Low Antithymocyte Globulin Research Articles

Late-Onset Noninfectious Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience.

We aimed to reveal the incidence of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome and risk factors involved in development. In this cross-sectional study, we retrospectively investigated 745 patients who underwent allogeneic hematopoietic stem cell transplantation in our hospital between January 2000 and December 2020. We evaluated demographic characteristics, comorbidities, and hematopoietic stem cell transplantation characteristics to determine possible risk factors affecting development of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome. Of 745 patients, 8.9% (n = 66) had late-onset noninfectious pulmonary complications. Complications included 38 patients with bronchiolitis obliterans syndrome, 13 with venous thromboembolism, 8 with cryptogenic organizing pneumonia, 5 with pneumothorax, 4 with interstitial lung disease-restrictive graft-versus-host disease, 5 with bronchiectasis, 2 with pneumomediastinum, and 1 with pleural effusion. Patients with and without complications were not significantly differentin terms of smoking history, hematopoietic stem cell transplantation characteristics, and conditioning regimens. Patients with complications had higher busulfan and lower antithymocyte globulin use than those without complications (both P<.05). Patients with complications more commonly had hematopoietic stem cell transplantation from related donors and chronic graft-versus-host disease (P < .05). Patients with bronchiolitis obliterans syndrome had more frequent use of busulfan (P <.05) but less frequent use of total body irradiation (P <.05) and antithymocyte globulin (P <.05) than those without this syndrome. Rate of hematopoietic stem cell transplantation from a related donor (P < .05) and frequency of chronic graftversus-host disease (P < .001) were significantly higher in patients with bronchiolitis obliterans syndrome, presented with bronchiectasis (78.6%), air trapping (67.9%), bronchial wallthickening (53.6%), and mosaic attenuation (39.3%) in thorax computed tomography. Pretransplant spirometry did not predict bronchiolitis obliterans syndrome development. Determining risk factors for late-onset noninfectious pulmonary complications is needed to aid in prevention and follow-up.

Rabbit Anti-Thymocyte Globulin (ATG) Exposure after Ex Vivo T-Cell Depleted Hematopoietic Cell Transplantation Is Highly Variable and Impacts Immune Reconstitution in Pediatric and Young Adult Patients

<h3>Background</h3> Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease and graft failure. Its main and unpredictable toxicity includes poor immune reconstitution (IR) associated with higher mortality: patients who early reconstitute CD4+ have lower non-relapse mortality (NRM) and higher survival. Recently, a population pharmacokinetic (PK) pharmacodynamic rATG model described the optimal ATG exposure in various T-replete HCT settings. No data is however available in EX VIVO T-Cell Depleted (TCD) HCT. The goal of this study is to determine the optimal exposure of rATG in a pediatric and young adult patient EX VIVO TCD HCT setting, allowing early IR. <h3>Methods</h3> Pediatric and young adult patients receiving their first allogeneic EX VIVO TCD HCT at Memorial Sloan Kettering Cancer Center (2008–2018) were included. No restrictions were applied in terms of donor source, indication, conditioning, and age. Only patients receiving rATG (alone) or no ATG were included in analyses. We estimated exposure of rATG, before, after and total as area under the curve; (AUC) (mg*d/L) for all patients using an established PK model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+ IR,defined as CD4+ levels >50/uL at two consecutive measures within 100 days, overall survival (OS), and NRM. We evaluated the association between ATG exposures and IR using a smoothed exposure to define optimal ATG exposure after HCT.Cox proportional hazard models, and multi-state competing risk models were used for analyses. <h3>Results</h3> 223 underwent a TCD HCT. 186 were included in the analysis as they received rATG (n=165) or no ATG (n=21).120(65%) had malignant and 66 (35%) had non-malignant indications for HCT. Median age was 10.5 (0.2–44) years. For those who received rATG, median rATG exposure after HCT was 34.2(range 0.622-104). A lower post AUC was associated with higher probability of IR (p<0.0001:Fig 1), increased OS(p=0.01), and lower NRM (p=0.01). The threshold for better IR and outcomes was found to be <20mg*d/L. Probability of CD4+ IR varied depending on the ATG exposure; No ATG vs.<20 vs. >20 (p<0.0001:Fig 2). There was a difference in NRM according to the ATG exposure;<20 vs. >20 (p=0.03:Fig 3), and in NRM according CD4 IR at day 100 (IR:CI 4+/- 4% vs. No IR; CI 30+/-10%;p <0.0001). <h3>Conclusions</h3> In patients who received EX VIVO TCD graft, rATG plays crucial role in probability of CD4+ IR. Patients who had rATG exposure <20 mg*d/L had highest IR, higher OS and lower NRM. These results emphasize the importance of individualizing ATG dosing to target to a low ATG exposure after HCT to improve early CD4+ reconstitution, decrease NRM, and increase survival chances.

Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation

AbstractSuccessful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti–thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P = .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT.

Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study.

Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings.Trial RegistrationClinicalTrials.gov NCT00548405

CD8 T cell dose impacts acute graft-versus-host disease after reduced intensity conditioning (RIC) for allogeneic stem cell transplantation

6633 Background: We previously reported that the incidence of acute GVHD (aGVHD) was significantly associated with the antithymocyte globulin (ATG) dose (Sangstat*) infused during RIC using fludarabine, busulfan and ATG. The impact of ATG is likely related to a dose-dependent in vivo T cell depletion. Here, we investigated whether a correlation exists between graft composition and transplant-related events. Methods: 71 consecutive pts from a single center receiving HLA-identical RIC allogeneic transplantation, were analyzed. Median age was 50 y. (18–60), diagnosis: 34 myeloid malignancies (48%) and 37 lymphoid malignancies (52%). 51 pts (72%) were high risk. 38 pts (53%) received a low ATG dose (2.5 mg/Kg), while 33 received the highest dose (7.5 or 10 mg/Kg). 40 pts (56%) received PBSC and 31 (44%) received BM. All pts received CsA alone for GVHD prophylaxis. Results: 42 pts had aGVHD [13 grade I (18%), 12 grade II (17%) and 17 grade III-IV (24%)]. Chronic GVHD (cGVHD) occurred in 36 [8 limited (11%) and 28 extensive (39%)] out of 55 evaluable pts. Univariate analysis showed that stem cell source, ATG dose, CD4+, CD8+, CD19+ and CD56+ cells infused, significantly influenced the risk of aGVHD. In multivariate analysis, CD8+ T cell dose (>69x10e6/Kg) was the only parameter significantly associated with the risk of aGVHD (P=0.0002; RR=3.5; 95%CI, 1.8–6.7). The impact of CD8+ cell dose on aGVHD could be also confirmed if restricting the analysis to PBSC recipients (P=0.02). In contrast, in multivariate analysis, the risk of cGVHD was not statistically associated with lymphoid subsets, but was associated with grade II-IV aGVHD (RR=2.5; 95%CI, 1.2–5.0) and stem cell source (PBSC; RR=2.35; 95%CI, 1.1–5.0), suggesting that other cell subtypes (e.g. dendritic cells…) might contribute to long term imune reactions. With a median FU of 31 m (5–58), 37 pts are alive with OS being significantly higher in pts experiencing aGVHD and/or cGHVD as compared to pts without GVHD (P=0.004). Conclusions: These results suggest that graft manipulation may have a significant impact on the probability of a favorable outcome after RIC transplantation. No significant financial relationships to disclose.