ATG Fresenius Research Articles

A comprehensive analysis of the major specificities of anti-human T lymphocyte porcine immunoglobulin (p-ATG).

Anti-human T lymphocyte porcine immunoglobulin (p-ATG) is a potent immunosuppressive agent derived from porcine sources used in various immunotherapy applications. It is compared with similar products derived from other species, such as rabbit anti-thymocyte globulin (r-ATG) and ATG-Fresenius (ATG-F), which have distinct biological and therapeutic properties. This study aims to elucidate the mechanisms of action and comparative efficacy of p-ATG in relation to r-ATG and ATG-F through a comprehensive in vitro analysis. A comparative analysis of p-ATG, r-ATG and ATG-F was performed, focusing on E rosette inhibitory potency, lymphocyte toxic potency, blocking activities of 24 CD molecules, and flow quantitative potency. Flow cytometric analysis was used to quantify these characteristics and assess the potency of the immunoglobulins. p-ATG exhibited lower E rosette inhibitory and lymphocyte toxic potencies compared to r-ATG but was significantly more potent than ATG-F at equivalent concentrations. At protein concentrations above 12.5µg/mL, p-ATG showed slightly lower potency than r-ATG and much higher potency than ATG-F in flow cytometry assays. Both p-ATG and r-ATG exhibited similar killing effects on lymphocytes within the peripheral blood mononuclear cells (PBMCs), including CD3 + T cells, with a dose-dependent response. Notably, p-ATG displayed more pronounced blocking activities against CD8, CD99, and TCR α/β compared to r-ATG. p-ATG offers certain advantages over r-ATG and ATG-F, particularly in its ability to inhibit specific CD molecules and its overall potency in immunosuppressive assays, providing valuable insights for assisting clinical decision-making regarding the selection of ATG types based on patient-specific needs and treatment objectives.

Reduced intensity conditioning regimen of fludarabine, busulfan, ATG based haploidentical stem cell transplantation for older or unfit patients.

Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30mg/m²/kg 6 days combined with busulfan 3.2mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2group was significantly higher than Bu3group(P = 0.045). However, the2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.

Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.

The impact of donor-to-recipient gender compatibility on outcomes of haploid hematopoietic stem cell transplantation in patients with hematological malignancies

Objective: To investigate how gender differences between the donor and the recipient affect the effectiveness of antithymocyte globulin (ATG) and pure peripheral blood stem cell (PBSC) hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of malignant hematological diseases. Methods: From February 2015 to September 2020, 648 hematological malignancies patients underwent myeloablative condition regimen haplo-HSCT treatment at the Bone Marrow Transplant Center of the First Affiliated Hospital of Zhejiang University. The median age was 32 (14-62) years, with 363 males (56.0% ) and 285 females (44.0% ) present. 242 cases of acute lymphoblastic leukemia (ALL) (37.3% ) , 293 cases of acute myeloid leukemia (AML) (45.2% ) , 56 cases of myelodysplastic syndrome (MDS) (8.7% ) , 27 cases of non-Hodgkin's lymphoma (NHL) (4.2% ) , and 30 cases of other hematological malignancies (4.6% ) . Results: ① The 3-year overall survival (OS) , DFS, the incidence of Ⅱ-Ⅳ grade acute graft-versus-host disease (aGVHD) , the incidence of Ⅲ-Ⅳ grade aGVHD, the 3-year incidence of moderate & severe chronic GVHD (cGVHD) , severe cGVHD, the 3-year incidence of relapse, and NRM of the whole group were (73.10±1.90) % , (70.80±1.90) % , (33.96±1.87) % , (13.08±1.33) % , (35.10±2.14) % , (10.66±1.38) % , (19.43±1.67) % , and (9.80±1.24) % , respectively. ②There was no statistically significant difference between the donor-recipient gender match and donor-recipient gender mismatch groups in the 28-day cumulative neutrophil engraftment rate, 28-day cumulative platelet engraftment rate, the incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, the cumulative incidence of relapse, NRM, and incidence of moderate & severe cGVHD, severe cGVHD. ③The 28-day cumulative neutrophil engraftment rate did not differ statistically between the male-female, female-female, male-male, and female-male groups (P=0.148) . The incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, cumulative relapse rate, and NRM, and the incidence of cGVHD were not statistically different among the four groups (P>0.05) . The 28-day cumulative platelet engraftment rate of the female-male group was significantly lower than male-female group, and the female-female group [ (91.45±2.63) % vs. (94.77±1.75) % , P=0.004; (91.45±2.63) % vs. (95.54±2.05) % , P=0.005]. No significant difference existed in the 28-day cumulative platelet engraftment rate between the female-male group and the male-male group [ (91.45±2.63) % vs. (95.08±1.41) % , P=0.284]. ④Among patients ≤35 years old, the 3-year incidence of severe cGVHD patients receiving sister donors and sibling donors were (26.71±5.90) % and (10.33±4.43) % , respectively (P=0.054) . Patients accepting daughter donors and son donors had a 3-year incidence of moderate and severe cGVHD that was 40.07% vs. 27.41% , respectively, among those over 35 (40.07±6.65) % vs. (27.41±4.54) % (P=0.084) . ⑤Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate compared to the other groups [ (91.45±2.63) % vs. (95.08±0.95) % , P=0.037]. ⑥ Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate than the other groups in the ATG-Fresenius (ATG-F) 10 mg/kg group [ (89.29±4.29) % vs. (94.49±1.45) % , P=0.037]. But when compared to the other groups in the Rabbit Antihuman Thymocyte Immunoglobulin (rATG-T) 6 mg/kg group, the 28-day cumulative platelet implantation rate between female donors and male recipients was not significantly different [ (93.44±3.38) % vs. (95.62±1.26) % , P=0.404]. Conclusion: The main clinical outcomes of patients with malignant blood diseases following transplantation are unaffected by the gender combination of the donor and patient in the haplo-HSCT mode based on ATG and PBSC sources. Female donors to male recipients have a lower 28-day cumulative platelet engraftment rate and longer platelet engraftment times.

ATG-F Versus ATG-T for Graft Versus Host Disease Prevention in Allogeneic Stem Cell Transplantation: A Retrospective Comparative Study

Background: Graft versus host disease (GVHD) is one of the major complications in allogeneic stem cell transplantation, leading to excessive post-transplant morbidity and mortality. Anti-Thymocyte Globulin (ATG) is a widely used anti GVHD prophylaxis adjunct, in addition to a calcineurin inhibitor and either methotrexate or mycophenolate mofetil. Among available ATG sera are antithymocyte globulin (ATG-T) (Sanofi Genzyme, Cambridge MA), derived from rabbit vaccination with human thymocytes, and the anti-T-lymphocyte globulin (ATG-F) (Neovii, Rapperswil, Switzerland, ATG Fresenius®), derived from the human Jurkat T-cell line. Data comparing the two agents, regarding transplant outcomes is still lacking. Methods: Since 2015, ATG-F (15 mg/kg) has become the preferred prophylactic agent at the Hadassah medical center. We retrospectively compared the transplant outcomes between 52 patients treated prophylactically with ATG-F (15 mg/kg) during 2015-2018 and 46 patients treated with ATG-T (10 mg/kg), during 2011-2018. Our research aims were directed towards investigating rates of engraftment, infections, GVHD, relapse, and overall survival. Results Demographic, disease and pre-transplant characteristics (median age, gender, disease status at transplantation entry, age adjusted comorbidity index) of the two groups were mostly similar. There was no significant difference in median recipient and donor age, and conditioning regimen intensity. There was a higher rate of patients transplanted for MDS and secondary AML in the ATG-F group while a higher rate of lymphoproliferative diseases in the ATG-T group (p=0.038). Comparing patients' characteristics for the available risk factors for GVHD, there was a borderline significant higher incidence of HLA mismatch in the ATG-T group compared to the ATG-F group (39.1% Vs. 21.2%; p=0.052), and a significantly higher number of patients received single agent cyclosporine in the ATG-T group (30.4% vs 3.8%, p<0.01). In terms of risk factors for infections, there was a significantly higher incidence of positive CMV-IgG in both donor and recipient in the ATG-F vs ATG-T group, 82.4% vs 60.9%, p=0.022). Analyzing transplant outcomes, the incidence of acute GVHD of any grade was significantly higher in the ATG-T group (p=0.007, Fig. 1), while the incidence of grade 3-4 acute GVHD was comparable (p=0.186). Incidence of any grade and moderate-severe chronic GVHD was comparable in both groups (p>0.05). There was no statistically significant difference in disease-free survival and overall survival rates between the groups (p>0.05). A combined analysis of moderate-severe chronic GVHD-free, relapse-free survival (GRFS) showed no difference between the groups (p=0.686, Fig. 2). Median time to absolute neutrophil count (ANC) and Platelet engraftment was 15 vs. 14 and 16 vs. 17 days in the ATG-T and ATG-F group, respectively. There was no difference in the incidence of bacteremia or CMV reactivation between the two groups (p=0.79; p=0.704, respectively). Conclusion Our retrospective study shows that ATG-F was non-inferior to ATG-T regarding engraftment rate, incidence of grade 3-4 acute GVHD and moderate-severe chronic GVHD, disease free survival and overall survival. The higher incidence of acute GVHD of any grade detected in the ATG-T group might reflect the higher rate of HLA mismatch and combination with single agent cyclosporine prophylaxis. Study limitations include its retrospective nature and changes in transplant care over the study years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Thymoglobulin and Grafalon as Induction Agents in Renal Transplantation: A Prospective Study

BackgroundInduction immunosuppression is used to reduce the incidence of acute rejection and prevent delayed graft function. The 2 rabbit anti-thymocyte globulins- thymoglobulin and Grafalon (ATG Fresenius) have been commonly used for induction immunosuppression and treatment of acute rejection in solid organ transplantation. There are very few studies comparing the efficacy and side effects of both the anti-thymocyte globulins therefore this prospective study comparing the 2 types of anti-thymocyte globulins would be of clinical interest. Patients and MethodsThis prospective single center study was conducted at Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, India from April 2019 to June 2020. Sixty-two ABO-compatible renal transplant recipients were included in the study. They were divided in 2 groups of 31 patients each. One group received thymoglobulin (3 mg/kg) and the second group received Grafalon (6 mg/kg). All patients were followed up for 12 months and the 2 groups were compared for incidence of rejections, infections, graft function, patient survival, and graft survival. ResultsThere was no significant difference in the incidence of rejections, infective episodes, graft function, posttransplant diabetes mellitus, graft survival and patient survival in thymoglobulin or Grafalon groups. The hematological parameters were similar in both groups at 7 days, 1 month, and 6 months of follow-up. The absolute lymphocyte count was significantly lower in the thymoglobulin group at 12 months posttransplant. ConclusionsThymoglobulin and Grafalon were found to be equivalent in terms of safety and efficacy in short term, with no difference in rejections, infections, graft survival, or patient survival.

Low-Dose ATG Combined with Facybu Conditioning Regimen Followed By Single Unrelated Cord Blood Transplantation in Hematological Malignancies

Objective: This study aims to evaluate the efficacy and safety of low-dose ATG combined with FACyBu conditioning regimen for single unrelated cord blood transplantation in hematological malignanciesMethod: From Jul 2013 to Feb 2017, 30 patients of hematological malignancies (15 patients with ALL,11 patients with AML,3 patients with NHL,1 patient with CML ) who underwent unrelated cord blood transplantation were followed up. The median age was 24(3.16-46)years. Seventeen patients were in complete remission(CR) while 13 patients were in progressive stage. All the patients were pretreated with low dose ATG(Fresenius) (24patients 10.0mg/kg/d, 6 patients 5.0mg/kg/d;d-5,d-4) plus FACyBu(a myeloablative FA-BUCY protocol of 25 mg/m2/day Fludarabine and high-dose 2 g/m2/day Cytarabine for 5 consecutive days from day −13 to day −9, 1.8g/m2/day CY from day −8 to day −7, 3.2mg/kg/day BU from day −6 to day −4 and MCCNU 250mg /m2 d-3). Cyclosporine and mycophenolate were applied for Graft-versus-host disease (GVHD) prophylaxis. The GVHD, RFS, nonrelapse mortality, relapse mortality, OS, DFS and graft-versus-host disease-free/relapse-free survival (GRFS) probabilities were investigated. The side effects of the regimens were also evaluated.Result: The median CD34+ cell infusion quantity was 0.17 (0.07-1.26)*106/Kg. the median neutrophil engraftment time was 18(10-27)days and the median platelet engraftment time was 33(15-49)days. The cumulative incidence of grades II-IV acute GVHD was 23.5%. It's interesting that no grade III-IV acute GVHD was observed. The cumulative incidence of limited chronic GVHD and extensive chronic GVHD was 5.0% , 9.1% respectively. The median follow-up time was 10.8(2.6-46.1) months. The nonrelapse mortality, relapse mortality, OS, DFS and GRFS were 27.6%,10.9%,64.5%,64.4% and 61.4%, respectively. For the CR patients, the OS, DFS and GRFS were 85.9%, 85.9%, 80.2%, respectively. While for the nonremission patients, the OS, DFS and GRFS were 38.5%,28.5%, 38.5%Conclusion: The clinical efficacy of low-dose ATG combined with FACyBu conditioning regimen followed by single unrelated cord blood transplantation in hematological malignancies patients is similar to that of alternative allogeneic bone marrow transplantation as reported. The incidence of GVHD was low .The patients who were treated with this regimen experience good quality of life. DisclosuresNo relevant conflicts of interest to declare.

Reduced Intensity Stem Cell Transplantation Followed By Adjunctive Lenalidomide Is Tolerable and Safe and Improves Complete Response Rate in Multiple Myeloma:a UK NCRI Phase 2 Feasibility Study (LenaRIC)

BackgroundThe role of allogeneic stem cell transplantation in the management of myeloma remains uncertain as it is a procedure with significant mortality and low long term rates of disease control. We sought to evaluate the feasibility of using adjunctive Lenalidomide (Revlimid®) to augment long term myeloma response following Reduced-Intensity Conditioned (RIC) allograft in the UK NCRI trial LenaRIC (Lenalidomide in Reduced Intensity Conditioned Transplant)-ISRCTN:16228367.Material & MethodsForty (40) patients were recruited in this single arm phase II trial at ten UK stem cell transplant centres from June 2011-June 2015. All patients were in CR/VGPR 1 or 2 and had undergone a Melphalan conditioned autologous transplant in the previous 6 months. They then underwent a RIC allograft using Fludarabine & 2Gy TBI with ATG (Fresenius) as in vivo T-cell depletion (planned tandem SCT programme). Patients were scheduled to receive Lenalidomide (10mg until 2013, reduced to 5mg thereafter on DMEC advice) from day +35 if stable donor engraftment was present in the absence of GvHD. Lenalidomide was planned to be discontinued 12 months post-transplant with donor lymphocyte infusions given to patients with evidence of residual disease, relapse or mixed chimerism.ResultsOf the thirty nine(39) patients transplanted within 42 days of study entry, 8 were in CR1, 16 in VGPR1, 7 in CR2 and 8 in VGPR2. The median age was 49 years (range 35-65) with peripheral blood as the graft source in the 39 patients, from either sibling (n=16) or 10/10 matched unrelated donor (n=23). 1 patient failed to proceed to transplant. Of thirty four (34) evaluable patients, 28 (82.4%) achieved full donor T-cell chimerism and 32 (94.1%) full donor in whole blood. 34 patients completed at least one cycle of Lenalidomide. Mean number of cycles received was 7.4 (range 1-12, median 9.0). Mean dose was 5.2mg, median 5mg. 16 patients completed at least 10 cycles and 5 patients completed 12 cycles as per protocol treatment; of those completing >= 10 cycles, 5/16 received DLI.Safety dataThere were eight (8) patients who had biopsy-proven aGVHD (4 of grade 1-2 and 4 of grade 3- all 4 within 3 cycles of Lenalidomide) and 3 patients with cGVHD (2 extensive and 1 limited). No Grade 3/4 aGVHD was seen following DMEC advice to reduce the Lenalidomide dose to 5mg daily. 8 patients experienced grade 3 or 4 non-Haem toxicity. The majority of AEs were grade 1-2. Significant (Grade 3/4) non-Haem SAEs in this transplant population included Gastro-intestinal (4 patients), metabolism (4 patients), infection (13 patients) and vascular (4 patients). One year relapse-free survival was 84.3%.Clinical OutcomesEfficacy was assessed at a median follow-up of 445 days. The pre-transplant CR rate of 38.4% was improved to 67.6% at best response post-transplant. PFS at 2 years was 43.1% (figure 1a), OS at years 75.7% with a 2 year disease-free survival of 59.1% (figure 1b). Of the 10 patients who have died, 6 have been recorded as disease-related.Conclusions1) Based on the pre-defined safety stopping rules, the LenaRIC study shows that post-graft Lenalidomide is safe and tolerated in a T-depleted RIC setting at a dose of 5mg daily- this results in a tolerable AE profile with an acceptable GVHD rate.2) Acute GVHD only occurred in the first 3 cycles of exposure to Lenalidomide- consideration should be given to examining the longer term use of Lenalidomide beyond 12 months following a T-depleted RIC allograft to augment long term outcomes3) CR rates were nearly doubled by this approach4) Further work correlating Lenalidomide exposure with clinical events and immune reconstitution is ongoing.An unrestricted educational grant was provided to support the trial & adjunctive science by Cancer Research UK and by Celgene. Lenalidomide provided free of charge by Celgene. Lenograstim provided free of charge by Chugai. The support and time of participating patients and their families is gratefully acknowledged. [Display omitted] DisclosuresCook:Janssen: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria. Brock:Merck: Other: travel expenses; Roche: Honoraria, Other: travel expenses; GlaxoSmithKline: Equity Ownership; Astra-Zeneca: Equity Ownership. Snowden:Sanofi: Honoraria. Hunter:Celgene: Other: Travel Support. Cavenagh:Takeda: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Celgene: Consultancy. Cook:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Ruxolitinib early administration reduces acute GVHD after alternative donor hematopoietic stem cell transplantation in acute leukemia

This study aimed to observe the safety and clinical efficacy of early application of ruxolitinib to prevent acute graft-versus-host disease (aGVHD) after alternative donor transplantation in acute leukemia. There were 57 patients undergoing allo-HSCT at the Affiliated Cancer Hospital of Zhengzhou University from July 2017 to October 2019. They were divided into control(16 patients) and ruxolitinib (41 patients) groups. For aGVHD prophylaxis, the control group received post-transplantation cyclophosphamide, antithymocyte globulin-Fresenius, cyclosporine A, and mycophenolate mofetil, while in the ruxolitinib group, ruxolitinib 5 mg/d in adults or 0.07–0.1 mg/(kg d) in children was administered from the day of neutrophil engraftment to 100 days post-transplantation based on control group. We found 55 patients had successful reconstitution of hematopoiesis; No significant difference was found in cGVHD, hemorrhagic cystitis, pulmonary infection, intestinal infection, Epstein-Barr virus infection, cytomegalovirus infection, relapse, death, and nonrelapse mortality. The incidences of aGVHD (50 vs. 22%, P = 0.046) and grade II–IV aGVHD (42.9 vs. 12.2%, P = 0.013) were significantly higher in the control group than in the ruxolitinib group. No significant differences were observed in overall survival (P = 0.514), disease-free survival (P = 0.691), and cumulative platelet transfusion within 100 days post-transplantation between two groups. This suggests early application of ruxolitinib can reduce the incidence and severity of aGVHD and patients are well tolerated.

A comparative study of porcine antihuman lymphocyte globulin versus antithymocyte globulin-fresenius in an allogeneic hematopoietic cell transplantation conditioning regimen for severe aplastic anemia

ABSTRACT Objectives To compare the outcomes of antihuman T lymphocyte globulin (ATG-F) and porcine antihuman lymphocyte globulin (p-ALG) as part of a conditioning regimen in hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA). Methods we performed a retrospective analysis, evaluating the outcome of patients with SAA who received ATG-F based conditioning (n = 26) with those receiving p-ALG conditioning (n = 34). Results The median time to neutrophil engraftment was 11 days (range, 8 − 38) and 11 days (range, 9 − 24) in the p-ALG and ATG-F groups (P = 0.857); the median platelet engraftment time was 15 (range, 9 − 330) days and 13 (range, 10 − 56) days (P = 0.155). There were no significant differences in grades II − IV acute graft-versus-host disease (aGVHD), grades III − IV aGVHD, chronic GVHD (cGVHD), and the moderate-severe cGVHD between the ATG-F and p-ALG groups (P>0.05). Discussion Patients in the ATG-F group functioned significantly better on role-physical (P = 0.006), general health (P = 0.029), and physical component summary (P = 0.009). The estimated overall survival and failure free survival rates at 5 years were 88.5% ± 6.3% vs. 82.4% ± 6.5% (P = 0.515), 84.6% ± 7.1% vs. 79.4% ± 6.9%, respectively (P = 0.579). The infection rates were 61.53% and 47.05%, respectively (P = 0.265). Conclusion As part of the conditioning regimen, p-ALG achieved a similar efficacy as ATG-F without increasing the incidence of transplantation complications in SAA patients.

Comparison of 2 Different Rabbit Anti-Thymocyte Globulin (r-ATG) Preparations: Thymocyte r-ATG versus T Lymphoblast Cell Line r-ATG in Allogeneic Hematopoietic Stem Cell Transplantation for Acquired Severe Aplastic Anemia: Propensity Score-Matched Analysis

We retrospectively analyzed the outcomes of 214 patients with severe aplastic anemia (SAA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with rabbit anti-thymocyte globulin (r-ATG) or ATG-Fresenius (ATG-F). Using propensity score matching, we performed a case-control study comparing 44 and 23 patients in the r-ATG and ATG-F groups, respectively. The median time was 11 versus 11 days (P = .368) for myeloid engraftment and 11 versus 13 days (P = .030) for platelet engraftment in the r-ATG and ATG-F groups, respectively. The r-ATG group showed a lower incidence of grade III to IV acute graft-versus-host disease (GVHD) than the ATG-F group (2.27% versus 17.39%, P = .026). Similar outcomes were observed between the r-ATG and ATG-F groups for infection rate (59.09% versus 56.52%, P = .840), grade II to IV acute GVHD (20.45% versus 21.74%, P = .948), overall incidence of chronic GVHD (26.83% versus 22.73%, P = .704), moderate to severe chronic GVHD (9.76% versus 13.64%, P = .648), and transplantation-related mortality (11.36% versus 4.35%, P = .614). There was no statistical difference in 5-year overall survival (86.40% versus 95.7%, P = .245); GVHD-free, failure-free survival (77.30% versus 78.30%, P = .986); or health-related quality of life (P > .05) between r-ATG and ATG-F.

Thymoglobulin vs. ATG-Fresenius as Induction Therapy in Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

Background: Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation.Materials and Methods: We performed a Bayesian network meta-analysis to compare THG with ATG-F by pooling direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) values were used to compare the superiority of one method over the other.Results: A total of 27 randomized controlled trials (RCT) were eligible for the network meta-analysis. Efficacy endpoints, as well as safety indicators, were statistically comparable. For efficacy endpoints, THG seemed inferior to ATG-F in preventing delayed graft function [odds ratio (OR): 1.27; SUCRA: 78% vs. 58%], patient deaths (OR: 2.78; SUCRA: 83% vs. 34%), and graft loss (OR: 1.40; SUCRA: 83% vs. 59%), but superior to ATG-F in biopsy-proven acute rejection (BPAR; OR: 0.59; SUCRA: 78% vs. 39%) and steroid-resistant BPAR prevention (OR: 0.61; SUCRA: 76% vs. 49%) within the first year. For safety endpoints, THG was associated with higher risk of infection (OR: 1.49, SUCRA: 79% vs. 54%), cytomegalovirus infection (OR: 1.04; SUCRA: 40% vs. 37%), de novo diabetes (OR: 1.10; SUCRA: 90% vs. 30%), and malignancy (OR: 8.40; SUCRA: 89% vs. 6%) compared to ATG-F. A subgroup analysis of patients at high risk for immunologic complications revealed similar results, but THG performed better for graft loss (OR: 0.82; SUCRA: 68% vs. 54%).Conclusion: ATG-F seemed to be more effective than THG in improving the short-term kidney transplantation outcomes. Prospective head-to-head comparison of THG and ATG-F with larger sample sizes and longer follow-up is still required.

Efficacy of anti-T-lymphocyte globulin-Fresenius as an induction agent in deceased-donor renal transplantation: A cohort study.

Anti-T-lymphocyte globulin (ATG) is frequently used in the induction regimen of renal transplantation, but its dose has not been standardized. In the present study, the efficacy of different ATG-Fresenius (ATG-F) doses was assessed in recipients of renal transplantation. A total of 131 adult recipients of renal transplantation who received ATG-F induction between August 2015 and July 2018 were included. The incidence of biopsy-confirmed acute rejection, graft function, as well as graft and patient survival within 12 months post-transplant, was assessed, and adverse events, including hematologic and infection-associated side effects, were compared between patients receiving a cumulative ATG-F dose of <7 or ≥7 mg/kg. The incidence of biopsy-confirmed acute rejection was similar between patients receiving cumulative doses of <7 and ≥7 mg/kg (7.5 vs. 4.7%, P=0.766). The incidence of infection within 12 months was lower in the ATG-F <7 mg/kg group compared with that in the ≥7 mg/kg group (26.9 vs. 50.0%, P=0.006), but the incidence of pneumonia did not differ between the ATG-F <7 and ≥7 mg/kg groups (10.4 vs. 20.3%, P=0.117). The incidence of urinary infection was higher in the ≥7 mg/kg group than in the <7 mg/kg group (20.4 vs. 7.46%, P=0.033), while the extent and duration of anemia and lymphopenia was similar between groups. There was no difference in graft function, delayed graft function, as well as overall and graft survival between the groups. In conclusion, a moderate reduction in the cumulative ATG-F dose was not associated with an increased risk of acute rejection, while the risk of infection was reduced. Optimization of the ATG-F dose for induction may facilitate the reduction of the risk of infection without compromising the induction efficacy in renal transplant recipients.

Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation.

Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6–10 mg/kg; ATG-FRES at 45–60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6–8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III–IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.

Post-Transplantation Cyclophosphamide Versus Low Doses ATG Fresenius As Part of Two Immunosuppression Regimens for Graft Versus Host Disease Prophylaxis: Low Severe Graft Versus Host Disease (GVHD) Incidence and y Similar Gvhd-Free and Relapse-Free Survival (GRFS)

BACKGROUND AND OBJECTIVES.Post transplantation High dose Cyclophosphamide (PTCY) used in haploidentical hematopoietic transplantations, has a high effectivity in acute Graft versus Host Disease (aGVHD), and chronic Graft versus Host Disease prophylaxis (cGVHD), however it is associated with high relapse rates. On the other hand, Anti-T-Lymphocyte Globulin (ATG-Fresenius ®) is also effective as immunosuppressive (IS) drug, but its benefit on Overall Survival (OS) and Relapse Free Survival (RFS) is unclear.The aim of this study was to compare the effectiveness of two GVHD prophylaxis regimes used in high risk transplantation: PTCY used in Haploidentical transplantation and ATG used for peripheral blood, non-related, related and mismatched donors.The primary endpoint was to evaluate the incidence of aGVHD and cGVHD, and its severity in both groups. As secondary endpoints we analyse the OS, RFS and GRFS (recorded adverse events include grade 3-4 aGVHD, systemic therapy-requiring cGVHD, relapse or death during median follow-up). We also consider transplantation related mortality (TRM) and post-transplantation complications.PATIENTS AND METHODS.We retrospectively analyse 111 allo-transplantations performed at our institution between 2012 and 2017. We analyse two cohorts: 49 haploidentical transplantation with PTCY (50 mg/kg, on day +3, +4) followed by Tacrolimus and Mycophenolate; and 62 peripheral blood related, non-related and mismatched with low dose ATG Fresenius (7mgr/Kg on days -3, -2, -1) associated with Tacrolimus/Cyclosporine starting on day -1 with a short course Methotrexate (on day +1, +3, +6) or Mycophenolate. Mycophenolate was stopped on day +28 and Cyclosporine or Tacrolimus were tapered on day +50.RESULTS.There were no differences in patients' age (49 vs 51), sex or pre-transplantation HCTI-score ≥ 3 (30 vs 26) between PTCY and ATG groups. We found differences between diagnosis (lymphoproliferative disorders (16 vs 4, p= 0.003), high DRI-score (18 vs 11, p = 0.04), number of previous transplantations (12 vs 5, p= 0.02), reduced intensity conditioning regimen (36 vs 20, p < 0.001) and bone marrow as stem cells source (38 vs 9, p < 0.001) between PTCY and ATG groups.The median time to neutrophil engraftment (>500/uL) was similar: 17 days [13-34] for PTCY and 16 days [9-33] for ATG. Median time to platelet recovery was higher in PTCY cohort (33 vs 18 days, p= 0.016). There were 3 secondary graft failures in PTCY group vs 4 graft failures in ATG (3 primary, 1 secondary).The were no differences in grade 2 - 4 aGVHD incidence between groups (PTCY:30.6% vs ATG:36.4%), but we found differences in grades 3 - 4 aGVHD (PTCY:4.1% vs ATG: 9%, p=ns).The global incidence of any NIH grade cGVHD was 56.1% in PTCY vs 66% in ATG group. Mild, moderate and severe cGVHD incidence were 31.7%, 19.5% and 4.8% for PTCY vs 28%, 26% and 12% in ATG (p=ns).The median duration of IS in alive patients with cGVHD was 6.5 months [3-19] in PTCY patients and 10 [3-34] in ATG group. Among moderate and severe forms, the median IS duration was 10 and 5 months in PTCY group vs 13 and 12 months in ATG respectively.PTCY cohort developed more non-infectious complications, especially, cardiac, lung, digestive and neurologic complications, (p=0.086), however there were not differences in infectious complications (Table 1).TRM was similar between groups, 18.4% for PTCY vs 22.5% for ATG, (p=0.250). We didn´t find differences in early toxic mortality (<100 days): 16.3% for PTCY and 14.5% for ATG (p=0,421).With a median follow-up of 27 months in alive patients (28 months for PTCY and 22 months for ATG) we report an 67.8 % and 61% OS at 12 and 24 months for PTCY and 68.8% and 59.9% for ATG (Log Rank=0.971). Relapse free survival at 12 and 24 months was 61% and 57.9% for PTCY and 69% and 54% for ATG (Log Rank=0.839).GRFS at 12 and 24 months was 46.5% and 42.9% for PTCY patients and 40.7% and 33% for ATG patients, (Log Rank = 0.433).CONCLUSIONS.Regardless the different scenarios between transplantation cohorts, the use of PTCY and low dose ATG are equally effective in the prophylaxis of severe forms of aGVHD and cGVHD, offering similar GRFS. PTCY shows higher early toxicity but a similar rate of infectious events. In order to validate these results, it would be necessary to carry out a randomized controlled trial. DisclosuresNo relevant conflicts of interest to declare.

A Cost-effectiveness Analysis of Rabbit Antithymocyte Globulin Versus Antithymocyte Globulin-fresenius as Induction Therapy for Patients With Kidney Transplantation From Donation After Cardiac Death in China

PurposeInduction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer. MethodsA 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospital database, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results. FindingsPatients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were ¥10,783 and ¥8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved ¥5423 over the 1-year and ¥7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost-effective compared with ATG-F in 86.81% of the simulations, considering <3 times the gross domestic product per capita as the threshold. ImplicationsFrom the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data.

No indication of increased infection rates using low-dose alemtuzumab instead of anti-thymocyte globulin as graft-versus-host disease prophylaxis before allogeneic stem cell transplantation.

Alemtuzumab as part of the conditioning protocol is effective in reducing graft-versus-host disease (GvHD), but may be associated with increased infection rates, especially when using high doses (ie, 100mg). We performed a retrospective, single-center, case-control study analyzing the rates of neutropenic fever, cytomegalovirus (CMV) reactivation, Epstein-Barr virus (EBV) reactivation, clinical manifest toxoplasmosis, and clinical manifest human herpesvirus-6 (HHV6) infection using low-dose alemtuzumab in comparison with anti-thymocyte globulin (ATG) as GvHD prophylaxis before allogeneic stem cell transplantation. Forty-four patients transplanted from unrelated donors between 2001 and 2012 were matched by age, diagnosis, and conditioning regimen and treated either with alemtuzumab 10mg at day -2 (respectively, 20mg in case of mismatch transplantation) or ATG. ATG Fresenius (10mg/kg for 3days) or Thymoglobulin (2mg/kg for 3days) were used. Rates of CMV reactivation, EBV reactivation, and clinical manifest HHV6 infection or toxoplasmosis did not differ significantly between both groups until 2years after transplantation. No case of post-transplant lymphoproliferative disorder was observed. Also, rates of neutropenic fever during inpatient treatment after transplantation did not differ significantly in both groups. We saw no indication of increased infections rates when using low-dose alemtuzumab as GvHD prophylaxis before allogeneic stem cell transplantation in this retrospective analysis.

Efficacy and Safety of ATG-Fresenius as an Induction Agent in Living-Donor Kidney Transplantation

BackgroundInduction therapy is mostly recommended for deceased-donor transplantation, whereas it has some controversies in live-donor transplantation. In this study, we described the outcomes of live-donor renal transplant recipients who received ATG-Fresenius (ATG-F) induction. MethodsLive-donor transplantations in patients over 18 years old with ATG-F induction between 2009 and 2015 were included. All patients received quadruple immunosuppression, one of which was ATG-F induction. Biopsies after the artery anastomosis (zero hour) and protocol biopsies at the 6th month and at the 1st first year were obtained. Acute graft dysfunction was defined as a 20% to 25% increase in creatinine level from baseline. All acute rejection episodes were biopsy-confirmed. All episodes were initially treated with intravenous methyl prednisolone (MP) or ATG-F if resistant to MP. Four hundred twenty-two patients with live-donor transplantation were evaluated. The mean age was 40 ± 13 (18–73) years. The mean panel-reactive antibody levels were 42% ± 30% and 45% ± 30% for class I and II, respectively. ResultsThe mean mismatch number for living unrelated donors (n = 112) was 4.6 ± 1.0. Acute rejection rate was 29.1% (123 patients) within the first year. The mean cumulative ATG-F doses for per patient and per kilogram were 344 ± 217 mg and 5.1 ± 2.7 mg, respectively. Patient survival rates were 98.3% and 96.7% for 12 months and 60 months, respectively. Death-censored graft survival rates were 97.6% and 92.1% for 12 months and 60 months, respectively. ConclusionsATG-F induction provided excellent graft and patient survival rates without any significantly increased side effects. Increasing sensitized patient numbers, more unrelated donors, increasing re-transplantation numbers, and more desensitization protocols make ATG-F more favorable in an induction regimen.

Immune Biomarkers Identify Sustained Quantitative and Functional Immune Reconstitution in the Setting of Adjunctive Lenalidomide Following T-Depleted RIC-Allo SCT for Multiple Myeloma

Background: Immune reconstitution after AlloSCT is a highly complex process influenced by both graft & recipient-related factors including post-graft therapies. Delayed T-cell reconstitution remains a source of morbidity & mortality and may contribute to limited anti-tumour effect. We sought to evaluate the immune reconstitution kinetics in the setting of post-graft Lenalidomide (Revlimid®) to augment the graft-versus-myeloma effect, by defining key immune biomarkers, in the NCRI LenaRIC phase II trial.Material & Methods: All patients recruited into the study underwent a reduced intensity conditioned (RIC) AlloSCT using Fludarabine & 2Gy TBI with ATG (Fresenius) as in vivo T-cell depletion, following a high dose melphalan ASCT (planned tandem SCT programme). Patients were scheduled to receive Lenalidomide (5mg-10mg/day) on day+35 if stable donor engraftment in the absence of GvHD. Lenalidomide discontinuation was planned at 12 months post-transplant, with donor lymphocyte infusions (DLI) given to patients with evidence of residual disease, relapse or mixed chimerism. Sequential peripheral blood samples were drawn at predetermined time frames before (baseline) and after graft infusion (D+30,+60,+90,+180,+270 & D+360) in all trial registrants. Using multi-parameter flow cytometry (MFC), a comprehensive panel of immune subset & functional/activation markers were used to define characteristics of T-cell, B-cell, regulatory T-cell & NK cells. The inflammatory proteome (IL-1b, IL-4, IL-5, IL-6, IL-10, IFNg, TNFa, CXCL8 & GM-CSF) and soluble immune checkpoints (PD-1 & ICOS) were analyzed using LUMINEX assays on serial serum samples at parallel points. PB cell subset-specific Complete Donor Chimerism (CDC) was analysed by single tandem repeat PCR at day (D)+100,+180,+270 and D+365.Results: From January 2011 to May 2015, 40 patients with myeloma ≥VGPR after 1st or 2nd ASCT, were recruited into the LenaRIC protocol. The median age was 49 years (range 35-65) with PB as the graft source (Matched Related Donor n=16, 10/10 Matched Unrelated Donor n=23; 1 patient not transplanted). Viable samples were received from 37/40 patients (92.5%), with no cycles of Lenalidomide received by 3/37 (8.1%) patients, 1-6 cycles received by 13/37 (35.1%) patients & >6 cycles received by 21/37 (56.8%) patients. 5 patients completed 12 cycles as per protocol treatment; of those completing >= 10 cycles, 5/16 received DLI.Only 10/37 (27%) of patients achieved a CD4+ cell count >200/µl in a median of 180 days compared with 30/37 (81%) of patients who achieved a CD8+ cell count >200/µl in a median of 60 days. In patients who did not receive any doses of Lenalidomide, higher levels of CD8+ cells (p=0.013) but lower NK cell levels (p=0.071) were evident at D+30 compared with those eligible to proceed with Lenalidomide. No difference was noted between Lenalidomide exposure subgroups in relation to CD8+ or CD4+ cell recovery. Treg cells were increased at D=270 & D+365 in those who received >6 cycles of Lenalidomide, though this corresponded with a higher level of HLA-DR expression on CD8+ T cells representing global immune activation. Significant differences between Lenalidomide exposure subgroups were evident in the inflammatory proteome readout at D+90. CXCL8 levels peaked at D+270, especially in those who received >6 cycles of Lenalidomide. Of 30 evaluable patients, T-cell CDC was seen in 63.3% at D100, with 84% of evaluable patients having CDC at D365. No difference between subgroups was evident in relation to rapidity of CDC and stability of CDC.Conclusions: The sequential monitoring of immune biomarkers in the setting of post-graft Lenalidomide following a T-deplete RIC-AlloSCT highlights the rapid and sustained quantitative and functional reconstitution of donor immune homeostasis. The clinical significance of these findings requires correlation with both the anti-tumour immune effect and theimmunopathy ofAlloSCT (GvHD).Unrestricted educational grants were provided by Cancer Research UK and byCelgene.Lenalidomideprovided free of charge byCelgene. The support and time of participating patients and their families is gratefully acknowledged [Display omitted] DisclosuresCook:Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Cook:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Cancer Research UK: Research Funding; Takeda: Honoraria.

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.