Antithymocyte Globulin Group Research Articles

Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Higher-Risk Myelodysplastic Syndrome

Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG).Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged <55 years, 2-days for 55 years), fludarabine. For GVHD prophylaxis, PTCy (50 mg/kg on days 3 and 4), cyclosporine, and mycophenolate mofetil were administered. In historical group, patients received 2- or 4-days of busulfan, fludarabine, and ATG with short course of methotrexate and cyclosporine.Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P<.001), respectively. Incidence of total and extensive chronic GVHD (50.0% vs. 49.1%, P=.567; 32.5% vs. 33.4%, P=.581), 1-year NRM (20.8% vs. 22.9%, P=.702), and 2-year relapse (16.0% vs. 18.1%, P=.605) were not different between two groups. Neutrophil and platelet engraftment was significantly faster with ATG than PTCy (median 12 vs. 15 for neutrophil; median 15 vs. 24 days for platelet).Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. DisclosuresChoi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.

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

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

Impact of in Vivo Lymphodepletion on Outcome in Children with Nonmalignant Disorders Receiving Peripheral Blood Stem Cell Transplantation

Peripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with nonmalignant disorders (NMDs). We aimed to provide an historical comparison of these 2 strategies regarding the prevalence of GVHD, viral reactivation, timing of immune reconstitution, and final outcomes. Data on 98 children undergoing PBSCT were collected from 5 European pediatric transplantation centers. Only patients with NMDs receiving treosulfan or myeloablative busulfan conditioning and 9-10/10 HLA-matched transplant were included. The patients were divided into 2 groups according to in vivo lymphodepletion with antithymocyte globulin (ATG) or with alemtuzumab. We compared rates of acute and chronic GVHD; Epstein-Barr virus, cytomegalovirus, and adenovirus reactivation; chimerism; lymphocyte recovery; overall survival (OS) and event-free survival (EFS) between the 2 groups. The rate of severe acute GVHD (grade III-IV) was significantly higher in patients receiving ATG (26% vs 10% in alemtuzumab recipients; P < .05), whereas viral reactivations occurred with a similar rate in the 2 groups (alemtuzumab, 56%; ATG, 57%). Alemtuzumab was the major risk factor for delayed T cell immune reconstitution in the first 3 months after transplantation (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.8 to 19; P < .005). Extended chronic GVHD, ADV reactivation, slower CD3+ cell recovery, and HLA-mismatch reduced the probability of survival. Infections were the main cause of mortality in our cohort, and delayed T cell recovery was significantly associated with mortality in multivariate analysis (OR, 12; 95% CI, 1.2 to 114; P < .05). Ultimately, no differences in OS and EFS survival were seen between the ATG and alemtuzumab groups. ATG and alemtuzumab showed similar impacts on outcomes of children undergoing PBSCT for NMDs. The 2 strategies of in vivo lymphodepletion showed specific drawbacks that were counterbalanced by benefits that ultimately led to a comparable survival rate. A patient-centered lymphodepletion strategy can be advised in children undergoing PBSCT for NMDs, by favoring T cell recovery in the presence of invasive infection or GVHD prevention in high-risk mismatched donor transplantation.

Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) As Gvhd Prophylaxis Is Effective in Haploidentical Peripheral Stem Cell Transplantation and without Increasing Risk of Relapse

Introduction:Post-transplant cyclophosphamide (PtCY) in combination with calcineurin inhibitors overcomes the barrier of haploidentical bone marrow transplantation, but for peripheral stem cell transplantation (HaploSCT), there are concerns about life-threatening cytokine release syndrome (CRS) and increased incidences of acute/chronic graft versus host disease (GVHD). Italy group reported sirolimus decreased incidence of GVHD without increasing disease relapse. Baltimore group reported anti-thymocyte globulin (ATG) combined with PtCy was an efficient alternative for protection from GVHD in non-hematologic diseases; yet it is unknown whether the combination increases the incidence of infection and disease relapse. In our hospital, since initial high incidences of acute GVHD with PtCy and cyclosporine, either sirolimus in substitution for cyclysporine, or ATG was used in combination with PtCY in our patients with hematologic malignancy. Therefore, we conducted a retrospective study to compare the two regimens which aimed to focus on disease relapse, GVHD, viral infection, and CRS.Methods:A total of 61 patients with hematological malignancies, who had an HaploSCT at our center from Jan 2013 to Dec 2016. Thirty-seven patients belonged to ATG group with GVHD prophylaxis consisting of rabbit ATG of total of 4.5mg/kg; PtCy of 50 mg/kg on Days +3 and +4 and cyclosporine/mycophenolate(MMF) from Day+5 onwards. Twenty-four patients were stratified into sirolimus group with GVHD prophylaxis consisting of PTCy and sirolimus/MMF.Results:Patients characteristics are provided in Table 1. There were no significant differences between ATG and sirolimus group.CRS was common in both group (ATG versus sirolimus:73% versus 83.3%, p=0.376) as seen in Figure 2. Three patients in sirolimus group developed grade 3-4 CRS. No patient in ATG group had grade 3-4 CRS. Serum cytokine profiles were available in 8 patients of each group. The level of IL2, IFNr and IL8 were significantly suppressed in ATG group compare to sirolimus group as seen in Figure 3. Other cytokines including IL-10, IL12p40,IL-12p70,IL-13,IL-15,IL-17A,IL-9,IL-4,IL-6,IL-7,MIP-1A ,MIP-1B, TNFa,IL-17F,IL-21,IL-23,IL-17E, and IL-27 showed no significant differences.Thrombotic thrombocytopenic purpura (TTP) occurred in 2 (8.3%) of 24 patients receiving sirolimus. No TTP occurred in ATG group. Hemorrhagic cystitis occurred in 25% patients of sirolimus group and 13.5% patients of ATG group. EBV reactivation occurredhigher in ATG group compared to sirolimus group (32.4% versus 8.3%, p=0.07). No post-transplant lymphoproliferative disorders were observed in both groups. There were 33.3% of CMV reactivation in sirolimus group, and 51.3% in ATG group (p=0.287). CMV diseases developed in 5 (20.8%) of 24 patients in sirolimus group compared to 6 (16.2%) of 37 patients in ATG group (p=0.734).There was no difference of cumulative incidence (CI) of grade II-IV acute GVHD (aGVHD) (ATG versus sirolimus (95%CI) : 21.9% (10.1%-36.6%) versus 16.9% (5.1%-36.6%), p=0.58) and grade III-IV aGVHD (5.4 % (0.9%-16.1%) versus 8.3% (1.4%-23.7%), p=0.34) at day 100 after HSCT, as seen in Figure 4. Similar CI of chronic GVHD (cGVHD) and moderate to severe cGVHD were noted between groups (cGVHD: ATG versus sirolimus :36.5% (20.7%-52.5%) versus 33.3% (15.3%-52.6%), p=0.58; moderate to severe cGVHD:13.5% (4.9%-26.6%) versus 16.7% (5.0%-34.3%), p=0.81), as seen in Figure 5.The 2-year non-relapse mortality of ATG versus sirolimus was 21.5% (9.2%-37.1%) versus 12.8% (3.0%-30.0%); p=0.07). The disease relapse of ATG group versus sirolimus group was 69.7% (37.1%-87.7%) versus 37.3% (20.6%-54.1%; p=0.07), as seen in Figure 6. Multivariate analsysis showed only disease risk index was an independent prognostic factor (HR, 95% CI:5.61 (1.02-30.7), p :0.05). The 2-year overall survival of ATG group versus sirolimus group was 46.3% (27.9%-62.9%)versus 21.7%(6.0%-43.8%); p=0.13) as seen in Figure 7.Fifty-five patients were followed up to determine the reconstitution of T cell subsets, as seen in figure 8. Compared to sirolimus group, ATG group had significantly lower CD3 and CD4 cell counts at day 180.Conclusion:ATG combined with PtCy is a feasible option as GVHD prophylaxis. Compared to sirolimus with PtCy, ATG/PtCy led to similar outcomes of overall survival, acute and chronic GVHD. Importantly, ATG did not increase the risk of disease relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ex Vivo T Cell-Depleted and In Vivo T Cell-Depleted Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in First Complete Remission Resulted in Similar Overall Survival Survival: On Behalf of the ALWP of the EBMT and the MSKCC

Background. Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established therapy for adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high-risk cytogenetics. However regimen-related toxicities, in particular graft-versus-host disease (GVHD) have limited its widespread use. Therefore several strategies have been developed to deplete T cells in order to prevent GVHD. In vivo T-cell depletion (TCD) using antithymocyte globulin (ATG) with an unmanipulated graft is widely used in some centers in Europe, while other centers have develop an effective platform based on ex-vivo TCD CD34 selected (CD34+) graft. The aim of the current study was to compare these two strategies for GVHD prevention.Patients and methods. This retrospective analysis assessed the outcome of all consecutives patients over 18 years at time of transplant with an AML in CR1 with intermediate or high risk cytogenetics who received an in-vivo or ex-vivo T cell depleted myeloablative allo-HSCT using busulfan or total body irradiation based conditioning regimen between 2005 and 2011 and reported to the EBMT ALWP registry centers or at Memorial Sloan Kettering Cancer Center (MSK), respectively. Patients treated in EBMT centers received in vivo TCD with either thymoglobuline or grafalon ATG. In addition, all patients in the ATG group received GVHD prophylaxis consisting of a calcineurin inhibitor in combination with another drug. Patients treated at MSK received an ex-vivo TCD graft (CD34+). TCD was performed by immunomagnetic CD34+ cell selection of peripheral blood grafts. No additional GVHD prophylaxis was administered in those patients. Main transplant outcomes including refined GVHD-free/relapse-free survival (GRFS) were evaluated.Results. A total of 525 patients were included (363 ATG, 162 CD34+) with a median age of 46 (19-77) and 58 (range, 20-73) years, respectively (p<0.001). The ATG cohort had more unrelated donors (67.5% vs. 54.9%, p=0.006). Median follow-up was significantly longer in the CD34+ cohort [58.0 (range, 6-139.0), vs. 24.5, 51.9-131.0) months, p<0.001], therefore all patients were censored at 2 years for comparison between groups. There were no additional differences between cohorts including donor/recipient gender, CMV status and cytogenetic risk. The CD34+ cohort had less relapse (21.6% vs. 30%, p=0.03), grade II-IV aGVHD (11.3% vs. 21.2%, p=0.006), III-IV aGVHD (1.3% vs. 6.2%, p=0.01), cGVHD (2.5% vs. 27.6%, p<0.0001) and extensive cGVHD (0.6% vs. 11.3%, p=0<0.0001) and a higher GRFS (61% vs. 47%, p=0.0007) while there was no difference regarding OS (67.6% vs. 56.4%, p=0.31), LFS (61% vs. 57.9%, p=0.29) and NRM (17.4%, vs 12.1%, p=0.16). In multivariate analysis, the cumulative incidence of grade II-IV aGVHD and chronic GVHD were higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p=0.02 and HR 15.1 (95% CI 5.3-42.2), p<0.0001]. There were no statistical differences between both approach in terms of relapse, NRM, OS, and LFS. Parameters associated with a lower GRFS were ATG group, adverse cytogenetic and use of an unrelated donor [HR 1.7 (95% CI 1.2-2.5) p=0.001; HR 1,7 (95% CI 1.3-2.2) p=0.0002 and HR 1.5 (95% CI 1.1-2.0) p=0.01]. Cytogenetic status (high risk versus intermediate risk) also has a significant impact on relapse incidence [HR 2.1 (95% CI 1.4-3.0), p<0.0001] and LFS [HR 1.7 (95% CI 1.2-2.3) p=0.0006]. Finally there was significantly more death related to infection in the CD34 group (16/52, vs. 19/112, p=0.04).Conclusion. The cumulative incidence of acute (total and severe) and chronic GVHD were higher after allo-HSCT with ATG, leading to a lower GRFS in those patients. In contrast, enhance immunosuppression in the CD34+ group lead to a higher incidence of infectious related death. Overall NRM, OS and LFS are similar after ex-vivo CD34 selected and in-vivo ATG TCD allo-HSCT from related/unrelated donors in patients with AML in CR1 and intermediate/high-risk cytogenetic. Both approaches are associated with a good disease control and a high OS, and should be compared in a prospective randomized trial. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors.

Antithymocyte globulin (ATG) has been shown to reduce chronic graft-versus-host disease (GVHD) particularly in allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors; however, anti-GVHD effects of lower doses of ATG remains to be elucidated. We conducted a nationwide retrospective study to compare the outcomes of unrelated PBSCT with or without rabbit ATG (thymoglobulin) in 287 patients. A median ATG dose was 2.0 mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%, P = 0.025). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse.

Impact of anti-thymocyte globulin dose for graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation from matched unrelated donors: a multicenter experience

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6–7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.

A clinical study of lyophilized intravenous human immunoglobulin containing high-titer cytomegalovirus-neutralizing antibody for the treatment of cytomegalovirus viremia after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection increases the risk of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, some patients do not respond to ganciclovir (GCV) or foscarnet sodium. Lyophilized intravenous human immunoglobulin containing high-titer CMV-neutralizing antibody (CMV-IVIG) is another option to further improve treatment safety and efficacy. This study was designed to evaluate the efficacy of the combination of CMV-IVIG with traditional antiviral drugs (GCV or foscarnet sodium) at different time points for the treatment of post-allo-HSCT CMV viremia and to determine the clinical value of CMV-IVIG as a preemptive treatment strategy. The clinical data of 73 patients who received allo-HSCT and concurrent CMV-IVIG to treat post-allo-HSCT CMV viremia at our hospital between January and September 2020 were retrospectively analyzed. The patients were divided into two groups based on the total dose of antithymocyte globulin (ATG) used in the pretransplant preconditioning regimen, i.e., the low-dose ATG group (rabbit ATG ≤6 mg/kg, porcine ATG ≤40 mg/kg) (n=19) and the high-dose ATG group (rabbit ATG >6 mg/kg, porcine ATG >40 mg/kg) (n=54). Real-time quantitative polymerase chain reaction (RQ-PCR) was performed to measure the peripheral CMV-DNA level. Patients with CMV viremia (CMV-DNA >1,000 copies/mL) received concurrent CMV-IVIG therapy [early (within 3 days after the diagnosis of CMV viremia) or late (after 3 days)]. The CMV-DNA conversion rate, the median time of CMV-DNA conversion, and the two-week response rate and reactivation rate were analyzed for different ATG doses and different time points of CMV-IVIG use. The overall response rate to CMV-IVIG combined with traditional anti-CMV drugs was 100%. Early use of CMV-IVIG significantly reduced the median time of CMV-DNA conversion (14 vs. 21 days, P=0.000), especially in the high-dose ATG group (14 vs. 23 days, P=0.000). For patients with post-allo-HSCT CMV viremia, early use of CMV-IVIG effectively accelerates CMV-DNA conversion and peripheral CMV clearance, significantly improves the two-week response rate, and reduces the two-week reactivation rate. These effects are more pronounced in the high-dose ATG group.

Prior antithymocyte globulin therapy and survival in post-transplant lymphoproliferative disorders

Background: Treatment with antithymocyte globulin (ATG) is a well-recognized risk factor for the development of post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, but it is unknown how its use affects overall survival after PTLD. Methods: A total of 114 patients with PTLD and available data on immunosuppressive regimen were included from a nation-wide case series of solid organ transplant recipients in Sweden. Prior use of ATG was correlated to clinical features, PTLD subtype, and survival. Results: A total of 47 (41%) patients had received ATG prior to the diagnosis of PTLD. The ATG-treated patients were more likely to be recipients of hearts or lungs, and less likely of kidneys (p < 0.01). They had experienced more acute rejections (p = 0.02). The PTLDs arose earlier, median 2.0 vs. 6.6 years post-transplant (p = 0.002) and were more often situated in the allograft (32% vs. 7%, p < 0.001) in patients with prior ATG vs. no ATG treatment. The PTLDs in the ATG group were more often Epstein–Barr virus-positive (80% vs. 40%, p < 0.001). There were more polymorphic PTLDs (17% vs. 1.5%, p = 0.004) and less T-cell PTLDs (4% vs. 19%, p = 0.02) in the ATG group than in the no ATG group. Diffuse large B-cell lymphoma was equally common in patients with and without prior ATG therapy, but the non-germinal center subtype was more frequent in the ATG group (p = 0.001). In an adjusted Cox proportional hazards regression model, prior ATG treatment and better performance status were associated with superior overall survival, whereas older age, T-cell subtype of PTLD, presence of B symptoms, and elevated lactate dehydrogenase were associated with inferior overall survival. Patients receiving ATG solely as rejection therapy had superior overall survival compared with those receiving ATG as induction therapy or both (p = 0.03). Conclusions: ATG therapy, especially rejection therapy, prior to PTLD development is an independent prognostic factor for superior overall survival after PTLD diagnosis.

Antithymocyte globulin induction therapy and myocardial complement deposition in pediatric heart transplantation.

Antithymocyte globulin (ATG) consists of polyclonal antibodies directed primarily against human T lymphocytes but may contain antibodies with affinity for other tissues in the transplanted organ, resulting in complement (C4d) deposition. This phenomenon has been demonstrated in endomyocardial biopsies (EMBs) of adult cardiac transplants. We examined the relationship of induction immunosuppression with ATG and C4d deposition in EMB of pediatric cardiac transplants. Results of C4d immunohistochemistry were available from all EMB of patients transplanted at our center between June 2012 and April 2018 (n=48) who received induction immunosuppression with either ATG (n=20) or basiliximab (n=28) as the standard of care. C4d deposition in the first year post-heart transplant was more commonly seen among patients who received ATG induction (20% of EMBs in ATG group vs 1% of EMBs in basiliximab group; p<.0001). C4d deposition related to ATG was observed early post-transplant (50% ATG vs 0% basiliximab on first EMB; p<.0001 and 35% ATG vs 0% basiliximab on the second EMB; p=.0012). While this difference waned by the third EMB (5% ATG vs 0% basiliximab; p=.41), positive C4d staining persisted to the sixth EMB in the ATG group only (6%). C4d deposition is common on EMB up to 1year post-pediatric cardiac transplant following ATG induction. This high rate of positive C4d staining in the absence of histologic AMR after ATG induction therapy must be accounted for in making clinical decisions regarding cardiac allograft rejection diagnosis and treatment.

Role of antithymocyte globulin in matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies.

Background:High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT.Methods:A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day −5 and 3.5 mg/kg on day −4 prior to transplant (the total dose was 5 mg/kg)Results:After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively.Conclusions:These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier NCT02677181). https://clinicaltrials.gov/ct2/show/NCT02677181.

Comparison of different induction dosing of CD3+ cell count based anti-thymocyte globulin for deceased donor kidney transplantation: single center experience

Background: The rabbit anti-thymocyte globulin (ATG) is the most widely used lymphocyte depleting agent in renal transplanta tion. This can be expected to have a profound immune inducing effect, but it has been not widely used in Korea due to concerns about side effects such as leukopenia, thrombocytopenia, and infection. This has made it necessary to find the minimum dosing to show adequate immunosuppressive effects. So, we compared the clinical features of CD3+ cell count based ATG use with a cumulative dose of 3 mg/kg and 4 mg/kg as an induction immunosuppressant. Methods: Fifty-one patients have received deceased donor kidney transplantation with ATG induction therapy in Bongseng Me morial Hospital from 2013 to 2020. And they were divided into two groups: patients who treated with cumulative dose 3.0 mg/kg of ATG (group A) and 4.0 mg/kg (group B). We compared patient’s survival and graft’s survival in both groups. The data were col lected regarding recipients’ panel reactive antibody, CD3+ lymphocyte count, immunosuppressant, viral infection, acute rejection, and adverse events. Results: The demographic characteristics of the two groups were comparable. The incidence of delayed graft function was sta tistically significantly lower in the cumulative dose 4 mg/kg group. There was no statistically significant difference in the graft’s survival and serum creatinine between the two groups, but it was slightly better in 4 mg/kg group. The incidence rates of acute rejection and infectious events as cytomegalovirus disease or urinary tract infection were not significantly different between the two groups. CD3+ lymphocyte count was statistically significantly decreased until 6 months after transplantation in both groups compared to before transplantation. Conclusions: We suggest that ATG induction with cumulative dose of 4 mg/kg would be safe and effective for deceased donor kidney transplantation in Korea.

High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease.

Antithymocyte globulin (ATG) reduces severe acute and chronic graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (PBSCT). However, risk factors for severe acute GVHD in PBSCT using ATG remain to be determined. We conducted a single-center, retrospective study to analyze the association of acute GVHD requiring systemic corticosteroid (SC-aGVHD) with absolute lymphocyte counts (ALC) before the administration of ATG or conditioning in 53 patients with HLA-matched PBSCT using low-dose thymoglobulin (2 mg/kg) after myeloablative conditioning. The cumulative incidence of SC-aGVHD was 17.0% and ALC before ATG were significantly higher in patients with SC-aGVHD compared to that in patients without it (median, 0.15 × 109/L vs 0.06 × 109/L, P = 0.047). The cumulative incidence of SC-aGVHD was significantly higher in patients with high ALC before ATG (≥ 0.15 × 109/L) than in those with low ALC (38.5% vs 10.0%, P = 0.016). Non-relapse mortality (NRM) was also significantly higher in the high ALC before ATG group than the low ALC before ATG group (2-year NRM: 23.9% vs 6.0%, P = 0.048), leading to worse survival (2-year overall survival: 69.2% vs 83.5%, P = 0.039). Our study suggested that high ALC before ATG is a risk factor for SC-aGVHD.

Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

Alemtuzumab Versus Anti-Thymocyte Globulin As Conditioning Method for Allogenic Hematopoietic Stem Cell Transplant; A Meta-Analysis

Objective: Anti-thymocyte Globulin (ATG) and Alemtuzumab (Ale) are common methods for T cell depletion in the setting of allogenic hematopoietic stem cell transplant. They are both used to promote engraftment and prevent graft-versus-host disease (GVHD). Currently, there's no comparative meta-analysis for safety and efficacy of Ale versus ATG. Therefore, we conducted a meta-analysis to compare the risk of acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), odd of relapse and overall survival (OS) between Ale and ATG. Method: We performed a comprehensive literature search in MEDLINE (Pubmed), Cochrane library and EMBASE database from inception to April 2020 for studies that compared the use of Ale and ATG. We conducted a random effect meta-analysis of 11 studies involving a total of 4,239 participants (Ale=1,293, ATG=2,946) and reported the pooled odd ratio (OR) for development of aGVHD, cGVHD, relapse and OS. Result: We found a significant decreased in odd of aGVHD and cGVHD in the Ale group compared to the ATG group (pooled OR 0.44, 95% CI 0.32-0.61, I2=56.1% and 0.58, 95% CI 0.44-0.77, I2=47.5% respectively) but there were no statistically significant increase in the odd of relapse and OS (pooled OR 1.14, 95% CI 0.81-1.59, I2=64.5% and 1.20, 95% CI 0.83-1.72, I2=76.3% respectively). Conclusion: There is significantly decreased odd of aGVHD and cGVHD with use of Ale compared to ATG, but there is no statistically significant increased odd of relapse or OS. We concluded that Ale could be the superior method of T cell depletion in terms of decreased aGVHD and cGVHD but there's no significant difference in odd of relapse and OS. Disclosures No relevant conflicts of interest to declare.

Use of Rabbit Anti-thymocyte Globulin as a Renal Sparing Strategy: Outcomes from a Single Center

Introduction Acute kidney injury (AKI) complicates up to 25% of patients undergoing orthotopic heart transplant (OHT) and can be exacerbated by the introduction of calcineurin inhibition (CNI). Induction with rabbit anti-thymocyte globulin (ATG) can provide immunosuppression to prevent early rejection until CNI therapy is introduced. However, current data regarding ATG use to allow delayed CNI initiation is limited. Hypothesis ATG induction with delayed initiation of tacrolimus as a renal sparing strategy will result in less renal failure without a significant increase in infection and rejection. Methods From January 2014 to December 2019, 143 patients underwent OHT. Dual organ transplantation, those requiring ATG for non-renal sparing reasons, and patients without 1 -year follow-up were excluded. Using standard statistical analysis, we compared in-hospital and post discharge outcomes at 1, 6, and 12 months between patients with and without ATG administration. Results ATG was given to 26/71 (36.6%) patients as a renal sparing strategy. Compared to the no ATG group, the ATG group had higher pre-transplant creatinine (1.5 vs 1.2 mg/dL, p=0.001) and lower glomerular filtration rate (GFR) (58.6 vs 76.4 ml/min, p=0.002), but no other significant differences in baseline characteristics. Tacrolimus was started later in the ATG group (3.6 vs 0.9 days, p=0.0001). The ATG group had lower GFR at 1 month (64.1 vs 82.5 ml/min, p = 0.009) and 6 months (44.2 vs 58.1 ml/min, p= 0.028) with a non-significant difference at 1 year (50.1 vs 62.4 ml/min, p=0.08). The ATG group was more likely to require renal replacement therapy (RRT) during the index admission (34.6 vs 4.4%, p=0.01). This difference persisted at discharge (19.2% vs 2.2%, p= 0.022) and 1 year (15.4% vs 0%, p= 0.015). No significant difference between the two groups in the rate of worsening chronic kidney disease at 1, 6 and 12 months. Freedom from readmission for infection was lower in the ATG group (53.8 % vs 80%, p= 0.03). There were no significant differences in in-hospital (p=1.00), 1 year mortality (p=0.19), and 1 year freedom from rejection (p=0.80) between groups. Conclusions ATG use as a renal sparing strategy in OHT recipients with renal dysfunction at baseline was associated with a high rate of early RRT but overall change in renal function over one year was similar. Freedom from readmission for infection was lower in the ATG group and freedom from rejection was equal in both groups. Thus, it appears in this retrospective analysis, that a strategy of induction therapy for renal sparing was not beneficial and increased the risk of infection.

COMPARATIVE STUDY OF ATG VS ATG-F (GRAFALON) AS AN INDUCTION AGENT IN ABO INCOMPATIBLE KIDNEY TRANSPLANTATION

Induction therapy is used prior to kidney transplant to prevent rejection. ABO-incompatible(ABOi) transplantation has a high risk of rejection owing to preformed antibodies. Polyclonal antibodies are used as an induction agent in high-risk kidney transplant.Two different forms of polyclonal antibodies are available for use- Rabbit Anti thymocyte globulin(ATG) and anti-human T-lymphocyte immunoglobulin (Grafalon).(1) The aim of this prospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either Rabbit Anti thymocyte globulin(ATG) and anti-human T-lymphocyte immunoglobulin(Grafalon) as an induction agent. All ABOi HLA-compatible patients that received a Lve donor kidney transplant between January 2017 and December 2018 at Sir Ganga Ram Hospital, New Delhi were included in the study. Twenty-five patients were given ATG and twenty-two patients received Grafalon. Baseline characters were similar between the two groups. Post-transplant immunosuppression was similar between both groups. All patients received Tacrolimus, Mycophenolate mofetil, and Prednisolone. There was no immediate infusion reaction observed with both induction agents. During the follow-up, no PTLD or malignancy occurred in both groups. The incidence of viral and bacterial infections was similar in both groups. The cumulative incidence of clinical and subclinical antibody-mediated allograft rejection, as well as T-cell, mediated allograft rejection during the first year between ATG and Grafalon was similar (20% versus 32%; p = 0.48 and 20% versus 9%;p = 0.36 respectively).within one year,two patients in ATG group and three patients in Grafalon group died. One patient in the ATG group underwent graft nephrectomy. Kaplan Meier survival analysis was done which showed survival was greater in the ATG group in comparison to Grafalon.

Antithymocyte Globulin for Matched Sibling Donor Transplantation in Patients With Hematologic Malignancies: A Multicenter, Open-Label, Randomized Controlled Study.

The role of antithymocyte globulin (ATG) in preventing acute graft-versus-host disease (aGVHD) after HLA-matched sibling donor transplantation (MSDT) is still controversial. We performed a prospective, multicenter, open-label, randomized controlled trial (RCT) across 23 transplantation centers in China. Patients ages 40-60 years with standard-risk hematologic malignancies with an HLA-matched sibling donor were randomly assigned to an ATG group (4.5 mg/kg thymoglobulin plus cyclosporine [CsA], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (CsA, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. From November 2013 to April 2018, 263 patients were enrolled. The cumulative incidence rate of grade 2-4 aGVHD was significantly reduced in the ATG group (13.7%; 95% CI, 13.5% to 13.9%) compared with the control group (27.0%; 95% CI, 26.7% to 27.3%; P = .007). The ATG group had significantly lower incidences of 2-year overall chronic GVHD (27.9% [95% CI, 27.6% to 28.2%] v 52.5% [95% CI, 52.1% to 52.9%]; P < .001) and 2-year extensive chronic GVHD (8.5% [95% CI, 8.4% to 8.6%] v 23.2% [95% CI, 22.9% to 23.5%]; P = .029) than the control group. There were no differences between the ATG and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, 3-year nonrelapse mortality (NRM), 3-year cumulative incidence of relapse (CIR), 3-year overall survival, or 3-year leukemia-free survival. Three-year GVHD relapse-free survival was significantly improved in the ATG group (38.7%; 95% CI, 29.9% to 47.5%) compared with the control group (24.5%; 95% CI, 16.9% to 32.1%; P = .003). Our study is the first prospective RCT in our knowledge to demonstrate that ATG can effectively decrease the incidence of aGVHD after MSDT in the CsA era without affecting the CIR or NRM.

P1775CMV VIREMIA IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING BASILIXIMAB OR LOW DOSE ANTI THYMOCYTE GLOBULIN INDUCTION WITHOUT VALGANCICLOVIR PROPHYLAXIS- SINGLE CENTRE EXPERIENCE IN INDIA

Abstract Background and Aims CMV is a major cause of morbidity in transplant recipients and manifests as tissue invasive disease or CMV viral syndrome. Controversy exists regarding best method for CMV prevention. Therefore, we intended to evaluate incidence of CMV viremia and symptomatic CMV infection in adult KTR with basiliximab or antithymocyte globulin (ATG) induction without the use of valganciclovir prophylaxis. This study will help developing a protocol for management of CMV infection/disease in Indian patients since there is no such data amongst Indians. Method A prospective, open-label, single centre study. Patients were monitored for CMV DNA-PCR twice a week for month 1 post-transplant, once a week in month2, and then every 2 weeks in month 3, and then once a month from month 4 to 6. Results We included 17 patients with low-dose ATG induction (group1) and 20 patients with Basiliximab induction (group2). Mean recipient age was 42.9 and 45.9 yr in group 1 and 2 whereas mean donor age was 50.6 and 51.6 yr respectively. Male recipients were 76.4% (13/17) and 65% (13/20) in group 1 and 2 respectively; male donors were 11.7% (2/17) and 20% (4/20) respectively (not signficant). Average HLA mismatches were 3.4/6 and 3.7/6 (not significant). In group1 average transfusions per patient were 6units (vs 1.7units in group2) and 65% pts in group1 had &amp;gt;3 units transfusion (p&amp;lt;0.05). Mean follow-up was 12.7 and 20.7 months respectively. Incidence of acute rejection was 5.8% (1/17) and 10% (2/20) in group 1 and 2 respectively. (not significant). Incidence of CMV viremia requiring valganciclovir therapy was 11.6% (2/17) and 10% (2/20) in group 1 and 2 respectively. (not significant). No patient developed CMV disease. Mean serum creatinine was 1.1 and 1.09 mg/dL at 1 month and 1.2 and 1.14 mg/dL at 3 months (not significant) Conclusion The incidence of CMV viremia is low and not significantly different in patients receiving basiliximab or low dose ATG induction in living donor kidney transplants on tacrolimus based immunosuppression. In our study patients in ATG group had significantly more transfusions vs basiliximab group and hence were more sensitised. Still the incidence of acute rejection remained low in both these groups (5.8% and 10%). Hence universal prophylaxis with valganciclovir may not be required in all the patients with basiliximab and low dose ATG induction especially in developing countries where cost of therapy is borne by the patients.