EFS. Causes of death were GVHD related (n=5) and infection/sepsis (n=3) in the hATG group versus no deaths in rATG group. Six month incidence of acute grade III-IV GVHD and 3 year incidence of chronic GVHD for hATG vs. rATG groups was 3.9% vs. 0% (p=0.319) and 16.8% vs. 15.5% (p=0.549) respectively. Prevalence of full donor myeloid chimerism was similar between the two groups at Day +30, Day +100 and >6months. Prevalence of full donor whole blood chimerism was significantly lower at day+100 and 1 year (p < 0.05) in the rATG group. Full donor T cell chimerism was similar at Day 30 and Day 100, but significantly less prevalent at >6 months in the rATG group (p = 0.001) (Table 1).Discussion/Conclusion: In our cohort mortality was low overall and the hATG and rATG groups had similar OS, EFS, and similar incidence of acute grade III-IV and chronic GVHD. However the prevalence of full donor T cell chimerism at greater than 6 months after HCT was significantly lower in the rATG group.Table 1. Incidence of full donor chimerism (≥ 95%) by lymphocyte depleting antibody, %Fig 1. Overall and Event Free survival of hATG vs. rATG based conditioning regimens in HCT for SCDFig 2. Incidence of acute grade III-IV and chronic GVHD in hATG vs. rATG based conditioning regimens in HCT for SCD [Display omitted] DisclosuresGuilcher:Jazz pharmaceuticals: Consultancy; Canada Market Research: Consultancy; Patient Access Solutions: Consultancy.

Impact of Two Different Types of Rabbit ATG on Immune Reconstitution and Overall Results after Allogeneic Hematopoetic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Children

Introduction Thymoglobulin® and Grafalon® are 2 polyclonal rabbit anti-thymocyte globulin (ATG) used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft rejection and graft-versus-host disease (GvHD). Differences in manufacturing lead to different types and concentrations of antibodies in each product. Few studies compare their effects on post-transplant immune reconstitution: indeed, the latter is essential to prevent post-transplant infections as well as relapse (in case of hematological malignancies). Methods We conducted a retrospective study on children or adolescents who received a first unrelated allo-HSCT for an Acute Lymphoblastic Leukemia (ALL) between 2007 and 2018, in the department of pediatric hematology of the Robert Debré Hospital in Paris, France. During this time period, 2 types of ATG were used: Thymoglobulin® at 7.5mg/kg or Grafalon® at 60mg/kg. We included patients with a B or T phenotype ALL aged 2 to 18 years at the time of HSCT indication. Stem cell source could be from unrelated matched or mismatched bone marrow, peripheral blood or cord blood. All patients received a myeloablative conditioning regimen consisting of 12 grays total body irradiation and etoposide (60mg/kg). We compared patients for engraftment, counts of total lymphocytes, B and T lymphocytes, T CD4+ and CD8+ lymphocytes and their sub-types (naïve, effector memory, central memory and effector memory RA+), regulatory T cells, NK cells, and compared lymphocyte proliferation assays at 1, 3, 6 and 12 months after transplant. We used joint models of longitudinal and survival data to further analyze evolution of total lymphocytes, B and T cells, T CD4+ and T CD8+ cells, and NK cells. Finally, we compared clinical outcomes between the 2 groups. Statistical analyses were performed according to EBMT guidelines (Iacobelli, 2013). Results 76 children were included: 23 received Thymoglobulin® and 53 received Grafalon®. Stem cell source was peripheral blood or bone marrow for 61 patients and cord blood for 15 patients. Initial characteristics of patients, disease status and HSCT were similar between the two groups except for the median total nucleated cells and CD34+ progenitor cells of the graft, that were significantly higher in the Grafalon® group. We found a delayed cumulative incidence of engraftment in patients who received Grafalon® compared to those who received Thymoglobulin®: 29 days [interquartile range 22-36] versus 22 days [19.5-29.5], p=0.004. We observed significantly higher counts of total and T CD4+ lymphocytes 1 month after transplant in patients who received Thymoglobulin® as compared to those who received Grafalon®: 238/mm3 [172-466] versus 137/mm3 [51-306] respectively (p=0.005), and 40/mm3 [31.5-70.5] versus 16/mm3 [2.5-41.5], respectively (p=0.011). No differences in immune cell population counts were found 3, 6 and 12 months after transplant (figure 1). However, joint models found no difference in the evolution of lymphocyte subsets analyzed depending on the ATG used, except a non-significant difference in slopes over time for CD8+ cells (p=0.13). In patients given Thymoglobulin® compared to those given Grafalon®, we found a higher proliferation in response to stimulation by CD3 3 month after HSCT (CD3 index 20.4 [12.4;41] versus 5.9 [3.3;6.4] respectively, p=0.0039), and a higher proliferation in response to stimulation by adenovirus (ADV) antigen 1 year after HSCT (ADV index 78.6 [58.8;163.1] versus 15.7 [2.8;59.3] respectively, p=0.027). We found no effect of ATG type on overall survival (OS), disease-free survival (DFS), treatment-related mortality and chronic GvHD. In a multivariate analysis, we observed no effect of the type of ATG on OS and DFS. Conclusions We found a higher count of total and T CD4+ lymphocytes 1 month after unrelated allo-HSCT for ALL in children who received Thymoglobulin® at 7.5mg/kg compared to those who received Grafalon® at 60mg/kg. From 3 months after HSCT, we found no difference in immune reconstitution. Joint models for longitudinal data and survival found no significant difference in evolution of the lymphocyte subsets analyzed. Clinical outcomes were similar between the two groups. However, we compared an intermediate dose of Thymoglobulin® to a high dose of Grafalon® that is not still the standard in clinical practice. A prospective study comparing Thymoglobulin® to a lower dose of Grafalon® would be needed. Disclosures Baruchel: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bellicum: Consultancy. Dalle:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

SUN-018 Exploring an affordable option for induction therapy for live donor kidney Transplantation- r-ATG (Anti thymocyte globulin) vs. low dose e-ATG Therapy in Sri Lanka

Induction therapy in the early post-transplant period has become a universally accepted method to get better outcomes in transplantation. ATG is being used widely especially in high risk transplantation. Antithymocyte globulin (ATG) is a poly clonal antibody that is used as induction therapy to treat acute rejection, It is a mixture of non-specific anti-lymphocyte immunoglobullins targeting T cell subsets and several immune and none immune cells. There are 2 types of ATG. r-ATG (rabbit) and e-ATG (equine) in comparison to other induction therapies like basiliximab, diclizumab and newer agents like alamtuzumab. These monoclonal therapies have a good outcome in renal transplantation and have their share of side effects. Our study is to compare the 2 types of ATGs as a cost benefit in comparison to the other more expensive alternatives. We have done a comparative study on a strictly alternative basis of r ATG vs. e ATG. The outcomes of both of these immunosuppressive therapies in a study done on 157 patients in the year 2016 at a private sector hospital in sri lanka .82 patients were given e-ATG and 75 were given r-ATG, calculated according to their body weight. at induction e-ATG was given at a dose of 15mg/kg which is a smaller dose in comparison to doses used in larger centers worldwide. 1250mg of e-ATG was given in 2 divided doses on Day 0(500-750mg) and Day 3(500mg) and r-ATG 125mg in 2 divided doses on Day 0 (75mg) and Day 3 (50mg) post kidney transplantation. We measures post induction reactions, Rejection rates, CDcounts, creatinine, lymphocyte counts and cost. Post induction reactions: Vital signs were monitored for both types of ATG. It was seen that 22% of patients in both groups had fever post induction. 33% have blood pressure alterations, 30% had chills, nausea or vomiting. And only 1% had a sever anaphylactic reaction. Post Transplant Rejection: We observed that only 21% of patient developed rejection in those who were given e-ATG and 21% developed rejection in those given r-ATG. Biopsies were also done in those who had strong chemical suspicion of rejection 26% had biopsies in the e-ATG group whereas nearly 28% of the r-ATG group got biopsies done. There was no significant difference in both groups. CD COUNTS: On Day 0 and day 10 Observations for absolute CD levels were noted. there was a 13% absolute reduction in e-ATG group and 11% decrease in r-ATG group. P value was <0.05 and was statistically significant. We have used r-ATG and low dose e-ATG and found very similar rejection rates, biopsy rates and infection rates in comparison to each other and in comparison to other induction therapies. The cost of induction therapy is cut down by 400 USD (62,000 LKR) per patient If using e-ATG and cost will be 1200 USD (190,000 LKR) more if on other induction therapies like basiliximab. Therefore we recommend the use of low dose e-ATG as an alternative to r-ATG as it provides cost savings and economic advantage and has a similar clinical outcome when compared to basiliximab, alamtuzumab and dicluzumab. We feel as we come from a middle income country and cost is a major factor in our daily practice e ATG is a good alternative to newer drugs with similar outcomes.

Allo-HSCT recipients with invasive fungal disease and ongoing immunosuppression have a high risk for developing tuberculosis

Patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk of acquiring tuberculosis (TB) due to a status of immunosuppression. We conducted a nested case control study to investigate the incidence and risk factors for TB after allo-HSCT. Between 2012 and 2017, 730 consecutive allo-HSCT recipients were enrolled, and 14 patients (1.92%) were diagnosed with TB. Relatively, 54 allo-HSCT recipients were selected as control. Patients who suffered TB had a significantly higher 3-year non-relapse mortality rate than the control group (30.36% vs 5.39%, P < 0.01). In multivariate analysis, invasive fungal disease (HR 4.87, 95% CI 1.39–17.09), treatment with a relatively high dose of prednisone (HR 10.34, 95% CI 1.12–95.47) and treatment with tacrolimus (HR 4.79, 95% CI 1.18–19.44) were identified independent risk factors for TB occurrence post allo-HSCT (P < 0.05). Meanwhile, donor type, dose and type of anti-thymocyte globulin (ATG) administrated, as well as treatment intensity, did not alter the incidence of TB. Therefore, allo-HSCT recipients with unexplained fever, especially those who suffer from invasive fungal disease and ongoing immunosuppression with a relatively high dose of prednisone or tacrolimus, are at a high-risk of developing active TB. Closely Monitoring TB occurrence, making a timely diagnosis and administering the proper treatment may be beneficial to those high-risk patients.

Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia.

For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3-year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.

Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation.

In patients undergoing allogeneic stem cell transplantation, conditioning regimens containing alemtuzumab instead of anti-thymocyte globulin (ATG) may result in an earlier platelet engraftment and a reduced number of platelet transfusions. We performed a retrospective, single-center, case-control study analyzing time to engraftment and transfusion needs using alemtuzumab in comparison with ATG as part of conditioning protocol. Median values for time to platelet engraftment, number of transfused platelet concentrates and number of transfused red cell concentrates were 12 versus 19.5 days (p < 0.001), 2 versus 14 (p < 0.001) and 6 versus 14.5 (p = 0.003) in the alemtuzumab and ATG group. Time to leukocyte engraftment did not differ with median 15 days in both groups. Patients in the ATG group showed a significant higher decrease in platelet count during conditioning (68 vs. 29 %, p = 0.001), leading to significant lower median platelet counts at the day of stem cell infusion (38 vs. 95.5 Gpt/l, p = 0.008), and higher values for median C-reactive protein after first antibody infusion (69.0 vs. 43.6 mg/l, p = 0.001) compared with alemtuzumab group. Test for significance was done by using Wilcoxon rank-sum test. Subgroup analysis considering the type of ATG used (Thymoglobulin vs. ATG Fresenius) revealed that differences between alemtuzumab and ATG group were more due to effects of ATG Fresenius than Thymoglobulin. The use of alemtuzumab in comparison with ATG as part of the conditioning regimen may be an approach to reduce the number of transfused platelet and red cell concentrates after allogeneic stem cell transplantation.

Predicting Response to Immunosuppressive Therapy By the Combination of Minor Paroxysmal Nocturnal Hemoglobinuria Clones and Lymphocyte Telomere Length in Children with Aplastic Anemia

Introduction: Acquired aplastic anemia (AA) is an immune mediated disease characterized by severe quantitative defects in stem cell number resulting in a hypocellular marrow and peripheral blood cytopenias. Immunosuppressive therapy (IST) using anti-thymocyte globulin (ATG) and cyclosporine A (CyA) is the standard therapy for patients with AA who lack a human leukocyte antigen (HLA)-matched sibling donor. Previous studies identified minor paroxysmal nocturnal hemoglobinuria (PNH) clones and short telomere length (TL) as predictive markers of the response to IST. However, the likelihood ratio of these markers was insufficient to influence clinical decisions. Here we assessed whether the combination of these markers could more accurately predict the response to IST.Methods: Between July 2001 and November 2013, 116 patients (65 boys and 51 girls) diagnosed with AA were examined to identify a minor population of PNH-type cells and TL of peripheral blood lymphocytes. Fifty-three patients received horse ATG (Lymphoglobulin, 15mg/kg/day for 5 days) and 63 received rabbit ATG (Thymoglobulin, 2.5−3.75 mg/kg/day for 5 days). CyA (6mg/kg/day) was started on day 1 and continued to at least day 180. The dose of CyA was adjusted to maintain trough levels between 100 and 200 ng/ml. Written informed consent was obtained from all patients’ parents. The ethics committee of each participating hospital approved the study. We used a flow cytometric assay to detect PNH-type granulocytes and red blood cells (RBCs). Presence of >0.007% CD13+ CD55− CD59− granulocytes and/or >0.009% glycophorin A+ CD55− CD59−RBCs was defined as PNH positive (PNH+), based on the results from healthy individuals. The average relative TL of peripheral lymphocytes was measured by flow-fluorescence in situ hybridization (flow-FISH) using a Telomere PNA Kit (Dako Cytomation). Based on our previous study, we defined −1.0 SD of age-adjusted controls as the cut-off value.Results: The median age at IST was 9.8 years (0.9−16.0). Disease severity of patients was assessed as moderate in 39, severe in 37, and very severe in 40, respectively. The causes of AA were idiopathic in 104 patients and hepatitis-associated in 12 patients. The median follow-up period from the time of IST was 36 months (range 1−134). Thirty-nine patients (34%) carried a minor PNH clone at diagnosis. Compared with healthy individuals, their median of TL was −1.08 SD (−4.01 to +3.01 SD). Overall, 60 of 116 patients (51.7%) responded to IST at 6 months after administration of ATG. In univariate analysis, the response rate at 6 months was higher in PNH+ patients than in PNH- patients (74.4% vs. 40.3%, respectively, p = 0.001). Longer TLs (≥−1.0 SD of age-adjusted control) were also associated with a favorable response to IST at 6 months (73.2% vs. 31.7%, p<0.001). In multivariate logistic regression analysis, PNH clone presence [odds ratio (OR), 4.41; 95% CI, 1.68−11.60; p = 0.003], longer TLs (OR, 5.59; 95% CI, 2.33−13.40; p < 0.001), and male gender (OR, 2.72; 95% CI, 1.12−6.62; p = 0.028) were found to be independent favorable predictors of response to IST at 6 months. Different types of ATG (horse vs. rabbit) did not affect response rate (OR, 1.94; 95% CI, 0.92−4.10; p = 0.084). According to these findings, the cohort was stratified into two groups: possible poor responders [PPR; PNH− and shorter TLs (<−1.0 SD), 45 patients] and possible good responders (PGR; PNH+ and/or longer TLs, 71 patients). The response rate at 6 months in the PPR group was as low as 24.4%, which was significantly lower than that in the PGR group (69.0%, p < 0.001). There was no significant difference in the incidence of relapse (0.0% vs. 20.8%, p=0.190) and clonal evolution (4.5% vs. 5.7%, p=1.000) between two groups. Five-year probabilities of transplant-free survival (TFS) and failure-free survival (FFS) were significantly lower in the PPR group than in the PGR group (TFS, 49.1% vs. 71.4%, p = 0.008; FFS, 42.6% vs. 57.3%, p = 0.020). However, 5-year overall survival showed no difference between the two groups (PPR, 97.7% vs. PGR, 95.5%, p = 0.910) because of the effective salvage therapies.Conclusion: Combination of the absence of a minor PNH clone and a short TL was an efficient predictor of poor response to IST. These patients had low chances to respond to IST, which challenges the current standard of treatment. Prospective clinical trials are required to confirm these findings. DisclosuresNo relevant conflicts of interest to declare.

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.

Comparison Between Lymphoglobuline- and Thymoglobuline-Based Immunosuppressive Therapy as First-Line Treatment for Patients with Aplastic Anemia.

Abstract 3194Poster Board III-131 BackgroundImmunosuppressive therapy (IST) is considered to be the first-line treatment in patients with severe aplastic anemia (AA) who are not eligible for hematopoietic stem cell transplantation (HSCT). Most IST schemes are based on the combination of anti-thymocyte globulin (ATG) plus cyclosporine A (CsA). Differently from other countries, two ATGs have been approved in Spain for AA from 2003 to 2007: Lymphoglobuline (LG) (raised in the sera of horses) and Thymoglobuline (TG) (produced in rabbits). So, during this period of time, the standard therapeutic protocol of the Spanish study group for AA included both options, and the physicians chose LG or TG based on their own wishes. Most published studies in AA are with LG, which is no longer manufactured. Recent limited data have confirmed therapeutic efficacy of TG, but no randomized studies have been performed comparing both products' activity. The aim of this report is to communicate the outcomes of a group of patients with AA who received either a LG- or TG-based scheme as first-line treatment. Patients and methodswe retrospectively investigated the outcome of 110 patients with AA treated with IST at front line between 2003 and 2008. Thirty-five patients (32%) got LG (15 mg/kg/day/x5 days), and 75 patients (68%) got TG (2.5 mg/kg/day/x5 days). All patients also received methylprednisolone and CsA. Response rate (RR) was assessed at post-IST day +90, day +180, and day +365. If complete response (CR) was not reached, patients received a second course of IST, a second-line therapy (HSCT or androgens), or no treatment. When a second course of IST was employed, it included LG at the same dose as in the first course (15 mg/kg/day/x5 days), or TG at a higher dose (3.5 mg/kg/day/x5 days). CR was defined as a neutrophil count >1.5×109/L, a platelet count >100 ×109/L, and a hemoglobin level >120 g/L. Partial response (PR) was defined as a neutrophil count >0.5×109/L, a platelet count >20 ×109/L, and a hemoglobin level >80 g/L. Subgroup analyses were conducted and differences in response were tested using the chi-square statistic test. ResultsAfter the first course of IST, CR was achieved in 31 patients (28%) (group A), and PR in 20 patients (18%). Overall response (OR) was similar for both globulins (LG: 49%, TG: 45%). Thirty-five of the patients who did not reach CR after the first IST course, received a second course of IST (6 with LG and 29 with TG) (group B), and 44 patients underwent a different approach (second-line therapy or no treatment) (group C). After the second course of IST, 14 patients achieved CR (40%) and 11 patients PR (31%). OR was similar for LG (67%) and TG (72%). If we exclude patients in group C, the RR among the remaining 66 patients (who underwent 1 or 2 courses of IST) was 85% (68% CR, and 17% PR). No major drug-related toxicities were reported in the whole group of patients. ConclusionsATG-based schemes with both LG and TG were well tolerated as treatment of patients with AA. OR after first course of IST was similar in the LG and in the TG group (49% versus 45%). RR after second course of IST was also similar when LG and TG were employed (67% versus 72%). After excluding those patients who, not having reached CR after the first course, underwent an approach different from a second course of IST, RR to IST was 85%, with 68% of CR. No statistical differences were found based on the type of ATG administered. The results of this study show that TG is, at least, as effective as LG for the treatment of AA patients. Based on these and other recently published data, the current standard therapeutic protocol of the Spanish study group for AA includes TG at the dose of 3.75 mg/kg/day/x5 days for both the first and, if necessary, second course of IST. To our knowledge, no reports are available in the medical literature comparing the outcome of patients with AA who received LG or TG as the first-line therapy for AA. So, in spite of the fact that our study is retrospective and not randomized, we think our data are unique and very useful for helping physicians in switching from LG to TG. DisclosuresNo relevant conflicts of interest to declare.

Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used

AbstractPatients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)—a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.

Antithymocyte Globulin (ATG) Plus Cyclosporine (CSA) for Aplastic Anemia (AA) and Low-Risk Myelodysplastic Syndrome (MDS).

We investigated the effectiveness of immunosuppressive therapy using ATG plus CSA in adult patients with AA and low-risk MDS. Between APR 2000 and JAN 2005, 93 patients, 82 AA and 11 MDS, from 4 institutes in Korea were included in this prospective study. Patients received one of 3 types of ATG according to the availability in Korea: horse ATG (Atgam®, Upjohn, Kalamazoo, MI; 40 mg/kg/d × 4 days), rabbit ATG (Thymoglobuline®, IMTIX-SANGSTAT, Lyon, France; 2.5 mg/kg/d × 5 days), or horse ALG (Lymphoglobuline®, IMTIX-SANGSTAT; 10 mg/kg/d × 5 days). Methylprednisolone 2 mg/kg/d was given before each dose of ATG. Oral CSA 3 mg/kg twice a day was administered for 3–6 months. In 38 patients, the HLA phenotyping results were available. The median disease duration before ATG/CSA therapy was 31 days (range, 3–3126). Eight patients were not evaluable for response because of early deaths in 4, early follow-up loss in 3, and clonal evolution to AML in 1 within 60 days after treatment. Of 85 patients who were evaluable for response, 46 (54.1%) showed response to ATG/CSA therapy: partial response in 23 and complete response in 23. Responses were observed in 44 (56.7%) of 75 AA patients and in 3 (30.0%) of 10 low-risk MDS patients (P=0.103). Patients with HLA B40 phenotype showed higher response (66.7% vs. 32.1%, P=0.043), but other HLA phenotypes did not show any significant influence on response. Cumulative incidence of response was 55.5% at 2-year. Multivariate analysis indicated that disease duration before ATG/CSA therapy (≤ 90 days vs. > 90 days; OR 0.154; P=0.001) and type of ATG (horse ATG vs. rabbit ATG; OR 0.235; P=0.006) were independent predictive factors for response. Nine patients, 7 AA and 2 MDS, relapsed and cumulative incidence of relapse was 25.9% at 5-year. Clonal or disease evolution occurred in 3 patients with AA (PNH, MDS, and AML in 1 of each) and in 3 patients with MDS (RAEB-1 in 2 and RAEB-2 in 1). Eighteen patients died and actuarial survival was 69.8% at 5-year: 76.9% in AA and 36.0% in MDS. No patient who attained at least PR died. Our results demonstrated the effectiveness of ATG/CSA therapy in AA and low-risk MDS. The effects of rabbit ATG was significantly inferior in our study probably due to dose problem rather than ATG type itself. The influence of HLA phenotype on response to ATG/CSA should be further investigated.

Is there a direct effect of antithymocyte globulin on hematopoiesis?

The efficacy of immunosuppressive therapy in aplastic anemia (AA) provides the strongest argument to support its immune-mediated pathophysiology. While several immunosuppressive effects of antithymocyte globulin (ATG) can be demonstrated in vitro, some reports have implied that the activity of ATG in AA may be rather due to a variety of positive hematopoietic effects. We studied the effects of horse (h) and rabbit (r) ATG on marrow progenitors in vitro. Both types of ATG bound to CD34 cells and, in colony assays performed with total marrow cells, hATG had a dose-dependent, triphasic effect, with maximal increase in colony formation between 1 and 10 microg/ml and inhibition between 100 and 1000 microg/ml. As determined using CD34 cells, these effects did not require accessory cells. rATG showed similar activity, but was about 10-fold more potent than hATG. In the presence of complement, no increased cytotoxicity was observed. At concentrations equivalent to those measured in patients immediately after infusion, ATG showed moderate suppression of colony formation, while the stimulatory concentrations in vitro correspond to those seen in vivo within the first weeks after ATG administration. In control experiments, the patterns of the biologic effects of preimmune rIgG or hIgG preparations were similar to those of rATG and hATG, indicating a nonspecific nature of the effects of ATG on progenitor cells. Biological activity in methylcellulose cultures was observed with the F(ab)(2) fragments but was not found in purified Fc IgG. In summary, the spectrum of effects of ATG on hematopoietic progenitors is dependent upon the concentrations of ATG and may not be related to its antigenic specificity.