Antithymocyte Globulin Administration Research Articles

Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection.

Anti-thymocyte globulin (ATG) is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients. Commercially available as Thymoglobulin (rabbit-derived, Sanofi, United States), ATG-Fresenius S (rabbit-derived), and ATGAM (equine-derived, Pfizer, United States), these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells, imparting immunosuppressive effects. Although the prevailing mechanism predominantly involves T-cell depletion via the com plement-mediated pathway, alternate mechanisms have been elucidated. Optimal dosing and treatment duration of ATG have exhibited variance across ran domised trials and clinical reports, rendering the establishment of standardized guidelines a challenge. The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever, chills, and skin rash in the acute phase to long-term concerns related to immunosuppression, including susceptibility to infections and malignancies. This comprehensive review aims to provide a thorough exploration of the current understanding of ATG, encom passing its mechanism of action, clinical utility in the treatment of acute renal graft rejections, specifically steroid-resistant cases, efficacy in rejection episode reversal, and a synthesis of findings from different eras of maintenance immunosuppression. Additionally, it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function. Furthermore, the review underscores the existing gaps in evidence, particularly in the context of the Banff classification of rejections, and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.

Impact of Anti-Thymocyte Globulin on Procalcitonin Levels Comparison during Fever in Allogeneic Stem Cell Transplantation Conditioning

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a complex medical procedure that offers hope for patients with various hematological disorders. However, one of the significant challenges associated with allo-HSCT is the risk of infection, which remains a major contributor to non-relapse mortality. Detecting and managing infectious diseases in febrile patients during the pre-transplant conditioning phase is of utmost importance to ensure successful transplantation outcomes. In this context, procalcitonin (PCT) has emerged as a valuable diagnostic tool, serving as an auxiliary marker for severe infections. Additionally, PCT has shown promise as a predictor of infections in patients undergoing allo-HSCT. Its ability to aid in early detection and subsequent intervention has made it an attractive biomarker for clinicians. However, the interpretation of PCT levels in patients receiving anti-thymocyte globulin (ATG) as part of their pre-transplant conditioning has posed specific challenges. ATG, a commonly used immunosuppressive agent in allo-HSCT, plays a vital role in reducing the risk of graft rejection and graft-versus-host disease. However, ATG administration is not without its drawbacks, as it can lead to various side effects such as fever and hypotension. These ATG-induced symptoms must be carefully distinguished from infectious diseases to ensure appropriate treatment decisions. One particular concern in this regard is the potential impact of ATG administration on PCT levels. Unfortunately, there is a paucity of data on PCT levels in febrile patients who have received ATG, making it difficult for clinicians to interpret the results accurately. Furthermore, a comprehensive analysis comparing the increase in PCT levels during the conditioning phase for allo-HSCT and its associated risk factors in ATG and non-ATG regimens is lacking. Understanding how ATG affects PCT levels during febrile episodes and whether PCT can effectively discriminate between infections and ATG-related symptoms is crucial for optimizing patient care. To address these gaps in knowledge, we conducted a retrospective analysis involving 76 patients who developed febrile episodes during the pre-transplant conditioning phase, and their PCT levels were measured and compared in our institution. Our study aimed to elucidate whether ATG administration could lead to increased PCT levels during febrile episodes in the context of pre-transplant conditioning and whether PCT could serve as a reliable marker for distinguishing infections during this critical period. The findings of our analysis shed light on the complex relationship between ATG administration, PCT levels, and infectious diseases. Notably, ATG administration was identified as the sole significant factor contributing to increased PCT positivity during fever (p = 0.01). In contrast, the presence of infectious diseases did not significantly impact PCT positivity in the ATG group (p = 0.24). Intriguingly, bloodstream infection emerged as a significant risk factor for PCT positivity in patients who received non-ATG regimens (p < 0.01). These results underscore the importance of considering ATG administration when interpreting PCT levels in febrile patients undergoing pre-transplant conditioning for allo-HSCT. The administration of ATG can confound the interpretation of PCT levels during febrile episodes, potentially leading to inaccurate diagnoses of infectious diseases. Clinicians must exercise caution and be aware of this confounding factor when incorporating PCT values into the diagnostic workup, particularly in patients receiving ATG regimens. In conclusion, our study highlights the complexity of using PCT as a diagnostic marker in febrile patients undergoing pre-transplant conditioning for allo-HSCT. While PCT shows promise as a valuable tool for predicting and detecting infections, its interpretation must be approached with caution in patients receiving ATG regimens. Future research is warranted to further elucidate the intricacies of PCT dynamics in the context of allo-HSCT, enabling clinicians to optimize its use and improve patient outcomes in this challenging and high-stakes medical procedure.

Peripheral Blood Grafts Vs Bone Marrow Grafts in Young Acute Myeloid Leukemia Patients with HLA-Matched Sibling Donors Undergoing Myeloablative Conditioning

In allogeneic hematopoietic cell transplantation (allo-HSCT), graft source has been changed from bone marrow grafts (Bone marrow stem cell, BMSC) to peripheral blood grafts (Peripheral blood stem cell, PBSC) mobilized by granulocyte colony-stimulating factor. PBSC transplantation is known to have numerous advantages over BMSC, including faster engraftment, improved survival outcomes, and for the donor, the elimination of invasive marrow harvesting procedure under general anesthesia. However, previous studies regarding graft source included various hematologic malignancies and lacked consistency in conditioning intensity and disease status at allo-HSCT. Still, there are limited data on the comparison of graft sources specifically in patients with acute myeloid leukemia (AML) undergoing myeloablative conditioning. In this background, we conducted an analysis to investigate the impact of graft source on transplant outcomes in AML patients who underwent HLA A, B, C, DR-matched sibling donor (MSD) HSCT with myeloablative conditioning. This study was a retrospective, single-center study for patients with AML who received first allo-HSCT from 2002 to 2022. We included the patients aged < 60 at the time of allo-HSCT, in a state of complete remission (CR) or CR with incomplete hematologic recovery, from a MSD, and underwent myeloablative conditioning. We classified the patients into three groups: the BMSC graft group (BMSC group), the PBSC graft group without antithymocyte globulin (ATG) (PBSC/ATG- group), and the PBSC graft group with ATG (PBSC/ATG+ group). Patients who received both PBSC and BMSC grafts were excluded from the analysis. We examined the differences in overall survival (OS), relapse-free survival (RFS) among these three groups. A total of 480 patients were included in this analysis, with 234 patients in the BMSC group, 66 patients in the PBSC/ATG+ group, and 180 patients in the PBSC/ATG- group. BMSC transplantation was mostly performed before 2010, whereas PBSC transplantation started in 2007, and allo-HSCT with ATG administration were conducted after 2014. In the PBSC/ATG+ group, the median ATG dose was 2.5 mg/kg (Interquartile range, IQR: 1.6-2.5). The BMSC group tended to be younger at the time of HSCT (median 38 years [31-46]) compared to the other groups (median age of PBSC/ATG+ group: 44 years [37-51], PBSC/ATG- group: 46 years [39-51], p<0.01). Of total patients in the three groups, there was only 1 case of neutrophil engraftment failure (in the PBSC/ATG- group) and 5 cases of platelet engraftment failure (3 in the BMSC group and the other 2 in the PBSC/ATG- group). BMSC patients demonstrated superior OS compared to PBSC patients, with the most pronounced difference was observed over PBSC/ATG- group (Figure A). Similar trends were presented in relapse-free survival (RFS) as well. After adjusting for other covariates through multivariate Cox modeling, the difference caused by the graft source remained significant, particularly in terms of RFS (Figure B). The hazard ratios for RFS of PBSC comparing to BMSC were as follows; PBSC/ATG+: 1.64 [1.04-2.58], PBSC/ATG-: 1.95 [1.45-2.63]. In conclusion, Despite the clear differences in allo-HSCT era between groups, even BMSC patients underwent allo-HSCT at an earlier time, patients receiving BMSC grafts showed superior survival compared to those receiving PBSC grafts in young AML patients undergoing MSD myeloablative allo-HSCT. Parallel evaluation of the transplant outcomes between BMSC and PBSC would be crucial for assessing the advantages and disadvantages of PBSC and BMSC grafts in this setting.

Letermovir Improves the Outcome of Allogenic Stem Cell Transplantation with Anti-Thymocyte Globulin By Reducing Relapse

Background: After an allogenic stem cell transplantation (allo-SCT), patients face the risk of infection, and cytomegalovirus (CMV) is a common pathogen. Severe CMV infections can be fatal, so prophylaxis or early treatment is critical. To manage CMV infections precisely, letermovir is administered for prevention of CMV reactivation. Letermovir also improved patients' overall survival (OS) after allo-SCT in several studies.However, some studies have found that letermovir did not affect OS, and it is still unknown whether letermovir can improve allo-SCT outcome. We investigated whether letermovir had an impact on allo-SCT outcomes. Methods: We retrospectively studied 443 patients over the age of 18 who received allo-SCT for hematological malignancies from 2004 to 2020 in Anjo Kosei Hospital. The patients were divided into letermovir (n = 56) and non-letermovir (n = 387) groups. Letermovir was administered from day 5 after allo-SCT to day 100 unless severe adverse events were observed. We conducted pp65 antigenemia tests for monitoring CMV reactivation. Results: For patients' characteristics, the median age was 49 (range: 18-71) in the letermovir group and 53 (range: 18-72) in the non-letermovir group (p = 0.12). Acute leukemia was the most common disease in both groups. There was no difference in sex (p = 0.77). As stem cell sources, relative peripheral blood cells (PB), unrelated bone marrow, unrelated PB, and cord blood (CB) were used in both groups. In letermovir group, more patients underwent allo-SCT in recent years (p < 0.001) and received anti-thymocyte globulin (ATG) (p < 0.001). The median duration of letermovir administration was 93 days (range: 14-110). The 3-year OS rates were 66% (95%confidence interval [CI]: 52%-77%) and 44% (95%CI: 38%-49%) in the letermovir and non-letermovir groups, respectively (p < 0.01) (Figure 1). Interestingly, non-relapse mortality (NRM) was equivalent, and the relapse rate was 15% (95%CI: 6.7%-25%) vs. 31% (95%CI: 27%-36%) and significantly lower in the letermovir group (p < 0.01) (Figure 1). The cumulative CMV reactivation incidence rates at day 100 were 7.0% (95%CI: 1.1%-26%) and 45% (95%CI: 34%-59%) in the letermovir and non-letermovir groups, respectively (p = 0.037). The GVHD incidence rate in both groups was comparable. Since we observed the difference in the number of ATG administration between the two groups, we conducted the stratification analysis in patients who experienced ATG administration (n = 85). In letermovir (n = 25) and non-letermovir (n = 60) groups, 3-year OS was 84% (95%CI: 63%-94%) and 44% (95%CI: 31%-56%). NRM was equivalent, and the relapse rate was 12% (95%CI: 2.9%-28%) vs. 44% (95%CI: 31%-56%) and significantly lower in the letermovir group (p < 0.01). The cumulative CMV reactivation incidence rates at day 100 were 8.0% (95%CI: 1.3%-23%) and 43% (95%CI: 31%-56%) in the letermovir and non-letermovir groups, respectively (p = 0.077). The incidence rate of GVHD was equivalent between the two groups. In multivariate analysis, letermovir was recognized as a significant factor for OS (hazard ratio [HR]: 0.30, 95%CI: 0.089-0.99, p < 0.05) and relapse rate (HR: 0.27, 95%CI: 0.092-0.80, p < 0.05). In patients who have not received ATG, 3-year OS (48% (95%CI: 30%-64%) vs. 43% (95%CI: 37%-48%), p = 0.86) and relapse rate (19% (95%CI: 7.3%-34%) vs. 30% (95%CI: 25%-35%), p = 0.17) were comparable between letermovir and non-letermovir groups. NRM was also equivalent. Conclusion: Letermovir administration suppressed the reactivation rate of CMV and improved the outcome of allo-SCT. Interestingly, the letermovir group showed lower relapse rate and this effect was mainly observed in allo-SCT with ATG. Letermovir can possess the positive effect for outcome of the allo-SCT with ATG.

Integration of Daily Patient-Reported Outcome Measures in Pediatric Stem Cell Transplantation

Patients' reports of their health status are increasingly used in hematopoietic stem cell transplantation (SCT) to better understand the negative impact on symptom burden and quality of life. Little is known regarding the implementation in routine clinical care, particularly how it can be used to improve supportive care. We sought to the evaluate feasibility of capturing daily patient-reported outcomes (PROs) in the acute phase of SCT to measure physical and psychosocial symptom burden. In this single-center prospective observational study, we assessed daily PRO from conditioning to neutrophil engraftment in children (age 1 to 18 year) who underwent allogeneic or autologous SCT for malignant and nonmalignant disease. The most common acute adverse effects of chemotherapy (pain, nausea, loss of appetite, sleep disturbance, and physical performance impairment) were reported daily via ePROtect, a web-based program designed to integrate health responses. From February 2021 to March 2023, 20 children undergoing allogeneic (allo-) SCT (n=11) or autologous (auto-) SCT (n=9) and their proxies consented to participation, all of whom were included in this analysis. A total of 359 PRO questionnaires were completed, corresponding to a median daily completion rate of 72.7% (interquartile range, 60.4% to 83.6%). After conditioning, pain perception anticipated the rise of infectious parameters and the development of mucositis, thus initiating supportive treatment. Patients reported the strongest symptom burden at a median of 8.5 days post-transplantation. At 4 weeks post-transplantation, baseline values were restored for all symptoms. There were no significant differences between auto-SCT and allo-SCT, except for nausea and loss of appetite after administration of antithymocyte globulin in allo-SCT. This study empirically documents the daily health status of children undergoing SCT and proposes an attractive modus operandi on how continuous feedback on health-related symptoms can be integrated into daily clinical practice.

Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes.

BACKGROUNDLow-dose anti-thymocyte globulin (ATG) transiently preserves C-peptide and lowers HbA1c in individuals with recent-onset type 1 diabetes (T1D); however, the mechanisms of action and features of the response remain unclear. Here, we characterized the post hoc immunological outcomes of ATG administration and their potential use as biomarkers of metabolic response to therapy (i.e., improved preservation of endogenous insulin production).METHODSWe assessed gene and protein expression, targeted gene methylation, and cytokine concentrations in peripheral blood following treatment with ATG (n = 29), ATG plus granulocyte colony-stimulating factor (ATG/G-CSF, n = 28), or placebo (n = 31).RESULTSTreatment with low-dose ATG preserved regulatory T cells (Tregs), as measured by stable methylation of FOXP3 Treg-specific demethylation region (TSDR) and increased proportions of CD4+FOXP3+ Tregs (P < 0.001) identified by flow cytometry. While treatment effects were consistent across participants, not all maintained C-peptide. Responders exhibited a transient rise in IL-6, IP-10, and TNF-α (P < 0.05 for all) 2 weeks after treatment and a durable CD4+ exhaustion phenotype (increased PD-1+KLRG1+CD57- on CD4+ T cells [P = 0.011] and PD1+CD4+ Temra MFI [P < 0.001] at 12 weeks, following ATG and ATG/G-CSF, respectively). ATG nonresponders displayed higher proportions of senescent T cells (at baseline and after treatment) and increased methylation of EOMES (i.e., less expression of this exhaustion marker).CONCLUSIONAltogether in these exploratory analyses, Th1 inflammation-associated serum and CD4+ exhaustion transcript and cellular phenotyping profiles may be useful for identifying signatures of clinical response to ATG in T1D.TRIAL REGISTRATIONClinicalTrials.gov NCT02215200.FUNDINGThe Leona M. and Harry B. Helmsley Charitable Trust (2019PG-T1D011), the NIH (R01 DK106191 Supplement, K08 DK128628), NIH TrialNet (U01 DK085461), and the NIH NIAID (P01 AI042288).

On Behalf of the SFGM-TC: Prophylactic Donor Lymphocyte Infusion in Patients Treated with Allogeneic Stem-Cell Transplantation for High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusion (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated. Methods: We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity. Results: In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99–79.23]) in the proDLI group versus the control group (29.31% [20.28–38.34], p = 0.067). However, 3-year overall survival (p = 0.892), progression-free survival (p = 0.239), and nonrelapse mortality (p = 0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen. Conclusion: The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy.

Reference guide for the treatment of aplastic anemia: key points of the 2022 revision

The "Reference Guide for the Treatment of Aplastic Anemia" has been revised for the first time in 3 years, and clinical questions have been formulated for the first time. As research demonstrated a benefit to combining antithymocyte globulin (ATG) and cyclosporine with eltrombopag (EPAG), the revised guide recommends that EPAG be started as soon as possible after ATG administration. In addition, it states that starting with immunosuppressive therapy and performing allogeneic bone marrow transplantation in the event of inadequate response or relapse is an option even for young adult patients with severe aplastic anemia who have HLA-matched allogeneic bone marrow donor candidates. The guide also discusses aggressive treatment of non-severe cases, ATG dosage and the maximum age for ATG administration, infection prevention, and G-CSF administration. It is necessary to continue collecting evidence and promoting clinical trials to build evidence in Japan.

Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy

Reducing the recipient’s T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.

Addition of ATG to Clofarabine-Based Reduced Intensity Conditioning Regimen with PBSC and Ptcy in Adults with Myeloid Malignancies

INTRODUCTION In allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the Clo-Baltimore (CloB) regimen is a variant of the Baltimore reduced-intensity conditioning (RIC) regimen that uses clofarabine in replacement of fludarabine and high-dose post-transplant cyclophosphamide (PTCY). This regimen provides good survivals for patients (pts) with myeloid malignancies (Chevallier et al., Oncotarget 2018). Yet, graft-versus host disease (GVHD) remains a major cause of morbidity and mortality in Allo-HSCT recipients. The administration of anti-thymocyte globulin (ATG) is a standard method to prevent GVHD in matched Allo-HSCT. Here, we retrospectively investigated whether the addition of ATG to CloB conditioning with PTCY was beneficial in terms of GVHD rates. METHODS This retrospective study included all consecutive Allo-HSCT adult recipients with myeloid malignancies transplanted between March 2014 and February 2022 in our hospital after CloB+/-ATG conditioning regimen. CloB consisted in clofarabine 30 mg/m²/day (d) from d-6 to d-2, cyclophosphamide 14.5 mg/kg/d on d-6 and d-5, and cyclophosphamide 50mg/kg/d on d+4 and d+5 after Allo-HSCT. In CloB+ATG, pts additionally received ATG 2.5mg/kg/d on d-2. GVHD prophylaxis consisted in the administration of cyclosporine A and mycophenolate mofetil to all patients. Graft source was exclusively peripheral blood stem cells. We determined overall (OS), disease-free (DFS) and GVHD relapse-free (GRFS) survivals, as well as non-relapse mortality (NRM) and relapse incidences. RESULTS Sixty-six pts (median age 61 years old, range 32-74) were included, with 36 pts treated with CloB conditioning between 2014 and 2017, and 30 with CloB+ATG between 2019 and 2022. Between the two periods other conditioning regimens were used in our Department. Diagnoses comprised acute myeloblastic leukemia (AML, n=32), myelodysplastic syndromes (MDS, n=18), myeloproliferative neoplasms (MPN, n=5), or MDS/MPN (n=10). The disease risk index (DRI) was low in 7 (11%) pts, intermediate in 43 (66%), and high in 15 (23%). The median HSCT-specific comorbidity index was 3 (range 0-7). Donors were haploidentical in 54 (82%) cases, and matched in 12. In the whole cohort, 18-months(m) OS, DFS and GRFS were 71±6%, 65±6%, and 55±6%, and 18-m NRM and relapse incidences were 14±4% and 21±5% respectively. A higher proportion of high DRI was observed in the CloB group (36 vs 10%, p=0.03). The median follow-up was 68 months (m) in the CloB cohort and 19.5 m in the CloB+ATG cohort. These two groups were otherwise comparable (Table 1). A lower proportion of acute GVHD was observed in the CloB+ATG group (23.3 vs 50%, p=0.05), with no statistical differences in terms of chronic GVHD (p=0.49). Of note, no extensive chronic GVHD was observed in the CloB+ATG group (vs 11% in CloB patients, p=0.17) In multivariate analysis, the addition of ATG to CloB conditioning was associated with a significant increase in 18-m GRFS (70±8% vs 43±8%, HR 0.38 [95%CI 0.17-0.85], p=0.02; Figure1). No differences were observed in terms of OS (HR 0.74, p=0.51), DFS (HR 0.58 p=0.22), NRM (HR 0.84, p=0.79), relapse rate (HR 0.51, p=0.25), median time of neutrophil (>1 109/L) and platelet (> 50 109/L) recovery (respectively 19d [range 12-27] vs 18d [8-32], p=0.69, and 36d [22-471] vs 31d [12-134], p=0.09). The results were similar when considering only patients with a haploidentical donor (n=54), with a benefit in terms of GRFS in the ATG group in multivariate analysis: HR 0.30 (95%CI 0.12-0.73; p=0.008). CONCLUSION Addition of ATG to the Clo-Baltimore RIC regimen with PTCY improved GRFS rates in this cohort without increasing infection-related mortality nor relapse rate in pts with myeloid malignancies and matched or haplo-donors. This strategy should be more widely implemented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia.

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.

Predictors, Risk Factors and Outcomes of Patients with SAA with Anti-HLA Class I Antibodies Treated with Immunosuppressive Therapy

Introduction: Platelet refractoriness, defined as persistently inadequate post-transfusion count increments, can be immune or non-immune. Human leukocyte antigen (HLA) Class I antibodies are the usual immune cause. The presence of HLA platelet antibodies (Abs) in hematologic disease has been associated with poorer clinical outcomes, graft failure in hematopoietic stem cell transplant, increased bleeding, and decreased survival. In immune severe aplastic anemia (SAA), literature addressing prophylactic transfusion of platelets is lacking, but most recommend transfusion with bleeding at a count <10 or <20 K/ µL if febrile or during ATG (anti-thymocyte globulin) administration. Chronic platelet transfusion is a risk for development of HLA Abs; nevertheless, some chronically transfused patients do not become alloimmunized while others do so rapidly, even after a single platelet transfusion. We analyzed our SAA patients to document the rate of HLA alloimmunization and its possible association with disease characteristics and outcomes after immunosuppressive therapy (IST). Methods: Clinical records from 444 SAA patients treated at the NIH Clinical Center from 2000 to 2022 were retrospectively reviewed. Demographics included: age, sex, HLA Class 1 Abs status, platelet refractoriness, peripheral blood counts, PNH clone, treatment and relapse, evolution to myeloid malignancy or chromosome abnormality, and overall survival (OS). Patients were tested for HLA Abs if they met 1 or more of 3 clinical criteria: 1) history of HLA Abs; 2) history of or current platelet transfusion refractoriness; 3) work up for bone marrow transplantation. Clinical refractoriness was defined as lack of platelet increment of >5 K/µL or a corrected count increment (CCI) of >5 K/µL. Patient lacking evidence of refractoriness were presumed anti-HLA negative and not tested, and those that tested negative for HLA Ab were transfused platelets unmatched for any HLA antigens. Logistic regression was used to analyze associations between age, sex, blood counts, PNH clone, and disease severity, and Kaplan Meier curves and Cox proportional hazards model for survival. Data were analyzed using R, and p<0.05 was considered statistically significant. Results: Demographic data were collected for 444 patients (Table.1). HLA Ab testing was performed in 155 patients while 289 didn't meet criteria for testing. Of 444 patients, 99 (22%) tested positive for HLA Class 1 Abs. Seventy-three of 99 patients responded to HLA matched platelets, whereas, 17 remained refractory and for 9 data were unavailable. Univariate analysis predicted male sex to be protective against HLA Abs formation (OR=0.59,p= 0.02), while more severe disease (VSAA, OR= 2.51, p<0.001) and lower baseline blood counts predicted alloimmunization. Low platelet counts (p<0.001) were most significant followed by absolute reticulocyte (ARC) and absolute neutrophil counts (ANC) with p=0.005. PNH was not associated with refractoriness, although data were incomplete. Only HLA Class 1 Ab status and age, and sex were strong predictors of survival in both univariate and multivariate analysis. ANC, ARC, and disease severity were significant predictors of survival in the univariate but not multivariate model. Median time to relapse was 2.4 years with a relapse rate of 36% at median follow-up. Rate of relapse was 46% in alloimmunized patients vs.34% in the Ab negative group, but this difference was not statistically significant (p=0.2). OS for the entire cohort was 84% at median follow up 4 years; HLA Ab-negative patients had a significantly higher OS compared with positive (86% and 75% respectively; p = 0.02). Rates of clonal evolution were also higher in the HLA Ab positive group but not statistically significant (25% vs. 13%, p=0.08). Conclusions: We report a large cohort of IST-treated SAA patients, comparing outcomes with and without HLA alloimmunization. Although SAA patients are usually heavily transfused platelets, we observed a rate of HLA alloimmunization of 22%. OS was decreased in HLA alloimmunized patients. Presence of HLA ab and age were strong predictors of survival. ANC, ARC and disease severity were predictors of survival only in the univariate model. Relapse and clonal evolution may be increased when HLA Abs are present. Overall, the presence of HLA Abs is associated with poorer outcomes in SAA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

348.5: Life Threatening, Cytokine Release Storm (CRS) With Antithymocyte Globulin (ATG) And Its Management

Introduction: Cytokine Release Storm (CRS) leading to fatal or near fatal hypotension has been reported in association with anti thymocyte globulin (ATG) administration. This is a very rare and unusual manifestation of ATG and early recognition and management of this unexpected manifestation will help save lives. We report a near fatal case of CRS, during renal transplantation, associated with ATG administration, its diagnosis and management. Materials and Methods: A 27-year-old, otherwise healthy male with Alport’s syndrome was undergoing live related preemptive renal transplant. Patient received morning dose of Solu-Medrol and CellCept and was getting Anti Thymocyte Globulin (ATG) slowly after the test does, as the recipient vascular bed was being prepared. Patient started to become hypotensive which was treated with IV fluids and pressors including norepinephrine, epinephrine and dopamine.There was no bleeding from recipient vascular bed.A stat chest x-ray, EKG and echocardiogram on the OR table were normal with good LV function. Despite maximum dose pressor support and IV fluids, the mean blood pressure was around 45 - 50 mm Hg and a systolic blood pressure was around 65-70 mm Hg, leading to severe metabolic acidosis and lactate buildup. The transplant was canceled and the donor was closed unharmed and the patient was moved to ICU, intubated. His response to colloids was slightly better, but transient, so he was transfused 4 units of blood as volume expander that does not leak into 3rd space.This brought his blood pressure to about 90 mm Hg. A presumptive diagnosis of ATG induced CRS was made. His inflammatory markers including IL-6, ferritin, D-dimers and CRP were very high. 400 mg of Tocilizumab (Actemra) an IL-6 inhibitor along with broad-spectrum antibiotics were given. Patient also started to developed disseminated intravascular coagulation (DIC) with deranged coagulation screen and some oozing from the wound which was treated with FFPs. In next 12 hours, the patient started to stabilize and in next 48 hours he was extubated. Discussion: Cytokine Release Storm (CRS) is a potentially fatal condition unless recognized and treated early and aggressively. In COVID pandemic, much better understanding of CRS along with its symptomatology, easy availability of its lab tests and IL- 6 inhibitors became possible. High index of suspicion is extremely important in making an early diagnosis and for early treatment. In transplant patients, use of ATG is now standard of care and very few cases of ATG induced CRS are reported. In our case, early diagnosis of CRS from ATG, use of blood as volume expander, early administration of IL-6 inhibitor and aggressive management of DIC turned out to be the life Saver. Conclusion: In patients receiving ATG, with unexplained hypotension, nonresponsive to IV fluids and pressors, high index of suspicion of ATG induced CRS with early diagnosis and aggressive management can save lives.

Epstein-Barr Virus Reactivation After Paediatric Haematopoietic Stem Cell Transplantation: Risk Factors and Sensitivity Analysis of Mathematical Model.

Epstein-Barr virus (EBV) establishes a lifelong latent infection in healthy humans, kept under immune control by cytotoxic T cells (CTLs). Following paediatric haematopoetic stem cell transplantation (HSCT), a loss of immune surveillance leads to opportunistic outgrowth of EBV-infected cells, resulting in EBV reactivation, which can ultimately progress to post-transplant lymphoproliferative disorder (PTLD). The aims of this study were to identify risk factors for EBV reactivation in children in the first 100 days post-HSCT and to assess the suitability of a previously reported mathematical model to mechanistically model EBV reactivation kinetics in this cohort. Retrospective electronic data were collected from 56 children who underwent HSCT at Great Ormond Street Hospital (GOSH) between 2005 and 2016. Using EBV viral load (VL) measurements from weekly quantitative PCR (qPCR) monitoring post-HSCT, a multivariable Cox proportional hazards (Cox-PH) model was developed to assess time to first EBV reactivation event in the first 100 days post-HSCT. Sensitivity analysis of a previously reported mathematical model was performed to identify key parameters affecting EBV VL. Cox-PH modelling revealed EBV seropositivity of the HSCT recipient and administration of anti-thymocyte globulin (ATG) pre-HSCT to be significantly associated with an increased risk of EBV reactivation in the first 100 days post-HSCT (adjusted hazard ratio (AHR) = 2.32, P = 0.02; AHR = 2.55, P = 0.04). Five parameters were found to affect EBV VL in sensitivity analysis of the previously reported mathematical model. In conclusion, we have assessed the effect of multiple covariates on EBV reactivation in the first 100 days post-HSCT in children and have identified key parameters in a previously reported mechanistic mathematical model that affect EBV VL. Future work will aim to fit this model to patient EBV VLs, develop the model to account for interindividual variability and model the effect of clinically relevant covariates such as rituximab therapy and ATG on EBV VL.

Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation.

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection.

BackgroundLate antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR.MethodsStudy subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15–75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m2 at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy.ResultsA total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m2 per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01–1.3), p = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1–1.4), p = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation.ConclusionOur study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation–likely representing a confounder in pre-sensitized recipients–were strongly associated with worse transplant outcomes.

Pulmonary Alveolar Proteinosis After Lung Transplantation

<h3>Introduction</h3> Secondary pulmonary alveolar proteinosis (PAP) is a minor subtype of the disease entity with poorer prognosis than common autoimmune PAP. It has been reported to complicate hematologic disorders, immunodeficiency, and infections. However, PAP associated with lung transplantation is not well recognized. Here, we report two cases of PAP after lung transplantation. <h3>Case Report</h3> Case 1: A four-year-old boy underwent a double-lung transplantation. He was maintained standard immunosuppressive regimen. The immediate post-operative course was uneventful. On post-operative day (POD) 23, chest computer tomography (CT) scan showed ground-glass opacities (GGOs) with interlobular septal thickening, along with worsening oxygenation. An acute rejection was clinically suspected, and the patient underwent steroid pulse therapy. It improved temporarily, but worsened again within a week. Despite the repeated steroid pulse, administration of anti-thymocyte globulin and inhibitors of the mammalian target of rapamycin, the situation gradually deteriorated and eventually complicated by infectious diseases. The patient died from respiratory failure on POD 248. At autopsy, diffuse intra-alveolar eosinophilic materials stained by surfactant apoprotein A immunohistochemistry were found and led to a diagnosis of PAP. Case 2: A 52-year-old man underwent double-lung transplantation. He was maintained standard immunosuppressive regimen. The post-operative course was uneventful. On POD 99, routine chest CT scan showed bilateral centrilobular ground-glass opacities mimicking rejection. A diagnostic trial of steroid increase was ineffective. Bronchoalveolar lavage fluid analysis and transbronchial biopsy demonstrated intra-alveolar eosinophilic materials which stained by periodic acid-Schiff. He was diagnosed with PAP and followed up with tapering immunosuppression in the standard manner, resulting in a clinical and radiological improvement. <h3>Summary</h3> PAP is a rare cause of graft dysfunction after lung transplantation. In case 1, the patient was misdiagnosed as acute rejection, and immunosuppression was intensified, which led to fatal consequences. PAP after lung transplantation is potentially a transient or slowly progressive pathology as seen in case 2. Transplant physicians should be aware of this rare complication.

Efficacy of anti-thymocyte globulin for platelet transfusion refractoriness in serious aplastic anemia patients

Platelet transfusion refractoriness (PTR) is a life threatening, intractable clinical issue suffered by some serious aplastic anemia (SAA) patients. Unlike immune thrombocytopenia, effective treatments for PTR remain largely unknown. In our clinical work, we noted that PTR in some SAA patients could be rapidly relieved with the application of anti-thymocyte globulin (ATG), therefore, we retrospectively analyzed its management and outcomes for PTR in SAA patients. A cohort including 29 SAA with PTR patients who received ATG administration was enrolled in this study. All patients suffered from PTR before ATG administration. Among the 29 PTR patients treated with ATG, 21 (72.4.0 %) patients had response, importantly, 13 (44.8 %) patients had an immediately response following the first dose of ATG administration. Bleeding events of grade 3 or above occurred in 23 patients (79.3 %). With the recovery of effective platelet transfusion, the bleeding events in responders could be quickly relieved. The non-responders suffered from aggravated bleeding, including intracranial bleeding in two non-responders, which appeared on eighth and 29th days after ATG administration. Our study indicated that ATG was an effective and safe intervention in the management of PTR in SAA patients.

Antithymocyte globulin for graft-versus-host disease prophylaxis, past, present and future

Antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis has been demonstrated for chronic GVHD inhibition by a series of randomized control trials. The optimal dose of ATG remained unestablished; however, the recommended dose of ATG by the European Group for Blood and Marrow Transplantation has recently decreased. While a lower ATG dose has been used in Japan, ATG usage is recommended in peripheral blood stem cell transplantation or human leukocyte antigens (HLA) 1-locus mismatched bone marrow transplantation with myeloablative conditioning from the nation-wide retrospective studies showing that ATG inhibited chronic GVHD and improved GVHD-free, relapse-free survival. The association of absolute lymphocyte counts (ALC) before ATG administration with transplant outcomes has been reported, which suggests a possible strategy to individualize the ATG dose according to ALC before ATG. Recent studies compared the transplant outcomes using ATG and post-transplant cyclophosphamide, which has rapidly spread in haploidentical transplantation; however, further studies are needed to establish those positioning in HLA-matched/mismatched transplantation.

Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation

Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n=1218; PBSCT without ATG [PBSCT-ATG(-)], n=2288; PBSCT with ATG [PBSCT-ATG(+)], n=93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P=.005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P=.011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.