Received Rabbit Antithymocyte Globulin Research Articles

Clinical outcomes of patients receiving three versus four doses of methotrexate with concomitant antithymocyte globulin in match unrelated donor allogeneic stem cell transplant: A single‐center experience

AbstractMethotrexate (MTX) doses on days +1, +3, +6, and +11 after match unrelated donor allogeneic stem cell transplant (MUD HSCT) is a common graft‐versus‐host disease (GVHD) prophylaxis regimen. However, the overlapping toxicity of MTX with conditioning chemotherapy sometimes warrants the omission of the fourth dose of MTX. Prior single‐institution studies showed conflicting results comparing the outcomes of patients who received three versus four doses of MTX, but to our knowledge, the effect of concomitant antithymocyte globulin (ATG) has not been reported. Charts of patients who underwent MUD HSCT between 2009 and 2023 were reviewed. Patients received rabbit ATG (Thymoglobulin), given at 0.5 mg/kg on day −3, 2 mg/kg on day −2, and 2.5 mg/kg on day −1. MTX is given at 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11. Severe mucositis was the most common indication for day +11 MTX omission (82%). We identified 292 patients (116 in 3 dose cohort and 176 in 4 dose cohort). Median follow‐up was 23 months (range 1–151). Patients in the 4 doses cohort were more frequently male (68% vs. 50%, p < 0.01), received a reduced intensity conditioning regimen (38.0% vs. 22%, p < 0.01), were older (median 58 vs. 54 years, p = 0.02), and received a transplant in the earlier era (median HSCT year 2014 vs. 2018, p < 0.01). A statistically significant difference was not evidenced between the cohorts for the following outcomes: acute GVHD (aGVHD) (HR 1.1, 95% CI 0.9–1.5), chronic GVHD (cGVHD) (HR 1.3, 95% CI 0.8–1.6), relapse‐free survival (RFS) (HR 1.0, 95% CI 0.6–1.5), non‐relapse mortality (NRM) (HR 1.4, 95% CI 0.9–2.2), and overall survival (OS) (HR 1.2, 95% CI 0.9–1.7). Both cohorts had similar median time to neutrophil engraftment at 14 days. When ATG is incorporated, omission of day +11 MTX does not significantly impact the rate of engraftment or cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS.

Predictive value of thyroid function in severe aplastic anemia patients treated with immunosuppressive therapy.

To explore the predictive value of thyroid function in severe aplastic anemia (SAA) patients treated with immunosuppressive therapy (IST), 149 SAA patients in our center were enrolled between February 2015 and June 2020 in this study. We assessed the thyroid function of 134 patients without primary thyroid diseases, and discovered that 89 patients were accompanied by abnormal thyroid hormone, especially low triiodothyronine (T3). Patients with higher pretreatment-free T3 (FT3) levels (>5 pmol/L) demonstrated superior response rates at 3 and 6 months after IST compared to those with lower FT3 levels (54.5% vs 35.4%, P = .020; 67.3% vs 46.9%, P = .020). Multivariate analysis indicated that shorter disease duration (≤56 days) and response at 6 months were independent favorable factors of overall survival (relative risk [RR] = 2.66, 95% confidence interval [CI] = 1.03-6.90, P = .040; RR = 30.10, 95% CI = 4.02-225.66, P = .001). The 6-year failure-free survival (FFS) was 53.8% (95% CI = 40.9%-65.1%). Multivariate analysis revealed that patients with a response at 6 months, shorter duration (≤56 days) and receiving rabbit antithymocyte globulin (ATG) had better FFS outcomes than those without a response at 6 months, with a longer duration and receiving porcine ATG (RR = 22.6, 95% CI = 7.9-64.9, P < .001; RR = 2.4, 95% CI = 1.3-4.5, P = .006; RR = 2.5, 95% CI = 1.1-5.8, P = .030). In conclusion, FT3 levels reflect the severity of SAA, and patients with higher FT3 levels (>5 pmol/L) had superior response rates than those with lower ones.

Comparison of Non-Myeloablative Conditioning Regimens Flu/Bu2, Flu/Mel 100 and Flu/TBI in Patients with AML and MDS

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment modality for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Non-myeloablative (NMA) conditioning regimens are used to decrease toxicity, making HSCT more tolerable and available to older patients or patients with co-morbidities. It remains unclear as to which NMA regimen leads to superior outcomes. Methods: We retrospectively compared outcomes of 3 NMA regimens in 98 patients with AML or MDS undergoing allogeneic HSCT from January 2017 to December 2021. The 3 regimens were: Flu/Mel 100: fludarabine 40 mg/m2 days -5 to -2, melphalan 100 mg/m2 day -2; Flu/Bu2: fludarabine 30 mg/m2 days -6 to -2, busulfan 130 mg/m2 days -3 to -2; Flu/TBI: fludarabine 30 mg/m2 days -4 to -2, total body irradiation 200-300 cGY on day-1. Patients conditioned with Flu/Mel 100 or Flu/Bu2 also received rabbit anti-thymocyte globulin 4-6 mg/kg. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus and low dose methotrexate for patients receiving Flu/Mel 100 or Flu/Bu2, and sirolimus, cyclosporine and mycophenolate mofetil for patients conditioned with Flu/TBI. Continuous variables were compared between conditioning regimens using Pearson's Chi-squared test or Fisher's exact test. PFS and OS survival probability and survival times were estimated with Kaplan-Meyer(K-M) procedure. To compare survival distributions between conditioning regimens, a log-rank test was used. We report 24-month survival probabilities in months with corresponding 95% confidence intervals. Results: Patient demographics were balanced between the 3 groups including age (range 54-80), gender, disease risk and cell source (Table 1). 24-month progression free survival (PFS) was not different between the groups: Flu/Mel 100 was 70% (47%-100%), Flu/Bu2 was 49% (39%-63%), and Flu/TBI was 33% (18%-61%) (p=0.3). For Flu/Mel 100 the 24-month overall survival (OS) was 70% (47%-100%), Flu/Bu2 was 53% (42%-66%), Flu/TBI was 32% (17%-61%) which was not statistically different ( p=0.3) (Figure 1). There was no difference between the 3 groups for non-relapse mortality (NRM) ( p=0.46). The incidence of all grade acute GVHD was 70% for Flu/Mel 100, 66% for Flu/Bu2 and 76% for Flu/TBI ( p=0.70). There was no difference in the incidence of chronic GVHD between the groups; Flu/Mel 100 50%, Flu/Bu2 55%, Flu/TBI 57% (p&amp;gt;0.99). Conclusions: All three NMA regimens were found to be statistically equivalent. NRM, PFS, OS and the incidence of acute and chronic GVHD was not statistically different between the groups. A limitation of the study is the relatively small number of patients in the Flu/Mel 100 group. Further study with a larger sample size is needed to evaluate for small differences between the regimens.

Antithymocyte Globulin in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia: Evaluating Outcomes According to Cytogenetic Risk

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an essential therapeutic approach for the management of acute myeloid leukemia (AML). Nevertheless, graft-versus-host disease (GVHD) remains a significant complication, significantly affecting the recipients' quality of life and overall survival. Antithymocyte globulin (ATG) has demonstrated promise in preventing GVHD during allo-HSCT. However, concerns persist regarding its potential impact on disease relapse. This retrospective single-center study aims to evaluate the prognostic implications of ATG based on cytogenetic risk stratification in AML patients undergoing transplantation from an HLA-matched sibling. A total of 124 AML patients who underwent allo-HSCT from an HLA-matched sibling in their first complete remission state between 2003 and 2022 were eligible for the study. Among them, fifty patients received rabbit ATG at a dose of 2.5mg/kg/day for days -2 to -1, while 74 patients did not receive ATG. All patients received cyclosporine and methotrexate in addition to their respective conditioning regimens (ATG or no ATG). The ATG group consisted of 38 patients classified as having a non-high cytogenetic risk, and 12 patients classified as having a high cytogenetic risk. Conversely, the non-ATG group included 68 patients with a non-high cytogenetic risk and 6 patients with a high cytogenetic risk. After a median follow-up of 48 months, there were no significant differences in median overall survival between the ATG and Non-ATG groups, regardless of cytogenetic risk status (non-high cytogenetic risk; 12.4 months vs. NA, p = 0.578; high cytogenetic risk; 13.2 months vs. 14.2 months, p = 0.729, Figure A-1,B-1). The ATG group in the non-high cytogenetic risk group demonstrated a significant decrease in the 1-year cumulative incidence (CI) of chronic GVHD compared to the non-ATG group (21.7% vs. 54.4%, p = 0.001, Figure A-2; and in those with moderate to severe cGVHD, it was 21.6% vs. 51.5%, p = 0.003, respectively). Additionally, the 1-year Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group of the non-high cytogenetic risk group (45.8vs. 26.5%; p = 0.048, Figure A-3). Moreover, there were no significant differences in 1-year CI of relapse and 1-year non-relapse mortality (NRM) within the non-high cytogenetic risk group (ATG vs. non-ATG; 29.7% vs. 20.6%, p = 0.225; 8.4% vs. 4.4%, p = 0.635, Figure A-4,5). In the subgroup analysis of patients with high cytogenetic risk, although there was no statistical significance, the ATG group showed a trend towards decreased 1-year CI of chronic GVHD and higher cGRFS compared to the non-ATG group (10.4% vs. 40.0%, p = 0.342; 31.2% vs. 16.7%, p = 0.929, Figure B-2,3). However, the ATG group exhibited a significantly higher 1-year CI of relapse compared to the non-ATG group (60.0% vs. 16.7%, p = 0.019, Figure B-4). In conclusion, our study findings indicate that ATG was effective in preventing chronic GVHD and demonstrated higher cGRFS in AML patients undergoing matched sibling donor HSCT. However, AML patients with high cytogenetic risk should carefully consider the use of ATG due to the associated higher risk of relapse. Further investigations are warranted to validate these findings and determine the appropriate dosage of ATG for high cytogenetic risk AML patients.

Subtle Changes in Tacrolimus Levels Have an Impact on Early Donor-Specific Antibodies in Kidney Transplantation.

Introduction: The impact of each immunosuppressive agent on de novo donor-specific antibodies in kidney transplant recipients varies among extant literature. Project aims: Patterns in immunosuppression and the effects on incidence of de novo donor-specific antibodies were evaluated. Design: Adult kidney transplant recipients from 2017 to 2019 without preformed antibodies were sampled. Allograft function, de novo donor-specific antibodies, tacrolimus concentrations, duration of goal-dose antiproliferatives, and steroid doses were recorded. Outcomes included incidence of de novo donor-specific antibodies, and their relation to tacrolimus concentrations, time at goal-dose antiproliferatives, and steroid doses. Results: Recipients (N = 153) were followed for 1 year; all were crossmatch negative and received rabbit antithymocyte globulin induction. Sixteen (10%) recipients developed de novo donor-specific antibodies in a median of 31 days [interquartile range, IQR: 12-67 days], most were Class II antibodies (87.5%). Incidence of de novo donor-specific antibodies did not differ based on induction dosing. Tacrolimus levels in the first month were lower for patients with de novo donor-specific antibodies (8.8 ng/mL vs 10.4 ng/mL, P < .01). There was no difference in time on goal antiproliferative doses, but higher steroid doses (0.4 vs 0.3 mg/kg/d; P = .02) were noted in patients with antibodies. Steroid dosing was likely impacted by baseline risk factors. Conclusion: A significant association was found between lower tacrolimus concentrations early post-transplant and incidence of de novo donor-specific antibodies. This highlighted the importance of clinician attention to subtle changes in tacrolimus and the impact it can have on antibody risk in the early post-transplant period.

A report of a prospective randomized trial of extended-release tacrolimus versus immediate release tacrolimus after liver transplantation with anti-thymocyte induction in a steroid free protocol.

Our study hypothesis was that once daily dosing of extended-release tacrolimus (XRT) would be a safe and effective immunosuppression (IS) with the potential to decrease adverse events (AEs) associated with immediate release tacrolimus (IRT) after liver transplantation (LT). All patients receiving LT at our center received rabbit anti-thymocyte globulin (RATG) induction therapy. Eligible patients were randomized in a 1:1 fashion to receive either XRT or IRT. Antimicrobial prophylaxis was the same between arms, and both groups received an antimetabolite for the first 6 months following LT. Patients were then followed at pre-determined study intervals for the following year after LT. We administered the RAND-36SF survey to assess patient's health-related quality of life at pre-determined intervals. All analysis was performed with an intention to treat basis. We screened 194 consecutive patients and enrolled 110. Our control and study arms were well matched. Transplant characteristics were similar between groups. At all timepoints, both arms had similar serum creatinine and estimated glomerular filtration rate (eGFR), calculated by MDRD6 equation, with post-transplant GFRs between 60 and 70mL/min/1.73m2 . Tacrolimus trough levels were similar between arms. The XRT arm had fewer AEs (166) and fewer serious AEs (70) compared to IRT (201 and 99, respectively). AEs most commonly were renal, infectious, or gastrointestinal in nature. While not statistically significant, XRT was held temporarily (25vs. 35 cases) or discontinued (3vs. 11 cases) less frequently than IRT and had fewer instances of rejection (7vs. 12 cases). This analysis showed that XRT is safe and effective as de novo maintenance IS in a steroid-free protocol with RATG.

Impact of early corticosteroid withdrawal on simultaneous pancreas-kidney transplant long-term outcomes: Single center experience and comparison to the International Pancreas Transplant Registry.

There remains a paucity of modern data comparing early steroid withdrawal (ESW) versus chronic corticosteroid (CCS) immunosuppression in simultaneous pancreas kidney (SPK) transplant recipients with long-term follow-up. Therefore, the purpose of this study is to assess the effectiveness and tolerability of ESW compared to CCS post-SPK. This was a retrospective single-center matched comparison with the International Pancreas Transplant Registry (IPTR). Patients from University of Illinois Hospital (UIH) represented the ESW group and were compared to those matched CCS patients from the IPTR. Included patients were adult recipients of a primary SPK transplant between 2003 and 2018 within the US receiving rabbit anti-thymocyte globulin induction. Patients were excluded if they had early technical failures, missing IPTR data, graft thrombosis, re-transplant, or positive crossmatch SPK. A total of 156 patients were matched and included in the analysis. Patients were predominantly African American (46.15%) males (64.1%) with Type 1 diabetes etiology (92.31%). Overall pancreas allograft survival (hazard ratio [HR] = .89, 95% confidence interval [CI] .34-2.30, p = .81) and kidney allograft survival (HR = .80, 95%CI .32-2.03, p = .64) were similar between the two groups. Immunologic pancreas allograft loss was statistically similar at 1-year (ESW 1.3% vs. CCS 0%, p = .16), 5-year (ESW 1.3% vs. CCS 7.7%, p = .16), and 10-year (ESW 11.0% vs. CCS 7.7%, p = .99). The 1-year (ESW 2.6% vs. CCS 0%, p>.05), 5-year (ESW 8.3% vs. CCS 7.0%, p>.05), and 10-year (ESW 22.7% vs. CCS 9.9%, p = .2575) immunologic kidney allograft loss were also statistically similar. There was no difference in 10-year overall patient survival (ESW 76.2% vs. CCS 65.6%, p = .63). No differences were found between allograft or patient survival post-SPK when comparing an ESW or CCS protocol. Future assessment is needed to determine differences in metabolic outcomes.

Age-related decline in anti-HBV antibodies in vaccinated kidney transplant recipients.

Hepatitis B virus (HBV) vaccination is indicated for all end stage kidney disease patients, including all solid organ transplant candidates. Maintenance of adequate immunity is especially important for immunosuppressed solid organ recipients who are at increased risk for donor or community acquired HBV. The impact of age and immunosuppression on long-term maintenance of HBV immunity postvaccination has not been fully investigated. We performed a single-center retrospective study of 96 kidney transplant recipients, transplanted between July 2012 and December 2020, who had Hepatitis B surface antibody (HBsAb) levels measured pretransplantation and 1-year posttransplantation. We compared the change in HBsAb levels stratified by patient's age (<45, 45-60, and >60) and by whether or not the patient received lymphocyte depleting induction therapy. Our results demonstrate that HBsAb IgG levels vary by age group, decreased significantly at 1-year posttransplant (p < .0001) and were significantly lower in the older cohort (p = .03). Among recipients who received rabbit anti-thymocyte globulin induction (rATG), the log HbsAb levels were significantly lower in the older age group (2.15 in age <45, 1.75 in age 45-60 and 1.47 in age >60, p = .01). Age group (p = .004), recipient HBcAb status (p = .002), and rATG (p = .048) were independently associated with >20% reduction in log HBsAb levels posttransplant. Significant declines in HBsAb levels occur postkidney transplantation, especially in older individuals, thus placing exposed older kidney transplant recipients at greater risk of HBV infection and associated complications.

Lymphopenia at the time of transplant is associated with short-term mortality after deceased donor liver transplantation

Absolute lymphocyte count (ALC) is considered a surrogate marker for nutritional status and immunocompetence. We investigated the association between ALC and post-liver transplant outcomes in patients who received a deceased donor liver transplant (DDLT). Patients were categorized by ALC at liver transplant: low (<500/μL), mid (500-1000/μL), and high ALC (>1000/μL). Our main analysis used retrospective data (2013-2018) for DDLT recipients from Henry Ford Hospital (United States); the results were further validated using data from the Toronto General Hospital (Canada). Among 449 DDLT recipients, the low ALC group demonstrated higher 180-day mortality than mid and high ALC groups (83.1% vs 95.8% and 97.4%, respectively; low vs mid: P = .001; low vs high: P < .001). A larger proportion of patients with low ALC died of sepsis compared with the combined mid/high groups (9.1% vs 0.8%; P < .001). In multivariable analysis, pretransplant ALC was associated with 180-day mortality (hazard ratio, 0.20; P = .004). Patients with low ALC had higher rates of bacteremia (22.7% vs 8.1%; P < .001) and cytomegaloviremia (15.2% vs 6.8%; P = .03) than patients with mid/high ALC. Low ALC pretransplant through postoperative day 30 was associated with 180-day mortality among patients who received rabbit antithymocyte globulin induction (P = .001). Pretransplant lymphopenia is associated with short-term mortality and a higher incidence of posttransplant infections in DDLT patients.

Basiliximab is associated with a lower incidence of De novo donor-specific HLA antibodies in kidney transplant recipients: A single-center experience

PurposeInduction immunosuppression has improved the long-term outcomes after kidney transplant. This study explores the association of different induction immunosuppression medications (Basiliximab vs. Alemtuzumab vs. rabbit Antithymocyte Globulin) used at the time of kidney transplant with the development of de novo donor-specific HLA antibodies (DSA) in the first 12 months post-transplant period. MethodsA total of 390 consecutive kidney transplant recipients (KTR), between 2016 and 2018, were included in the analysis. A 104 (26.6%) received Basiliximab, 186 (47.6%) received Alemtuzumab, and 100 (25.6%) received rabbit Antithymocyte Globulin (rATG) for induction. All recipients had a negative flow cytometry crossmatch before transplant. Serum samples at 4- and 12-months post-transplant were assessed for the presence of de novo HLA DSA. kidney allograft function was compared among the three groups with calculated Creatinine Clearance on 24 h urine collection. ResultsDe novo HLA DSA were detected in total of 81 (20.8%) patients within 12 months post-transplant. De novo HLA DSA were detected in 12/104 (11.5%), 43/186 (23.11%), and 26/100 (26%) KTR that received Basiliximab, Alemtuzumab, and rATG respectively (p = 0.006). KTR that received Basiliximab were significantly older, and the last follow-up creatinine clearance was significantly lower at 42 ml/min compared to KTR that received Alemtuzumab or rATG (p = 0.006). ConclusionInduction immunosuppression utilizing Basiliximab is associated with significant reduction in development of de novo DSA within the first 12-months post kidney transplant but had lower creatinine clearance with long-term follow up.

Avatrombopag Added to Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Acquired aplastic anemia is immune-mediated bone marrow failure disease. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for severe aplastic anemia (SAA), but only 12-17% of patients achieve complete response at 6 months. Complete hematologic response predicts better survival of patients, so clinicians have been trying to further improve the complete response rate. Addition of eltrombopag improves both the overall response rate and complete response rate of SAA patients, but its hepatotoxicity is still worrying. Avatrombopag is a novel, oral, small-molecule thrombopoietin receptor agonist being developed to provide a predictable increase in platelet counts in immune thrombocytopenia and thrombocytopenia in patients with chronic liver disease. To date, there is no report on the effectiveness of avatrombopag in treating aplastic anemia. Here we enrolled 32 severe and very severe aplastic anemia (SAA/VSAA) patients who received ATG, cyclosporine and avatrombopag as first-line treatment between June 2021 and March 2022. Thirty-one patient received porcine ATG (20mg/kg.d for 5 consecutive days) and one patient received rabbit ATG (3mg/kg.d for 5 consecutive days). Avatrombopag was added within 3 months after ATG initiation at dose of 40-60mg per day and administered for at least 3 months. Cyclosporine was given orally at dose of 3.5-5mg/kg.d. There were 17 SAA patients and 15 VSAA patients. The median neutrophil count was 0.31 (range 0.01-1.01) ×109/L, median reticulocyte count was 8 (range 2-54) ×109/L, and median platelet count was 5 (range 1-16) ×109/L. All patients achieved the end-point of 3 months and 23 patients achieved end-point of 6 months. One patient with VSAA died at 1 month due to infections and was counted as no response at 3 months and 6 months. The rate of complete response was 15.6% and rate of overall response was 46.9% at 3 months. The rate of complete response at 6 months was 30.4% and rate of overall response was 65.2%. The complete response rate at 3 months and 6 months were both higher than historical results of standard IST (ATG and cyclosporine, 5.2% at 3 months and 14.6% at 6 months). Avatrombopag was safe, and there was no drug-related liver dysfunction. No patient discontinued avatrombopag due to adverse events. In conclusion, the addition of avatrombopag to IST was safe and associated with higher complete response rate among patients with SAA/VSAA.

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.

Tolerability of mycophenolate mofetil in elderly kidney transplant recipients: A retrospective cohort study

Optimal immunosuppression in elderly kidney transplant recipients (KTRs) is not well defined, with mycophenolate mofetil (MMF) being poorly tolerated. Study aim was to compare MMF dose reduction incidence and reason(s) in elderly vs. nonelderly KTRs in the 1st year after transplant with a protocol dose of 1g/day. In this single-center retrospective study, first or repeat KTRs receiving rabbit antithymocyte globulin (rATG), MMF 1g/day, tacrolimus, and prednisone, were stratified by age [≥60 (elderly) or <60 years (nonelderly)]. Primary outcome was MMF dose reduction incidence in the first year. Secondary outcomes included dose reduction rationale, 1-year patient and graft survival, graft function, rejection, infection, hospital presentation, and time to dose reduction. Of 335 KTRs, dose reduction incidence was significantly greater in the elderly group (66% and 54%, p=0.04), though this did not remain significant when adjusted for sex, race, and valganciclovir use. Most common rationale was leukopenia in the elderly group and CMV in the nonelderly group. There were no significant differences in secondary outcomes. Mycophenolate mofetil 1g/day was poorly tolerated in both elderly and nonelderly KTRs receiving lymphocyte-depleting induction with a high incidence of dose reductions; however, no short-term adverse graft outcomes were identified.

Survival Rate of Renal Transplant and Factors Affecting Renal Transplant Failure.

The most important complication in kidney transplant is acute/chronic rejection. In this study, we investigated the factors affecting kidney rejection and transplant survival. In this survival analysis study, 352 patients (mean follow-up of 12.9 ± 4.4 years) who underwent renal biopsy due to increased creatinine level from 2012 to 2016 were identified by glomerular filtration rate level and rejection. Probable factors affecting renal function and survival rate after transplant rejection were assessed. P < .05 was considered as significant. Among our study patients, 40.9% developed early and 59.1% developed late acute kidney injury. Graft survival rates at 1 and 5 years were 98.9% and 68.5%, respectively, which was significant when rejection type was considered (P = .002). In addition, patient survival rates at 1 and 5 years were 99.7% and 98.6%, respectively. Graft survival at 5 years was significantly lower among older subjects, those with diabetes, those who received deceased donor organs, and those with late acute kidney injury (P < .002). Patient survival was significantly higher among young patients, those with systemic lupus erythematosus, those who received living donor organs, and those without cytomegalovirus infection (P < .003). We observed that recipient age, type of donor, underlying disease, infection, and late acute kidney injury had great negative impacts on renal dysfunction and survival. In our center, because of the large number of kidney transplants from deceased donors, the necessity of antithymocyte globulin induction therapy was considered, since this study showed that patients who received rabbit antithymocyte globulin induction had better outcomes.

Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Antithymocyte Globulin Administration Schedules in Allogeneic Stem Cell Transplantation

Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor-derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft-versus-host disease (GVHD), infection risk, and disease response. While the latter is contingent on disease biology and thus may be less predictable, the former 2 manifestations are more likely to be directly proportional to the magnitude of donor-derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in 2 cohorts of HLA-matched allograft recipients who received rabbit antithymocyte globulin (ATG) on different schedules (days -9 to -7 versus days -3 to -1). Monocyte as well as donor-derived T cell (ddCD3) recovery was superior in those given ATG early in the course of disease (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, driven largely by CD3+/CD8+ cells in the first month post-transplantation. Early monocyte recovery was associated with later T cell recovery and improved survival. In contrast, rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modeling "early-term immune reconstitution" following HCT yields insights that may be useful in the management of post-transplantation immunosuppression and adaptive cellular therapy to optimize clinical outcomes. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Surge in Procalcitonin Levels Post ATG During Stem Cell Transplantation for Aplastic Anemia: A Diagnostic Dilemma with Sepsis?

Allogenic Stem Cell Transplantation (AlloSCT) has paved way for curative therapy in numerous hematologic diseases such as Aplastic Anemia. Anti-Thymocyte Globulin (ATG), a polyclonal T-cell antibody is an integral part of the numerous conditioning regimens. Its purpose is the T-cell depletion of the recipient, which is of utmost importance for the prevention of graft rejection and successful engraftment. Febrile responses after ATG administration pose a diagnostic dilemma in these patients who are frequently neutropenic [1]. During the conditioning phase before AlloSCT, patients undergo substantial immunosuppression and immune-alteration under the effect of pharmacotherapy and total body irradiation. Conditioning with ATG can be associated with febrile episodes, circulatory instability and/or respiratory insufficiency. The severity of this reaction especially in a neutropenic patient can closely resemble sepsis. Since blood cultures can take a few days in reporting, biochemical markers of inflammation, such as C-Reactive Protein (CRP) and Procalcitonin (PCT) levels have a diagnostic value. In contrast to CRP, Procalcitonin is a sensitive and specific marker for systemic bacterial infection and fungal sepsis [2,3]. We observed a surge in procalcitonin levels after ATG administration in a patient suffering from severe aplastic anemia undergoing conditioning for allogenic bone marrow transplantation from a matched sibling donor. The patient weighing 72 kilograms, received rabbit ATG as GVHD prophylaxis at the rate 1.5mg/kg (5 vials of 25mg each) on Day - 3 of conditioning and developed high grade fever with chills, reaching a peak temperature of 103.6 degrees Fahrenheit. Microbiological cultures and procalcitonin levels were sent to rule out sepsis as part of the protocol. First line intravenous antibiotics were started and antipyretics were administered. Fever settled on its own once the ATG therapy was completed. On day -2 and -1, the same dose of ATG was given and the patient did not develop any febrile episodes. The median PCT elevation on day 1 after ATG infusion was 87.68mcg/L, nearly 70 times the baseline level. Patient was clinically stable with no features of sepsis. There was a steady decline in PCT levels over the next 4 days, 58.54, 24.79, 4.38 and 1.13 (mcg/L) respectively. No derangements in liver function tests or renal function tests were observed. Subsequently, the microbiological cultures were sterile ruling out sepsis. Several previous reports suggested limited diagnostic value of PCT and CRP in the presence of anti-T-lymphocyte antibodies. Dornbusch et al. compared 15 consecutive febrile episodes after T cell antibody infusion without clinical signs of infection with nine episodes of Gram-negative sepsis. After T-cell antibody infusion PCT and CRP serum levels increased to a similar extent as in Gramnegative sepsis. They concluded that during T-cell antibody treatment neither PCT nor CRP are adequate for differentiating between fever due to infection or to unspecific cytokine release. The median PCT elevation on day1 after T-cell antibody infusion was nearly 40 times the baseline [4]. In our patient, the levels reached 70 times the baseline value probably related to higher ATG dose according to the weight of the patient. Brodska et al., prospectively evaluated the validity of CRP and PCT to diagnose infection in patients receiving ATG prior to hematopoietic stem cell transplantation. They assessed renal and liver functions and their relationship to PCT and CRP changes. They found no interrelationship between PCT levels and BL markers of renal or liver functions (P &gt; 0.05 for all comparisons) [5]. Similarly in our patient, no derangements in LFT or RFTs were seen. To conclude, febrile episodes during treatment with ATG are associated with markedly elevated levels of PCT directly proportional to the dose of ATG given. This causes a diagnostic dilemma with sepsis and early use of antimicrobials, which may be kept in reserve during actual crisis in the post-transplant period. In such a scenario, detailed clinical assessment of patient’s condition and careful interpretation of biochemical and microbiological investigations is of utmost importance for judicious use of antimicrobials in this era of emerging antibiotic resistance.

Study of the outcome of pediatric patients with aplastic anemia treated with immunosuppressive therapy-Single center experience

Background: Immunosuppressive therapy is the Initial therapy for children with severe Aplastic anemia (SAA) and lacking a matched related donor. Cyclosporine A (Cy A) alone has been tried as single agent in resource poor Countries. Patients and Methods: This retrospective study was done to assess the outcome of immunosuppressive therapy (IST) in SAA children. It included 23 patients treated at Ain Shams University Pediatrics Hospitals between 2011- 2019 with IST, they received rabbit anti-thymocyte globulin (r ATG) plus (Cy A) (Group I, 8 patients) or Cy A alone (Group II, 15 patients). The median follow- up duration was 59 months. Results: one patient (4.3%) developed AML clone. another patient (4.3%) developed PNH clone. There was no significant difference in response between the two groups, Complete response was 34.7%, 43.5%, and 47.8% and partial response was 34.7%, 26.1%, 21.7% at 3, 6, and 12 months, respectively in the whole cohort. NR was present in 30.4% at 3, 6, and 12 months. Hypertension in 62.5% and higher levels of ALT, total and direct bilirubin were observed in group I as compared to group II. HAAA was clinically evident in 7 patients; 4 of them were hepatitis A, 1 was EBV, and 2 were seronegative for all viruses. At presentation they had significantly higher level of ALT, total bilirubin, and direct bilirubin. Conclusion: IST is an effective therapy in patients with SAA with overall response of 70%. Cy A alone can be an effective therapy in developing countries.

A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin

Background aimsIntensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors’ center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2–4 acute GVHD or moderate to severe chronic GVHD. MethodsThis was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD. ResultsThere was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk. ConclusionsPre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).

Heterogeneous Manifestations of Posttransplant Lymphoma in Renal Transplant Recipients: A Case Series

Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell–Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia

Depletion of αβ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αβ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P=.07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p=ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P=.002). Recovery of both αβ- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αβ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.