Insufficient immune reconstitution (IR) is a major determinant of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Strategies for graft-versus-host disease (GVHD)-prophylaxis, such as anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy), modulate immune recovery, but their effects on IR in matched unrelated donor (MUD) allo-HCT remain incompletely defined. In this retrospective bi-centric study, we analyzed patients with myeloid malignancies undergoing MUD allo-HCT who received ATG or PTCy per center policy. Longitudinal IR and clinical outcomes were assessed. IR was defined as sustained recovery of CD3+CD4+ cells >200/μl and CD19+ cells >50/μl. The impact of GVHD-prophylaxis (ATG vs PTCy) on IR dynamics was explored. A total of 252 patients were included. By day +365, 16.7% achieved IR, which was independently associated with superior OS (HR 0.39, 95% CI 0.17-0.90; p=0.026) and lower TRM (HR 0.08, 95% CI 0.01-0.63; p=0.017). In multivariable competing-risk analyses, younger donor age (sHR 0.97, 95% CI 0.94-1.00; p=0.037) and PTCy (sHR 0.49, 95% CI 0.27-0.84; p=0.01) were associated with higher probability of IR by month +18. The association between PTCy and IR was attenuated after adjusting for therapy-requiring acute or chronic GVHD, which independently delayed IR (HR 0.31, 95% CI 0.20-0.48; p<0.001). ATG and PTCy showed distinct IR trajectories: ATG associated with earlier NK expansion, PTCy led to enhanced adaptive T- and B-cell recovery from day +100. IR strongly predicted survival, independently of GVHD-prophylaxis. Prospective studies are warranted to better define determinants of IR after MUD allo-HCT in the PTCy era.

Hematopoietic stem cell transplantation (HSCT) remains an effective treatment for severe aplastic anemia (SAA), but the optimal conditioning regimen has yet to be established. This study aimed to evaluate the safety and efficacy of a conditioning regimen consisting of fludarabine (Flu), cyclophosphamide (Cy), and porcine anti-lymphocyte globulin (p-ATG). This prospective single-arm clinical trial enrolled 48 SAA patients who underwent HLA-matched sibling transplantation. The conditioning regimen consisted of p-ATG (120 mg/kg), Cy (120 mg/kg), and Flu (120 mg/m[2]). All patients achieved neutrophil engraftment (median time of 12 days), with 98% attaining platelet recovery (median time of 13 days). Complete donor chimerism was achieved in 95.8% of patients by day + 30. Cardiac toxicity was observed in three patients. No grade 4 regimen-related toxicity was observed. The cumulative incidences of grade acute GVHD and chronic GVHD were 21.0% (95% CI: 8.5% to 31.8%) and 15.8% (95% CI: 4.2% to 25.9%), respectively. The 1-year overall survival rate was 97.9% (95% CI: 94% to 100%). In this single-arm study, these results indicate that the conditioning regimen of p-ATG combined with Flu and Cy is associated with stable engraftment, an acceptable safety profile, and a manageable incidence of GVHD.

Anti-thymocyte globulin (ATG) is a polyclonal antibody used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. While recent studies have worked towards understanding the pharmacokinetic-pharmacodynamic relationship via population pharmacokinetic modeling, dosing remains weight-based and largely empirical in clinical practice. In this study, conventional and novel ATG dosing regimens were evaluated using Monte Carlo simulation and an in silico population of 10,000 representative adult patients. Individualized ATG dosing was examined using empirical Bayesian estimation and an optimisation function. Post-transplant exposure was calculated, and the probability of target attainment was determined for each regimen. No conventional ATG dosing regimen was able to dose > 25% of patients within the defined therapeutic target range of 60-95 AU·day/mL, with regimens utilizing total ATG doses of 4-5 mg/kg having the highest target attainment. Dose optimisation approaches were only able to improve on target attainment over baseline by up to 7%. In all cases, empirical Bayesian estimation of individual pharmacokinetic parameters was poor, with shrinkage > 30% noted on three of the five parameters. These findings suggest that improving target attainment of ATG by means of model-informed precision dosing is unlikely to be of clinical benefit in hematopoietic stem cell transplant recipients. Further research into factors affecting the pharmacokinetic parameters of ATG is required to allow for dose individualisation and treatment optimisation.

Graft versus host disease (GVHD) is a serious side effect of allogenic stem cell transplantation (allo-SCT). Anti-thymocyte globulin (ATG) reduces GVHD but raises the risk of infections following allo-SCT. Preventive therapy is recommended for cytomegalovirus (CMV), which is a major pathogen. Prophylactic administration of letermovir has shown a significant reduction in CMV reactivation. We hypothesized letermovir could reduce CMV reactivation and affect the outcome of allo-SCT. We retrospectively studied 88 patients who received allo-SCT with ATG for acute leukemia or myelodysplastic syndromes (MDS) from 2014 to 2022. The patients were divided into letermovir (n = 34) and non-letermovir (n = 54) groups. 3-year overall survival rates were 85% (95%Confidence interval [CI]: 67%-93%) and 47% (95%CI: 33%-60%) in the letermovir and non-letermovir groups, respectively (p < 0.01). Non-relapse mortality rate was equivalent, and the relapse rate was 21% (95%CI: 9.0%-36%) vs. 47% (95%CI: 33%-60%) and significantly lower in the letermovir group (p = 0.015). The cumulative CMV reactivation incidence rates at day 100 were 5.9% (95%CI: 1.0%-17%) and 43% (29%-55%) in the letermovir and non-letermovir groups (p = 0.012). These findings suggest letermovir helped the suppression of CMV reactivation and improved the outcome of allo-SCT with ATG by lowering relapse.

This retrospective study aimed to compare reduced-dose anti-thymocyte globulin (ATG) plus post-transplant cyclophosphamide (PTCy) versus standard ATG for GVHD prophylaxis in haplo-HSCT. A total of 61 patients (median age, 35 years; range, 4-62) who received a myeloablative conditioning regimen between 2019 and 2024 were included. Patients received either reduced-dose ATG with PTCy (n = 30) or standard ATG (n = 31). The primary outcome was chronic GVHD (cGVHD) incidence. With a 38.5-month median follow-up, the 2-year cGVHD rate was significantly lower in the ATG-PTCy group (10.0% vs. 38.7%, p = 0.012). Rates of grade II-IV acute GVHD, engraftment times, infections (CMV/EBV), non-relapse mortality, and relapse were statistically comparable between groups. Consequently, 2-year overall survival (83.3% vs. 77.4%) and disease-free survival (80.0% vs. 71.0%) showed no significant difference. A favorable trend toward less hemorrhagic cystitis was observed with ATG-PTCy. In conclusion, the combination of reduced-dose ATG with PTCy is associated with a significantly reduced risk of chronic GVHD after haplo-HSCT.

State-of-the-art immunosuppressant therapies recommend the use of induction therapy after kidney transplantation. Anti-interleukin-2 receptor antibody (basiliximab) is used for low-risk patients whereas polyclonal anti-lymphocyte sera (ALS) are recommended for medium/high-risk patients. There are two commercially available rabbit-derived ALS, namely anti-thymocyte globulin (RATG; Thymoglobulin®) and anti-lymphocyte globulin (RATLG; Grafalon®). We retrospectively compared the efficacy and safety of RATG or RATLG induction therapy in high-risk kidney transplant recipients with preformed donor specific antibodies (DSAs; n = 124). Forty-seven recipients received 1.25 mg/kg RATG for 2 to 3 days. Seventy-seven recipients were treated with 9 mg/kg RATLG on day 0 followed by 4 mg/kg RATLG for 2 to 3 days (n = 21) or a single dose of 9 mg/kg RATLG on day 0 (n = 56). Overall there were no significant differences observed between patients treated with RATG and RATLG. Similarly, no difference was observed between patients who had been given a single dose of RATLG and multiple doses of RATLG or RATG. At one year, patient and graft survival rates, acute rejection rate and type of rejection, kidney function, infections and malignancies did not differ between groups. Kidney transplant patients with preformed DSA showed similar clinical outcomes when treated with RATG or RATLG induction therapy. Polyclonal antibodies in high immunological risk kidney transplant patients.

To compare the efficacy and safety of the FABT regimen versus the conventional FCA regimen in patients under 40 years old with aplastic anemia (AA) underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This single-center retrospective study included 75 AA patients under 40 years old who underwent haplo-HSCT between January 2021 and January 2025. Patients were categorized into the Fludarabine-ATG-Busulfan-Thiotepa (FABT) group (n = 25) and the Fludarabine-Cyclophosphamide-ATG (FCA) group (n = 50) based on their conditioning regimen. The FABT regimen featured reduced-dose busulfan, fludarabine, cyclophosphamide, thiotepa, and low-dose anti-thymocyte globulin (ATG), followed by post-transplant cyclophosphamide (PTCy), calcineurin inhibitors, and mycophenolate mofetil for Graft-versus-host disease (GVHD) prophylaxis. Primary endpoints were GVHD-free/relapse-free survival (GRFS) and overall survival (OS). Secondary endpoints included engraftment rates, incidence of acute and chronic GVHD, viral reactivation and treatment response. The 3-year GRFS was significantly higher in the FABT group compared to the FCA group (96% vs. 76%, P = 0.032). The 3-year OS was 96% for FABT and 88% for FCA (P = 0.263). The FABT group demonstrated a significantly higher 1-year complete response (CR) rate (96% vs. 78%, P = 0.021) and a lower 3-year CMV reactivation rate (12% vs. 30%, P = 0.019). No significant differences were observed in engraftment rate, EBV reactivation, or cumulative incidence of acute or chronic GVHD between the two groups. The FABT conditioning regimen demonstrates superior outcomes compared to the FCA regimen in young AA patients underwent haplo-HSCT, characterized by significantly improved GRFS and CR rates, and reduced CMV reactivation, without compromising engraftment or increasing GVHD. This regimen represents a promising therapeutic strategy for this patient population.

This study evaluated the efficacy and safety of high-dose romiplostim (ROMI) combined with horse anti-thymocyte globulin (hATG) and cyclosporine A (CyA) as first-line immunosuppressive therapy for aplastic anemia (AA). We retrospectively analyzed eight patients who received hATG + CyA + ROMI at a single institution between October 2023 and January 2025. ROMI was initiated at 10 μg/kg/week and escalated to 20 μg/kg. Hematologic responses were evaluated at weeks 14 and 27. At week 27, the overall response rate was 100% and the complete response rate was 85.7%. Only one episode of grade ≥ 3 anaphylaxis attributed to hATG was observed. High-dose ROMI combined with hATG and CyA demonstrated favorable efficacy and tolerability as a first-line treatment for transfusion-dependent AA. However, larger prospective studies are required to confirm these findings.

For patients with high-risk acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (HCT) remains standard of care. In the setting of an HLA-matched unrelated donor HCT, in vivo T-cell depletion (TCD) for prophylaxis of graft versus host disease (GVHD) relies on anti-thymocyte globulin (ATG) in Europe and alemtuzumab in the UK. In a retrospective study from the EBMT registry, we pair-matched 90 ALL patients aged ≥40 years transplanted in CR1 according to age (median 56 years) and ALL subtype (37.8% Ph-negative B-ALL, 46.7% Ph-positive B-ALL, 15.6% T-ALL). Reduced-intensity conditioning included fludarabine/melphalan (94.4%) in the alemtuzumab and fludarabine/busulfan (36.7%), fludarabine/total body irradiation (21.1%), fludarabine/melphalan (14.4%) and thiotepa/busulfan/fludarabine (13.3%) in the ATG group. Two-year leukemia-free and overall survival were similar between groups (Alemtuzumab: 56.4% vs ATG: 50.7%, HR 0.82, p = 0.34, and 62.7% vs 62.9%, HR 0.91, p = 0.67), as were cumulative incidence of relapse (23.7% vs 23.9%, HR 0.89, p = 0.69) and non-relapse mortality (19.9% vs 25.4%, HR 0.75, p = 0.32), resulting in similar GVHD- and relapse-free survival (GRFS) of 48.9% vs 42.1%, HR 0.8, p = 0.24. With GVHD and infections as main reasons for death in both groups, we conclude that both IS strategies are both safe for RIC HCT of these ALL patients.

Systemic immunosuppression remains essential for preventing allogeneic transplant rejection, but its chronic use causes substantial toxicity. Conceptually, local, site-specific immunomodulation offers a promising alternative, yet comparative mechanistic insight into how immunosuppressants behave when delivered directly to the graft is lacking. Here, we leveraged the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, a subcutaneous, vascularized cell-encapsulation platform, as a spatially defined and reproducible model to study local immunomodulation in allogeneic islet transplantation. We systematically profiled the safety, local and systemic immunomodulatory effects, pharmacokinetics, and longitudinal biodistribution of five clinically relevant agents delivered locally at the graft site: CTLA4-Ig, anti-lymphocyte serum, anti-CD40L, anti-CD2, and anti-IL6. Sustained in situ exposure did not impair islet viability or function, and immunosuppressants were confined within the graft, with up to 100-fold lower systemic concentrations. Individual agents produced distinct immune signatures, spanning lymphocyte depletion and shifts in T-cell activation that can guide rational, mechanism-informed combinations for allogeneic cell transplantation. These findings provide a comparative framework for evaluating localized immunosuppression with the potential to transform immunoprotection in cell therapy.