Antithymocyte Globulin Therapy Research Articles

Anti-Thymocyte Globulin as a Therapy for Chronic Lung Allograft Dysfunction: A Single-Center Experience.

Anti-thymocyte globulin (ATG) is a polyclonal antibody formulation which has been used as a second-line therapy for chronic lung allograft dysfunction (CLAD).Limited data exist evaluating its efficacy; however, several single-center retrospective studies have variably demonstrated either improvement or stabilization of spirometry parameters after administration of ATG.ATG has been in use at UT Southwestern for treatment of CLAD since at least 2010; here, we seek to evaluate the effectiveness of this intervention at our center. METHODS: A retrospective chart review was conducted of a total of 136 patients who underwent lung transplantation at UT Southwestern Medical Center between 2010 and 2022. Of these, 72 patients had received ATG specifically for treatment of CLAD, and the remaining 64 had never received ATG. Two separate analyses were performed: in the first, among those who received ATG for CLAD, spirometry data from the 6 months preceding and following ATG administration were reviewed and rates of change in FEV1 were calculated for each time period. Descriptive statistics were performed to summarize the baseline clinical characteristics and outcomes after ATG, with patients classified as having either a full response (positive rate of change in FEV1) or partial response (>20% attenuation in rate of FEV1 decline) to ATG. In the second analysis, survival was described among those who received ATG for CLAD and comparison was provided between propensity-score matched cohorts from the ATG and non-ATG groups. Of the 63 patients who received ATG for treatment of CLAD (and had adequate spirometry measurements available to trend FEV1), 49 (77.8%) had at least a partial response to therapy; 8 (12.7%) experienced an overall improvement in FEV1. Response to ATG was found to be associated with a more rapid rate of pre-ATG decline in FEV1; no other baseline parameters were found to be predictive of a response to ATG. Median post-CLAD graft survival was 31.7 months among those who received ATG, and only baseline absolute neutrophil count was found to be associated with worse post-CLAD graft survival among this group. Anti-thymocyte globulin therapy, when given for CLAD, was associated with at least a modest attenuation in rate of FEV1 decline in most patients but only rarely preceded an absolute improvement in FEV1. Further study is warranted to better define the role for ATG in treatment of CLAD, a challenging disease state with limited therapeutics available.

Fulminant myocarditis caused by influenza B virus in a male child: a case report and literature review

BackgroundInfluenza B virus induced myocarditis is a rare complication with potentially wide variations in severity and clinical presentation, and the pathogenesis is unclear.Case presentationWe describe a rare case of a 7-year-old boy who developed fulminant myocarditis (FM) due to influenza B virus infection. Treatment measures included mechanical ventilation, vasoactive agents, Extracorporeal membrane oxygenation (ECMO), Continuous Renal Replacement Therapy (CRRT), anti-inflammatory, antiviral, anti-infection, and enteral nutrition support. After 10 days of treatment, the patient succumbed to multiorgan failure.ConclusionsAfter a systematic review of the literature, we found that this disease predominantly affects females, with pediatric cases exceedingly rare. Fulminant myocarditis (FM) progresses rapidly, poses significant treatment challenges sporadic, and carries a poor prognosis. Interestingly, literature reports suggest that anti-thymocyte globulin therapy may have a positive impact in treating FM, potentially offering new insights into its pathogenesis and clinical management.

A comparative analysis of kidney allograft outcomes in steroid use versus steroid discontinuation after basiliximab and ATG induction: AUNOS database study.

The relative safety and efficacy of early steroid withdrawal in kidney transplant patients after basiliximab compared to anti-thymocyte globulin (ATG) induction therapy is unknown. We aimed to compare kidney allograft outcomes in steroid use versus steroid discontinuation after basiliximab and ATG induction from the United Network for Organ Sharing (UNOS) database. We conducted a retrospective cohort analysis of the UNOS database and included first kidney transplant recipients who received ATG or basiliximab induction therapy. We compared graft and patient outcomes in those who received steroid maintenance and those who were discharged off steroids. Of 106,061 patients, 25,344 (86.7%) received basiliximab induction and were maintained on steroids (B-Sm), and 3,880 (13.3%) were on a steroid-free regimen (B-Sf). Graft failure rate was significantly higher in the B-Sf compared to B-Sm at 1-year (4.1 vs. 1.8%, p<0.001), 3-year (6.0 vs. 4.3%, p<0.001) and 5-year follow-up (7.7 vs. 6.4%, p=0.0004). The mortality rate was significantly higher in B-Sf at 1-year (3.3 vs. 2.4%, p=0.0005), 3-year (7.6 vs. 5.5%, p<0.001) and 5-year follow-up (11.5 vs. 8.8%, p<0.001) when compared to the B-Sm. 76,837 recipients received ATG induction therapy, 51,745 (72.4%) were on steroid maintenance therapy (A-Sm) and 25,092 (32.6%) were on a steroid-free regimen (A-Sf). The graft failure rate was significantly higher in A-Sf compared to A-Sm at 1-year follow-up (2.6 vs. 2.3%, p=0.0006), however, there was no difference at 3-year (5.0 vs. 5.0%, p=0.53) or 5-year follow-up (7.2 vs. 8.1%, p=0.17). There was no difference in mortality rates between A-Sf vs. A-Sm at 1 year (2.5 vs. 2.4%, p=0.98) and at 3 years (5.5 vs. 5.4%, p=0.45), respectively. Patients who were maintained on steroids after basiliximab induction had better 5-year allograft survival and patient survival compared to those who were not maintained on steroids. However, steroid maintenance conferred no additional benefit after ATG induction and was associated with higher mortality.

Efficacy and safety of single-dose anti-thymocyte globulin versus basiliximab induction therapy in pediatric kidney transplant recipients: A retrospective comparative cohort study.

This study aimed to compare the efficacy and safety of basiliximab (BAS) versus a single dose of anti-thymocyte globulin (r-ATG) induction therapy in pediatric kidney transplant recipients (KTRs). This single-center retrospective comparative cohort study included all pediatric KTRs from May 2013 to April 2018 and followed up to 12 months. In the first period, all recipients received BAS, while from May 2016, a single 3 mg/kg dose of r-ATG was instituted. Maintenance therapy consisted of a calcineurin inhibitor plus prednisone plus azathioprine or mycophenolate. A total of 227 patients were included (BAS, n = 113; r-ATG, n = 114). The main combination of immunosuppressive drugs was tacrolimus, prednisone, and azathioprine in both groups (87% vs. 88%, p = .718). Patients receiving r-ATG showed superior survival-free of the composite endpoint (acute rejection, graft loss, or death; 76% vs. 61%, p = .003; HR 2.08, 1.29-3.34, p = .003) and lower incidence of biopsy-proven acute rejection (10% vs. 21%, p = .015). There was no difference in the overall incidence of CMV infection (33% vs. 37%, p = .457), PTLD (1% vs. 3%, p = .309), 30-day hospital readmissions (24% vs. 23%, p = .847), and kidney function at 12 months (86 ± 29 vs. 84 ± 30 mL/min/1.73m2, p = .614). These data suggest that induction therapy with a single 3 mg/kg dose of r-ATG is associated with higher efficacy for preventing acute rejection and similar safety profile compared to BAS.

Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

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.

Outcomes of Antithymocyte Globulin and Cyclosporine for Severe Aplastic Anemia

Background: Aplastic anemia (AA) is mediated by T cell destruction of hematopoietic stem and progenitor cells causing pancytopenia and bone marrow hypoplasia. The current standard of care for severe aplastic anemia (SAA) is hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine (CsA) with or without eltrombopag (Epag), a thrombopoietin receptor agonist. HSCT is preferred for SAA in young adults as a curative option, but only a small proportion of patients have histocompatible siblings and mortality increases with age. The IST plus CsA combination with or without Epag has led to survival rates comparable with those observed with HSCT recipients. However, complete hematologic remission is rare with IST and there is a considerable risk of clonal complications, including PNH evolution and progression to MDS. The aim of this study was to evaluate outcomes of ATG plus CsA therapy in a large cohort of SAA patients. Methods: We retrospectively analyzed medical records of 156 patients with SAA, aged ≥2 years treated with ATG plus CsA with or without Epag at our institution between July 2000 and January 2023. Hematologic responses were evaluated at 3-, 6- and 12-months post therapy initiation. Super response (SR) was defined as hemoglobin ≥12 g/dL, platelet count ≥150x10 9/L and absolute neutrophil count (ANC) ≥1.0x10 9/L; complete response (CR) was defined as hemoglobin ≥10 g/dL, platelet count ≥100x10 9/L and ANC ≥1.0x10 9/L. Partial response (PR) was defined as not meeting the criteria for CR and SAA. Overall response encompassed SR, CR, and PR. Statistical analyses were performed with the use of Chi-squared test and Kaplan Meier method. Results: The median age at diagnosis was 52 (IQR 30-66) years, 47% were male, and 86% were Caucasian. Twenty three percent of the cohort had coexisting paroxysmal nocturnal hemoglobinuria. Most patients were treated with ATG plus CsA (92%), the remaining 8% additionally received Epag. Overall response rates were 70%, 67%, and 77% at 3-, 6- and 12-months post-treatment initiation, respectively. CR was achieved in 10%, 15%, and 18% at 3-, 6- and 12-months, respectively. SR was achieved in 16.3% of patients at 12 months, as shown in Figure 1. Patients who achieved SR were young with median age at diagnosis of 28 years, while those who achieved PR or no response had a median age of 54 and 56 years, respectively. Patients who responded to the ATG + CsA therapy had significantly higher baseline ANC (p=0.04), absolute reticulocyte count (ARC) (p&amp;lt;0.001) and absolute lymphocyte count (ALC) (p&amp;lt;0.001). Pre-treatment median values of ANC, ARC and ALC were higher for patients who achieved SR compared to the rest of responders. With a median follow up time of 4.5 years, the estimated median relapse free survival was 9.2 years (95% CI, 3.2 - not reached [NR]) (Figure 2). Of the entire cohort, 21 (13%) patients progressed to acute myeloid leukemia or myelodysplastic syndrome. At data cut off, a total of 66 patients had died; the estimated median OS was 11.6 years (95% CI, 8.4 - NR). In particular, 30 patients died within the first 12-months, 13 within 3-months of ATG initiation from treatment-related complications, 6 from pneumonia and the rest from unknown causes. Conclusion: The findings of our study demonstrate that ATG plus CsA is an effective and safe treatment option for patients with SAA, especially in the older patient population where HSCT-related toxicities can lead to high mortality. Those with higher baseline ALC, ANC and ARC were more likely to respond to therapy compared to those with lower counts. A small percentage of patients progressed to myeloid neoplasia. Mortality within the first 12-months was high, indicating the need for close monitoring to avoid treatment-related mortality.

Impact of Induction Immunosuppressants on T Lymphocyte Subsets after Kidney Transplantation: A Prospective Observational Study with Focus on Anti-Thymocyte Globulin and Basiliximab Induction Therapies.

Induction immunosuppressive therapy for kidney transplant recipients (KTRs) primarily includes interleukin-2 receptor antagonists, such as basiliximab (BXM) or lymphocyte-depleting agents, and anti-thymocyte globulin (ATG). This study aimed to investigate their effects on T cell dynamics during the early post-transplantation period. This prospective observational study included 157 KTRs. Peripheral blood samples were collected from each patient within 5 days before and 4 and 12 weeks after transplantation. Flow cytometric analysis was performed to assess various T cell subsets whose changes were then analyzed. In the ATG group, CD4+ T cell expression decreased significantly compared with that in the BXM group. However, CD4+CD161+ and CD4+CD25+CD127low T cell expression levels increased significantly. In the CD8+ T cell subset, a decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cell expression was observed in the ATG group. However, among patients diagnosed with biopsy-proven acute rejection, T cell subset expression did not significantly differ relative to non-rejection cases. In conclusion, ATG induction therapy resulted in more pronounced changes in T lymphocyte subsets than BXM induction, with increased CD4+CD161+ and CD4+CD25+CD127low T cells and an early decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cells, some of which are associated with acute rejection.

Aplastic Anemia with Epstein-Barr Virus Reactivation after Anti-thymocyte Globulin Therapy.

Lymphoproliferative disorders and Epstein-Barr virus reactivation (EBV-LPDs) have various forms of onset, ranging from infectious mononucleosis-like syndrome (IM-like) to lymphoma, although whether or not IM-like progresses to lymphoma remains unclear. A 61-year-old man was diagnosed with aplastic anemia (AA). Polyclonal atypical B-lymphocytes were observed in the peripheral blood, and IM-like was diagnosed. Atypical lymphocytes disappeared, but a gastrointestinal examination revealed diffuse large B-cell lymphoma (DLBCL). Rituximab was initiated but later discontinued because of severe acute respiratory syndrome coronavirus 2 infection. Pancytopenia due to AA exacerbation recurred. The patient ultimately died of multiple organ failure due to bacterial infection.

Repeated immunosuppressive rabbit antithymocyte globulin therapy for adult patients with relapsed or refractory aplastic anemia.

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A is the standard treatment for aplastic anemia (AA). However, the efficacy of repeated IST with rabbit ATG (rATG) as salvage therapy remains unclear in patients with relapsed or refractory AA. We retrospectively evaluated the efficacy and safety of IST2 with rATG (IST2-rATG) in 19 consecutive patients with relapsed or refractory AA who received first-line IST with rATG in two centers between 2009 and 2020. The overall 6-month response rate of the patients was 58%. The response rates were similar between patients with relapsed and refractory AA. The presence of glycophosphatidylinositol-deficient blood cells was associated with a better response to IST2-rATG. Despite retreatment with the same rATG, serum disease and severe allergic reactions were not observed. IST2-rATG is effective and safe for the treatment of adult patients with relapsed and refractory AA after receiving first-line IST with rATG.

An investigation of long-term outcome of rabbit anti-thymocyte globulin and cyclosporine therapy for pediatric severe aplastic anemia.

Children with severe aplastic anemia (SAA) face heterogeneous prognoses after immunosuppressive therapy (IST). There are few models that can predict the long-term outcomes of IST for these patients. The objective of this paper is to develop a more effective prediction model for SAA prognosis based on clinical electronic medical records from 203 children with newly diagnosed SAA. In the early stage, a novel model for long-term outcomes of SAA patients with IST was developed using machine-learning techniques. Among the indicators related to long-term efficacy, white blood cell count, lymphocyte count, absolute reticulocyte count, lymphocyte ratio in bone-marrow smears, C-reactive protein, and the level of IL-6, IL-8 and vitamin B12 in the early stage are strongly correlated with long-term efficacy (P < .05). Taken together, we analyzed the long-term outcomes of rabbit anti-thymocyte globulin and cyclosporine therapy for children with SAA through machine-learning techniques, which may shorten the observation period of therapeutic effects and reduce treatment costs and time.

Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications.

Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis. In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87). Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1). Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.

Eltrombopag Preserves the Clonogenic Potential of Hematopoietic Stem Cells During Treatment With Antithymocyte Globulin in Patients With Aplastic Anemia.

Aplastic anemia (AA) is frequently caused by a T-cell mediated autoimmune depletion of the hematopoietic stem and progenitor cell (HSPC) compartment. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine represents the first-line treatment of AA. One side effect of ATG therapy is the release of proinflammatory cytokines such as interferon-gamma (IFN-γ), which is considered a major factor in the pathogenic autoimmune depletion of HSPC. Recently, eltrombopag (EPAG) was introduced for therapy of refractory AA patients due to its ability to bypass IFN-γ-mediated HSPC inhibition among other mechanisms. Clinical trials have evidenced that EPAG started simultaneously with IST leads to a higher response rate compared with its later administration schedules. We hypothesize that EPAG might protect HSPC from negative effects of ATG-induced release of cytokines. We observed a significant decrease in colony numbers when both healthy peripheral blood (PB) CD34+ cells and AA-derived bone marrow cells were cultured in the presence of serum from patients under ATG treatment, as compared with before treatment. Consistent with our hypothesis, this effect could be rescued by adding EPAG in vitro to both healthy and AA-derived cells. By employing an IFN-γ neutralizing antibody, we also demonstrated that the deleterious early ATG effects on the healthy PB CD34+ compartment were mediated at least partially by IFN-γ. Hence, we provide evidence for the hitherto unexplained clinical observation that concomitant use of EPAG in addition to IST comprising ATG leads to improved response in patients with AA.

Acute Myeloid Leukemia Transformed from Aplastic Anemia following Anti-thymocyte Globulin Therapy: A Case Report with Clinicopathologic and Molecular Findings

Abstract: Aplastic Anemia (AA) incidence is threefold higher in Asia compared to the western world. It is associated with pancytopenia that is induced by impaired bone marrow function. Cytopenias of at least two lineages are required for the diagnosis. Symptoms include pallor, weakness, fever, frequent infections, bruises, petechiae, and mucosal bleeding. Bone Marrow Transplant (BMT) and immunosuppressive therapy are the treatment options. Patients with Severe Aplastic Anemia (SAA) are susceptible to developing malignancies like acute myeloid leukemia (AML) or Myelodysplastic Syndrome (MDS). In this report, we present a case of SAA who transformed to AML/MDS. 5 years of post- Anti-Thymocyte Globulin (ATG), she acquired monosomy 7, RUNX1 &amp; SETBP1 gene mutations. RUNX1 and SETBP1 mutations are correlated with poor overall survival and are predicted to have a lack of response from hypo-methylating agents. As the aspect of somatic mutation is complex and still not fully understood, it should be cautiously analyzed along with morphologic and cytogenetic results.

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

P827: EFFICACY AND SAFETY OF ROMIPLOSTIM ADDED TO IMMUNOSUPPRESSIVE THERAPY AS A FIRST-LINE TREATMENT IN PATIENTS WITH APLASTIC ANEMIA: A PHASE 2/3 CLINICAL TRIAL

Background: Romiplostim, a thrombopoietin (TPO) mimetic protein, has been shown to promote tri-lineage hematopoiesis in patients with acquired aplastic anemia (AA) refractory to immunosuppressive therapy (IST) or eltrombopag; however, its effectiveness in the combination therapy with antithymocyte globulin (ATG) plus cyclosporine (CsA) as a first-line treatment remains unknown. Aims: To clarify this issue, we conducted a phase 2/3 clinical trial to evaluate the efficacy and safety of romiplostim combined with rabbit ATG plus CsA in patients with AA requiring transfusions who had not been exposed to IST. Methods: This study was a multi-national, open-label study with romiplostim in IST-naïve adult patients with AA (NCT03957694). 10 µg/kg of romiplostim was started on day 1 of ATG therapy (2.5mg/kg/day for 5 days) and was weekly given for the first 4 weeks. The dose was adjusted from 5 to 20 µg/kg according to the prespecified dose adjustment procedure. Treatment lasted until Week 26. For those who intend to continue treatment, romiplostim administration was extended to Week 52. The primary endpoint was the hematological response rate (HRR) at Week 27 based on the response assessment criteria (Table 1). The secondary endpoints included the HRR at Week 14; the time to the hematological response; the proportion of patients who achieved transfusion independence or who showed a reduction of transfusion requirement among patients who had received a transfusion within 8 weeks prior to the first romiplostim administration. The bone marrow and cytogenetic analyses were performed prior to enrollment and at Week 27 and 53. Results: Twenty-six patients were screened, of which 17 (9 Japan, 7 Korea, and 1 Taiwan; 5 transfusion dependent non-severe AA, 6 severe AA (SAA) and 6 very SAA) were enrolled in the study. The median age was 44.0 years (range: 25-70). Two patients discontinued romiplostim before Week 27. The HRR (CR or PR) at Week 27 was 76.5% (95% CI: 50.10%, 93.13%), of which 6 (35.3%) achieved CR. The HRR at Week 14 was 41.2% (95% CI: 18.44%, 67.03%). The median day to achieve the first hematological response was 93.0 (range: 63-181). Of the 16 patients who depended on platelet transfusion before romiplostim administration, 14 (87.5%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. In addition, of 16 who required erythrocyte transfusion at baseline, 13 (81.3%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. The frequently reported adverse events (AEs) were constipation (41.2%) followed by headache (35.6%). The frequently reported drug-related AEs were headache (12.9%) followed by muscle spasms (9.7%), alanine aminotransferase increased, fibrin D dimer increased, malaise, and pain in extremity (each 6.5%). In bone marrow examination, increases of reticuline grade (grade 1 to 2) were observed in 3 patients at Week 27 and 1 patient at Week 53. No chromosomal abnormality or transformation into MDS and/or AML was observed. Image:Summary/Conclusion: This is the first clinical trial of romiplostim combined with rabbit ATG plus CsA in patients with acquired AA requiring transfusions who were previously untreated with IST. This regimen produced higher HRR at Week 27 (76.5%) than those of historical control received rabbit ATG plus CsA (approximately 50% at 6 months), with manageable AEs, and could therefore serve as a new first-line treatment option in patients with AA.

QuantiFERON-Cytomegalovirus Assay for Prediction of Cytomegalovirus Viremia in Kidney Transplant Recipients: Study From High Cytomegalovirus Seroprevalence Country.

BackgroundEarly studies showed the utility of pretransplant QuantiFERON-Cytomegalovirus (QF-CMV) assays for CMV-disease prediction post kidney transplant (KT). However, recent data are conflicting.MethodsThis prospective cohort study enrolled adult patients undergoing KT between July 2017 and May 2019. Patients with antithymocyte globulin therapy or negative pretransplant CMV IgG were excluded. QF-CMV assays were performed on transplantation day and one month thereafter, and CMV viral loads were obtained 1, 3, and 6 months posttransplantation. The primary outcome was CMV viremia within 6 months. The QF-CMV assay–posttransplant CMV viremia association was analyzed.Results Fifty-five patients were enrolled (male, 58.2%; mean (SD) age, 46.5 (10.2) years). Fifty-two (94.5%) received CMV-seropositive donor kidneys. Over 6 months, 29 patients developed CMV viremia (52.7%), with 14 (25.5%) having significant viremia requiring antiviral therapy. The CMV-viremia incidence of patients with nonreactive and reactive baseline QF-CMV assays did not differ significantly (55.3% and 47.1%; p = 0.573). Among patients with reactive pretransplant QF-CMV assays, there was a trend toward a lower incidence of CMV viremia for those who were persistently reactive at 1 month after KTs, although there was no statistically significant difference (50% vs 83%; p = 0.132).ConclusionsOur study could not support the use of single-timepoint pretransplant or 1-month posttransplant QF-CMV assays as a predictor for posttransplant CMV viremia in CMV seropositive KT recipients. Investigation of the association between dynamic QF-CMV-status changes and CMV-viremia incidence are needed.

IL-6 Responsiveness of CD4+ and CD8+ T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy.

Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3+CD4+ and CD3+C8+ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3+CD4+ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3+CD4+ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3+CD4+ cells together with increased mTOR (Ser2448) responses for the CD3+CD8+ cells. Thus, early post-transplant CD3+CD4+ and CD3+ CD8+ T cell subsets differ in their IL-6 responsiveness; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.

Is ATG Induction with Delayed Initiation of CNI Protective of Renal Function in Patients with Mild Renal Insufficiency?

<h3>Purpose</h3> Rabbit anti-thymocyte globulin (ATG) therapy has been used for induction to allow delay of initiation of calcineurin inhibitor (CNI) immediately post-heart transplant (HTx) in patients with moderate to severe renal insufficiency. In our program, this approach has been routine for patients with serum creatinine >2.0 mg/dL. Although this mode of therapy has been shown to be effective for renal protection, its benefit has not been established for patients with less renal insufficiency, in the 1.5-2.0 mg/dL range. Therefore, we reviewed our patient population to assess whether ATG induction was renal-protective for these patients. <h3>Methods</h3> Between 2010 and 2020, we assessed 84 patients with baseline creatinine in the 1.5-2.0 mg/dL range who underwent HTx, and divided them into those who underwent ATG with delay of initiation from CNI to those patients who did not. Patients given ATG (x 5 days) had delayed CNI beginning on days 3-5 post-operatively once urine output was established. Endpoints included comparison of glomerular filtration rate (GFR) at baseline, with change at 6- and 12-months for each group. In addition, 1-year freedom from temporary and chronic dialysis (occurring greater than 30 days postop) and freedom from rejection (any treated rejection [ATR], acute cellular rejection [ACR], antibody mediated rejection [AMR]) was assessed. <h3>Results</h3> There was no significant difference in the ATG induction compared to control in renal function (creatinine/GFR) at baseline and change in GFR at 6 months and 1 year post-HTx. In addition, there was no difference between groups in 1-year freedom from temporary or chronic dialysis, and freedom from ATR, ACR, or AMR. <h3>Conclusion</h3> ATG induction with delay of CNI does not appear beneficial for kidney function in patients with mild renal insufficiency. Larger studies are needed to confirm these findings.

Research Highlights

C3 Complement Inhibition Prevents Antibody-mediated Rejection and Prolongs Renal Allograft Survival in Sensitized Nonhuman Primates Schmitz R, Fitch ZW, Schroder PM, et al. Nat Commun. 2021;12:5456. Current therapeutic strategies for desensitization in renal transplantation have shown limited efficacy.1 Because a major downstream effector arm of donor-specific antibody (DSA) is the complement cascade,2 complement inhibition strategies are gaining interest.3 Following C1 and C5 inhibition strategies, the C3 inhibitor Cp40 has recently been added to this field of promising candidates with a successful first-in-human study (NCT03316521) of its derivate AMY-101. In the study from Schmitz et al,4 Cp40 treatment was assessed in a nonhuman primate sensitized renal transplantation model, in which animals received donor skin transplants before the kidney transplant. Induction therapy with rhesus-specific antithymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and methylprednisolone were administered with (n = 6) or without (n = 5) peritransplant Cp40 treatment (day –2 to day 14). Although all animals showed a significant DSA increase after transplant, Cp40 treatment reduced acute antibody-mediated rejection and prolonged graft survival clearly (15.5 versus 4 d). Although initial lymphocyte depletion was not affected by Cp40, activation and proliferation proved to be markedly disrupted. Interestingly, virtually no intragraft C3d deposition could be detected during the treatment period with Cp40, which contrasted with controls and treated animals after discontinuation of Cp40. Within the treatment group, there were early (ie, during Cp40 treatment) and late rejectors. Although overall DSA levels were similar, late rejectors had less antibody-mediated rejection and less graft infiltration with CD68+ macrophages in parallel to downregulated complement-related genes. Late rejectors also had higher numbers of CD4+ CD25+ FoxP3+ regulatory T cells 1 wk after transplant, reduced T- and B-cell proliferation, and lower immunoglobulin (Ig)M DSAs with lower complement activation. The authors concluded that because of heterogeneity of IgM DSA levels, Cp40 doses could have been insufficient in animals bearing the highest immunologic burden. These data provide crucial evidence for C3 inhibition in a relevant preclinical model. Notably, overall DSA levels were not predictive of rejection in this study, yet treatment success correlated with IgM DSA load. This study sets the stage for early phase clinical trials of Cp40 in transplantation in which identification and stratification of potential benefit and dosage requirements in patient populations could be incorporated according to IgM DSA levels. An Aged Immune System Drives Senescence and Aging of Solid Organs Yousefzadeh MJ, Flores RR, Zhu Y, et al. Nature. 2021;594:100–105. The decline of immune responses with aging, termed immunosenescence, is linked to increased morbidity and mortality, likely related to reduced immunosurveillance, poor antipathogen immunity, and reduced vaccination responses.1,2 Given the broad role of the immune system in homeostasis, targeting immune cells to influence systemic aging may be a useful strategy for the reversal of age-related tissue pathology. In the landmark study from Yousefzadeh et al in Nature,3 the authors knocked out Ercc1 (which encodes the crucial DNA repair protein endonuclease ERCC1-XPF) in mouse hematopoietic cells, thereby selectively altering senescence in lymphoid organs. The impact of this genetic modification was evaluated in the context of aging. Compared with normal aging in wild-type mice, mutant mice developed peripheral leukopenia in adulthood and overall immune cells decreased in all compartments, as did thymic and splenic weights. Lymphoid tissues were less active and delayed-type hypersensitivity reactions demonstrated decreased innate and adaptive immune functions in older mutant mice, whereas younger ones had similar responses to wild-type littermates. Mutant mice displayed increased oxidative stress in lymphoid tissues and senescence onset in several immune cell subsets when compared with aged wild-type mice. Notably, older mutant mice had systemic changes associated with normal aging measured by DNA damage, oxidative stress, and senescence markers in many solid organ tissues, with peripheral senescence chronologically following immune senescence. Tissue damage appeared in nondeleted organs such as the liver, pancreas, intervertebral discs, brain, and muscles. Accordingly, the lifespan of mutant mice was markedly reduced. Interestingly, some of these effects could be transferred by simple transplantation of aged donor cells into separate recipient mice. Here, transplantation of aged or senescent splenocytes into reporter mice appeared to result in an acceleration of systemic aging and a decreased lifespan. Conversely, adoptive transfer of young wild-type splenocytes was able to attenuate peripheral organ senescence and tissue damage in older recipients. Finally, mechanistic target of rapamycin inhibition with rapamycin mitigated immune senescence characteristics connected with systemic aging. These findings underscore the driving role of immunosenescence in systemic aging, related tissue damage, and fatal outcomes. Additionally, the data highlight some of the molecular mechanisms linking aging and immunosenescence, which may be amenable to therapeutic targeting.