Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population.

Introduction: The aim of our study is to explore the relationship of rabbit anti-thymocyte globulin (R-ATG) on development of post-transplant lymphoproliferative disease (PTLD) and its aggressive forms (monomorphic PTLD and Hodgkin lymphoma) in renal transplant recipients.Methodology: All patients diagnosed with PTLD post-renal transplant in the United States' Organ Procurement and Transplantation Network from 2003 till 2013 and followed up till 2017 were retrospectively reviewed. Multi-variable logistic regression analysis assessed association of R-ATG to development of PTLD and its aggressive form.Results: Risk of developing PTLD post renal transplant is 1.35%. In comparison to interleukin-2 blocker induction therapy, R-ATG is associated with increased risk of development of PTLD (Odds Ratio = 1.48, confidence interval ranges from 1.04 to 2.11, p = .02) and is associated with higher risk of development of aggressive PTLD (Odds Ratio = 1.83, confidence interval ranges from 1.001 to 3.34, p = .04).Conclusion: We conclude that R-ATG induction is associated with a higher risk of PTLD and its aggressive form (monomorphic PTLD and Hodgkin lymphoma). Careful monitoring for development of PTLD in renal transplant recipients receiving R-ATG induction therapy is advised.

Different impact of rATG induction on CMV infection risk in D+R- and R+ KTRs.

BACKGROUND: Rabbit antithymocyte globulin (rATG) induction is associated with profound immunosuppression, leading to a higher risk of cytomegalovirus (CMV) infection compared with anti-interleukin 2 receptor antibody (anti-IL-2RA). However, this risk, depending on the baseline CMV serological recipient/donor status, is still controversial. METHODS: The CMV DNAemia-free survival between rATG- and anti-IL-2RA-treated patients was analyzed in donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients in 1 discovery cohort of 559 kidney transplant recipients (KTRs) and 2 independent cohorts (351 and 135 kidney KTRs). The CMV-specific cell-mediated immunity (CMI) at baseline and at different time points after transplantation was assessed using an interferon γ enzyme-linked immunosorbent spot assay. RESULTS: rATG increased the risk of CMV DNAemia in R+ but not in D+R- KTRs. In R+ CMI-positive (CMI+) patients, the CMV DNAemia rate was higher in rATG-treated than in anti-IL-2RA-treated patients; no difference was observed among R+ CMI-negative (CMI-) patients. Longitudinal follow-up demonstrated a deeper depletion of preformed CMV CMI in R+ rATG-treated patients. CONCLUSIONS: D+R- KTRs have the highest risk of CMV DNAemia, but rATG adds no further risk. Among R+ KTRs, we described 3 groups, the least prone being R+CMI+ KTRs without rATG, then R+CMI+ KTRs with rATG, and finally R+CMI- KTRs. CMV serostatus, baseline CMV-specific CMI, and induction therapy may lead to personalized preventive therapy in further studies.

Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis.

INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.

Markers of graft microvascular endothelial injury may identify harmful donor-specific anti-HLA antibodies and predict kidney allograft loss.

Graft microvasculature is a major target of donor-specific antibodies (DSA) and endothelial damage is direct evidence of antibody-mediated rejection (ABMR). Using immunohistochemistry, we analyzed the expression of three microvascular endothelial activation markers (fascin, vimentin, and hsp47), suggestive of endothelial-to-mesenchymal transition (EndMT) in 351 graft biopsies from 248 kidney recipients, with concomitant screening of circulating antihuman leukocyte antigen (HLA) DSA at the time of the biopsy. The factors associated with EndMT marker expression were DSA and the presence of microvascular inflammation (MI). EndMT expressing grafts had significantly more allograft loss compared to EndMT negative grafts (P < .0001). The expression of EndMT markers positively correlated with anti-HLA DSA class II mean fluorescence intensity (MFI) levels and especially identified DQ and DR antibodies as being more closely associated with microvascular injury. Moreover, only DSA linked to positive EndMT score affected allograft survival, regardless of DSA MFI levels or presence of C4d deposition. Thus, EndMT markers could represent a clinically relevant tool for early identification of ongoing endothelial injury, harmful DSA, and patients at high risk for allograft failure.

Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients.Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay.Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P=0.93). Patients without DSA had a 10-year graft survival of 78%.Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.

T-cell receptor αß+ and CD19+ cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. OBJECTIVE: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αß CD3+ cells from the graft. METHODS: CD3+TCRαß+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. RESULTS: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CONCLUSION: CD3+TCRαß+ and CD19+ cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.

Prognostic value of preoperative anti-thyroglobulin antibody in differentiated thyroid cancer.

CONTEXT: The coexistence of differentiated thyroid cancer (DTC) and thyroid autoimmune disease could represent a better or worse prognosis. This study investigated the prognostic importance of preoperative anti-thyroglobulin antibody (TgAb) in DTC patients. DESIGN AND PATIENTS: This retrospective hospital-cohort study enrolled 1171 consecutive DTC patients with preoperative TgAb data, who underwent total thyroidectomy between January 2006 and December 2011. Clinical parameters studied included demographics, primary tumour characteristics, radioiodine therapy, thyroid function tests, preoperative thyroglobulin (Tg) and TgAb levels, and cancer persistence/recurrence. RESULTS: A total of 254 (21.7%) patients were preoperatively TgAb positive. The percentage positive for thyroid peroxidase (TPO) antibody and lymphocytic thyroiditis was significantly higher in the TgAb-positive group. The TgAb-positive group had a significantly higher rate of lymphatic invasion and lymph node metastasis both overall and in patients without TPOAb and lymphocytic thyroiditis (non-HT group). The mean number of total and central lymph nodes dissected and rate of lateral lymph node dissection were significantly higher in the TgAb-positive group, both overall and in non-HT patients. In regression analysis, preoperative TgAb was an independent risk factor for lateral lymph node metastasis. Over 50.2±14.5 months of follow-up, disease persistence/recurrence was not significantly different between patients with and without TgAb, both overall and in non-HT patients. Preoperative TgAb showed no significant correlation with final disease status. CONCLUSION: Positive preoperative serum TgAb is associated with worse primary tumour characteristics but rarely showed poor prognosis, probably due to more aggressive treatment of these subjects.

Cellular immune profile of kidney transplant patients developing anti-HLA antibodies during childhood.

BACKGROUND: In the field of kidney transplantation, identifying early signatures of humoral rejection is a key challenge. METHODS: We investigated the presence of anti-HLA antibodies and the distribution of lymphocyte subpopulations in 77 kidney-transplanted children and young adults compared to 23 healthy controls. Moreover, we tested whether the presence of anti-HLA antibodies could be related to modification in lymphocyte phenotype. Finally, we correlated the presence of anti-HLA antibodies and specific alteration of lymphocyte subsets with clinical outcomes. RESULTS: In kidney-transplanted children who developed anti-HLA antibodies, we observed an expansion of double-negative B cells (CD19 + CD27-IgD-), indicating premature aging of this compartment. Moreover, we reported signs of impaired B cell regulation, indicated by a higher IL-21R+ B cell frequency associated with an abnormal increase of follicular helper T cells. Finally, a considerable reduction in CD8+ effector T and invariant Natural killer T (NKT) cells was observed. The stability of graft function over time is significantly correlated with the frequency of peripheral effector CD4+ and CD8+ T cells and invariant NKT cells. CONCLUSIONS: This study supports the usefulness of lymphocyte subset as one of a spectrum of early diagnostic tools required to identify patients at risk of developing donor alloimmune response.

ATG-induced accelerated immune senescence: clinical implications in renal transplant recipients.

Persistent ATG-induced CD4(+) T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR -62 patients receiving ATG and 35 receiving anti-CD25 mAb (α-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34(+) hematopoietic progenitor cells (CD34(+) HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased one-year posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57(+) /CD28(-) T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4(+) T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

Interferon Gamma ELISPOT Testing as a Risk-Stratifying Biomarker for Kidney Transplant Injury: Results From the CTOT-01 Multicenter Study.

Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell-depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNγELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNγELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells.

Short-term kinetics of torque teno virus viraemia after induction immunosuppression confirm T lymphocytes as the main replication-competent cells.

Torque teno virus (TTV) is increasingly considered a universal marker of global immune function. The virus is supposed to replicate in lymphocytes, but poor information is available about fluctuations of viraemia after administration of anti-lymphocyte agents. We studied TTV kinetics in a cohort of 70 kidney±pancreas recipients receiving one of two different anti-T-cell induction immunosuppressants. During the first 30 days after anti-T-cell antibody administration, we report kinetics of TTV viraemia compatible with replication in T lymphocytes, and highly dependent on the potency of the anti-T-cell drug administered.

Automated CD34+ cell isolation of peripheral blood stem cell apheresis product.

BACKGROUND AIMS: Immunomagnetic enrichment of CD34+ hematopoietic "stem" cells (HSCs) using paramagnetic nanobead coupled CD34 antibody and immunomagnetic extraction with the CliniMACS plus system is the standard approach to generating T-cell-depleted stem cell grafts. Their clinical beneficence in selected indications is established. Even though CD34+ selected grafts are typically given in the context of a severely immunosuppressive conditioning with anti-thymocyte globulin or similar, the degree of T-cell depletion appears to affect clinical outcomes and thus in addition to CD34 cell recovery, the degree of T-cell depletion critically describes process quality. An automatic immunomagnetic cell processing system, CliniMACS Prodigy, including a protocol for fully automatic CD34+ cell selection from apheresis products, was recently developed. We performed a formal process validation to support submission of the protocol for CE release, a prerequisite for clinical use of Prodigy CD34+ products. METHODS: Granulocyte-colony stimulating factor-mobilized healthy-donor apheresis products were subjected to CD34+ cell selection using Prodigy with clinical reagents and consumables and advanced beta versions of the CD34 selection software. Target and non-target cells were enumerated using sensitive flow cytometry platforms. RESULTS: Nine successful clinical-scale CD34+ cell selections were performed. Beyond setup, no operator intervention was required. Prodigy recovered 74 ± 13% of target cells with a viability of 99.9 ± 0.05%. Per 5 × 10E6 CD34+ cells, which we consider a per-kilogram dose of HSCs, products contained 17 ± 3 × 10E3 T cells and 78 ± 22 × 10E3 B cells. CONCLUSIONS: The process for CD34 selection with Prodigy is robust and labor-saving but not time-saving. Compared with clinical CD34+ selected products concurrently generated with the predecessor technology, product properties, importantly including CD34+ cell recovery and T-cell contents, were not significantly different. The automatic system is suitable for routine clinical application.

Thymoglobulin induction in heart transplantation: patient selection and implications for maintenance immunosuppression.

Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.

In kidney transplant patients, alemtuzumab but not basiliximab/low-dose rabbit anti-thymocyte globulin induces B cell depletion and regeneration, which associates with a high incidence of de novo donor-specific anti-HLA antibody development.

In this single-center matched-cohort study, we evaluated the phenotype of repopulating B cells and its correlation with donor-specific anti-HLA Ab development and long-term graft function in 16 renal transplant recipients and 32 age- and gender-matched controls induced with alemtuzumab or basiliximab (Bas)/low-dose rabbit anti-thymocyte globulin (rATG), respectively. Alemtuzumab, but not Bas/rATG, profoundly depleted peripheral B cells in the first 2 mo posttransplantation. Early posttransplant, naive B cells were significantly depleted, whereas Ag-experienced and memory B cells were partially spared. Transitional B cells transiently increased 2 mo posttransplant. At month 6 posttransplant, pregerminal center B cells emerged, a process promoted by increased BAFF serum levels. Thereafter, B cell counts increased progressively, mainly due to expansion of naive B cells. Conversely, Bas/rATG did not modify the B cell phenotype throughout the follow-up period. Alemtuzumab was associated with a higher incidence of de novo DSA compared with Bas/rATG. DSA development was predicted by changes in the B cell compartment and correlated with worse long-term graft function. Thus, alemtuzumab-induced B cell depletion/reconstitution may promote chronic humoral responses against the graft.

Polyclonal antithymocyte globulin and cardiovascular disease in kidney transplant recipients.

T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)-induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8(+) T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs.

Allogeneic hematopoietic stem cell transplantation in children with aplastic anemia.

The aim of this study was to prospectively investigate the efficacy and safety of fully matched allogeneic hematopoietic stem cell transplants in children with severe aplastic anemia in China. A total of twenty patients with severe aplastic anemia were enrolled in our study. Thirteen cases underwent transplantation with fully human leukocyte antigen (HLA)-matched, granulocyte-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood stem cells (PBSCs) from matching sibling donors. One patient received fully HLA-matched bone marrow from an unrelated donor. Six patients received fully HLA-matched G-CSF-primed PBSCs from unrelated donors. The conditioning regimen included fludarabine, cyclophosphamide, and rabbit anti-thymocyte globulin. Graft-versus-host disease prophylaxis was conducted with cyclosporin A and short-course methotrexate. The median follow-up duration was 3.08 years (range, 0.83-8.41years). The median time of neutrophil recovery (>0.5 x 10(9)/L) was 14 days (range, 10-20 days), and the median time of platelet recovery (>20 x 10(9)/L) was 19 days (range, 14-31 days). The survival rate at the cutoff point of follow-up was 95.0% (19/20). Initial engraftment rate was 95% (19/20). Late graft failure (graft failures occurring 1 year or longer after transplantation) was observed in one patient. Only one patient developed Grade I acute graft-versus-host disease. Two cases suffered from Epstein- Barr virus (EBV)-associated post-transplant lymphoproliferative disorder and remitted after treatment with rituximab. One patient was diagnosed with hyperthyroidism 2.5 years after transplantation. Our study indicated that allogeneic hematopoietic stem cell transplantation is an effective and safe treatment for children with severe aplastic anemia in China.

Calcineurin inhibitors in HLA-identical living related donor kidney transplantation.

BACKGROUND: Given the nephrotoxicity of calcineurin inhibitors (CNIs), we asked whether their addition improved living related donor (LRD) human leukocyte antigen (HLA) identical kidney transplant recipient outcomes. METHODS: We performed a comprehensive literature review and a single-center study comparing patient survival (PS) and graft survival (GS) of LRD HLA-identical kidney transplants for three different immunosuppression eras: Era 1 (up to 1984): anti-lymphocyte globulin (ALG) induction and maintenance immunosuppression with prednisone and azathioprine (AZA) (n = 114); Era 2a (1984-99): CNI added; evolution from ALG to thymoglobulin; AZA to mycophenolate (n = 262). Era 2b (1999-2011): rapid discontinuation of prednisone (thymoglobulin induction, CNI and mycophenolate) in recipients having first or second transplant and not previously on prednisone (n = 77). RESULTS: Demographics differed by era: recipient (P < 0.0001) and donor age (P < 0.0001) increased and the proportion of Caucasian donors (P = 0.02) and recipients (P = 0.003) decreased with each advancing era. There was no significant difference in PS (P = 0.6); cause of death (P = 0.5); death-censored GS (P = 0.8) or graft loss from acute rejection by era. Graft loss from chronic allograft nephropathy (P = 0.02) and hypertension (P = 0.005) were greater in the CNI eras. There were no significant differences in the 1/creatinine slopes between eras for the first (P = 0.6), second (P = 0.9) or >2 years post-transplant (P = 0.4). Literature review revealed no clear benefits for CNI in these human leukocyte antigen (HLA) identical LRD graft recipients. CONCLUSIONS: This study confirmed that there are no benefits of CNIs for HLA-identical LRD recipients. Moreover, we did find evidence of potential harm. Thus, monotherapy or early discontinuation of CNI should be given consideration in these patients.

First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation.

BACKGROUND: Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti- N -glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models. METHODS: This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1. In an ascending dose cohort (n = 5), a primary kidney transplant recipient at low immunologic risk (panel reactive antibody [PRA] < 20%), received LIS1 for 5 d at either 0.6, 1, 3, 6, or 8 mg/kg. After each patient completed treatment, the data safety monitoring board approved respective dose escalation. In the therapeutic dose cohort (n = 5) in patients with PRA <50% without donor specific antibodies, 2 patients received 8 mg/kg and 3 patients 10 mg/kg. RESULTS: CD3 + T cell depletion <100/mm 3 at day 2 was observed in all patients who received 6, 8, and 10 mg/kg of LIS1. The terminal half-life of LIS1 was 33.7 d with linearity in its disposition. Lymphocyte repopulation was fast and pretransplant lymphocyte subpopulation counts recovered within 2-4 wk. LIS1 was well tolerated, neither cytokine release syndrome nor severe thrombocytopenia or leukopenia were noticed. Antibodies to LIS1 were not detected. CONCLUSIONS: In this first-in-human trial, genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T cell depletion in low- and medium-risk kidney transplant recipients.

First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation.

BACKGROUND: Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti- N -glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models. METHODS: This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1. In an ascending dose cohort (n = 5), a primary kidney transplant recipient at low immunologic risk (panel reactive antibody [PRA] < 20%), received LIS1 for 5 d at either 0.6, 1, 3, 6, or 8 mg/kg. After each patient completed treatment, the data safety monitoring board approved respective dose escalation. In the therapeutic dose cohort (n = 5) in patients with PRA <50% without donor specific antibodies, 2 patients received 8 mg/kg and 3 patients 10 mg/kg. RESULTS: CD3 + T cell depletion <100/mm 3 at day 2 was observed in all patients who received 6, 8, and 10 mg/kg of LIS1. The terminal half-life of LIS1 was 33.7 d with linearity in its disposition. Lymphocyte repopulation was fast and pretransplant lymphocyte subpopulation counts recovered within 2-4 wk. LIS1 was well tolerated, neither cytokine release syndrome nor severe thrombocytopenia or leukopenia were noticed. Antibodies to LIS1 were not detected. CONCLUSIONS: In this first-in-human trial, genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T cell depletion in low- and medium-risk kidney transplant recipients.

Reduced toxicity conditioning and allogeneic stem cell transplantation in adults using fludarabine, carmustine, melphalan, and antithymocyte globulin: outcomes depend on disease risk index but not age, comorbidity score, donor type, or human leukocyte antigen mismatch.

Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient- and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health-defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI.