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Christian P. Larsen - One of the best experts on this subject based on the ideXlab platform.

  • optimization of de novo Belatacept based immunosuppression administered to renal transplant recipients
    American Journal of Transplantation, 2021
    Co-Authors: Allan D Kirk, Christian P. Larsen, Flavio Vincenti, Antoine Durrbach, David Wojciechowski, Mandy L Ford, Andrew B Adams, David A Hildeman, Steve E Woodle
    Abstract:

    Kidney transplant recipients administered Belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved Belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo Belatacept-based maintenance regimens. Steroid-sparing, Belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with Belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative Belatacept-based regimen for minimizing early cellular AR occurrence.

  • cmv high risk status and posttransplant outcomes in kidney transplant recipients treated with Belatacept
    American Journal of Transplantation, 2021
    Co-Authors: Geeta Karadkhele, Idelberto R Badell, Thomas C Pearson, Julien Hogan, Wairimu Magua, Weiwen Zhang, Aneesh K Mehta, Marshall Lyon, Stephen O Pastan, Christian P. Larsen
    Abstract:

    Introduction Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of Belatacept on CMV infection remains understudied. In this study, we assessed the impact of Belatacept on patient and graft survivals. Methods CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under Belatacept vs tacrolimus were compared. Results Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 Belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with Belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. Conclusion Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with Belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

  • the impact of Belatacept on third party hla alloantibodies in highly sensitized kidney transplant recipients
    American Journal of Transplantation, 2020
    Co-Authors: Ronald F Parsons, Christian P. Larsen, Idelberto R Badell, Arslan Zahid, Shalini Bumb, Hannah Decker, Harold C Sullivan, Frances Eunhyung Lee, Mandy L Ford, Thomas C Pearson
    Abstract:

    Recent evidence suggests that Belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of Belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on Belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in Belatacept-treated patients compared to controls who did not receive Belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant Belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest Belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

  • posttransplant reduction in preexisting donor specific antibody levels after Belatacept versus cyclosporine based immunosuppression post hoc analyses of benefit and benefit ext
    American Journal of Transplantation, 2018
    Co-Authors: Robert A Bray, Robert M Townsend, H U Meierkriesche, M Polinsky, L Yang, Howard Gebel, Mustimbo Roberts, Christian P. Larsen
    Abstract:

    BENEFIT and BENEFIT-EXT were phase III studies of cytotoxic T-cell crossmatch-negative kidney transplant recipients randomized to Belatacept more intense (MI)-based, Belatacept less intense (LI)-based, or cyclosporine-based immunosuppression. Following study completion, presence/absence of HLA-specific antibodies was determined centrally via solid-phase flow cytometry screening. Stored sera from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of donor-specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present. The effect of Belatacept-based and cyclosporine-based immunosuppression on MFI was explored post hoc in patients with preexisting DSAs enrolled to BENEFIT and BENEFIT-EXT. In BENEFIT, preexisting DSAs were detected in 4.6%, 4.9%, and 6.3% of Belatacept MI-treated, Belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 6.0%, 5.7%, and 9.2%. In both studies, most preexisting DSAs were of class I specificity. Over the first 24 months posttransplant, a greater proportion of preexisting DSAs in Belatacept-treated versus cyclosporine-treated patients exhibited decreases or no change in MFI. MFI decline was more apparent with Belatacept MI-based versus Belatacept LI-based immunosuppression in both studies and more pronounced in BENEFIT-EXT versus BENEFIT. Although derived post hoc, these data suggest that Belatacept-based immunosuppression decreases preexisting DSAs more effectively than cyclosporine-based immunosuppression.

  • de novo donor specific antibodies in Belatacept treated vs cyclosporine treated kidney transplant recipients post hoc analyses of the randomized phase iii benefit and benefit ext studies
    American Journal of Transplantation, 2018
    Co-Authors: Robert A Bray, Robert M Townsend, H U Meierkriesche, M Polinsky, L Yang, Howard Gebel, Mustimbo Roberts, Christian P. Larsen
    Abstract:

    Donor-specific antibodies (DSAs) are associated with an increased risk of antibody-mediated rejection and graft failure. In BENEFIT and BENEFIT-EXT, kidney-transplant recipients were randomized to receive Belatacept more intense (MI)-based, Belatacept less intense (LI)-based, or cyclosporine-based immunosuppression for up to 7 years (84 months). The presence/absence of HLA-specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid-phase flow-cytometry screening. Samples from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of Belatacept MI-treated, Belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan-Meier analysis, de novo DSA incidence was significantly lower in Belatacept-treated vs cyclosporine-treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, Belatacept-based immunosuppression was associated with numerically lower MFI vs cyclosporine-based immunosuppression. Although derived post hoc, these data suggest that Belatacept-based immunosuppression suppresses de novo DSA development more effectively than cyclosporine-based immunosuppression.

Flavio Vincenti - One of the best experts on this subject based on the ideXlab platform.

  • optimization of de novo Belatacept based immunosuppression administered to renal transplant recipients
    American Journal of Transplantation, 2021
    Co-Authors: Allan D Kirk, Christian P. Larsen, Flavio Vincenti, Antoine Durrbach, David Wojciechowski, Mandy L Ford, Andrew B Adams, David A Hildeman, Steve E Woodle
    Abstract:

    Kidney transplant recipients administered Belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved Belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo Belatacept-based maintenance regimens. Steroid-sparing, Belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with Belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative Belatacept-based regimen for minimizing early cellular AR occurrence.

  • the impact of Belatacept on the phenotypic heterogeneity of renal t cell mediated alloimmune response the critical role of maintenance treatment and inflammatory load
    Clinical Transplantation, 2020
    Co-Authors: Dejan Dobi, Flavio Vincenti, Sindhu Chandran, John R Greenland, Christopher N Bowman, Adeline Chen, Henrik Junger, Zoltan Laszik
    Abstract:

    Belatacept offers superior long-term outcome relative to calcineurin inhibitor (CNI)-based immunosuppression. However, the higher frequency of early T cell-mediated rejection (TCMR) in Belatacept-treated patients hampered the widespread adoption of costimulation blockade. Here, we applied gene expression analysis and whole-slide inflammatory cell quantification to assess the impact of Belatacept on intragraft immune signature. We studied formalin-fixed, paraffin-embedded renal biopsies from 92 patients stratified by histopathologic diagnosis (TCMR, borderline changes, or normal) and immunosuppression regimen (Belatacept, CNI). An interaction model was built to explore maintenance treatment-dependent expression level changes of immune response-related genes across diagnostic categories of normal, borderline changes, and TCMR. Ninety-one percent of genes overexpressed in TCMR showed significant correlation with whole section inflammatory load. There were 27 genes that had a positive association with Belatacept treatment. These were mostly related to myeloid cells and innate immunity. Genes negatively associated with costimulation blockade (n = 14) could be linked to B-cell differentiation and proliferation. We concluded that expression levels of genes characteristic of TCMR are strongly interconnected with quantitative changes of the biopsy inflammatory load. Our results might suggest differential involvement of the innate immune system, and an altered B-cell engagement during TCMR in Belatacept-treated patients relative to CNI-treated referents.

  • outcomes at 7 years post transplant in black vs nonblack kidney transplant recipients administered Belatacept or cyclosporine in benefit and benefit ext
    Clinical Transplantation, 2018
    Co-Authors: Sander Florman, Flavio Vincenti, Antoine Durrbach, Lionel Rostaing, Barbara A Bresnahan, V D Garcia, Marwan S Abouljoud, Laura L Mulloy, Kim Rice, Carlos Zayas
    Abstract:

    Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to Belatacept more intense-based, Belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, Belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); Belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for Belatacept-treated vs cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for Belatacept, but declined for cyclosporine. Outcomes were similar in Belatacept-treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.

  • ten year outcomes in a randomized phase ii study of kidney transplant recipients administered Belatacept 4 weekly or 8 weekly
    American Journal of Transplantation, 2017
    Co-Authors: Flavio Vincenti, Gilles Blancho, Antoine Durrbach, G Grannas, J Grinyo, H U Meierkriesche, M Polinsky, L Yang, Christian P. Larsen
    Abstract:

    In the phase II IM103-100 study, kidney transplant recipients were first randomized to Belatacept more-intensive-based (n = 74), Belatacept less-intensive-based (n = 71), or cyclosporine-based (n = 73) immunosuppression. At 3-6 months posttransplant, Belatacept-treated patients were re-randomized to receive Belatacept every 4 weeks (4-weekly, n = 62) or every 8 weeks (8-weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine-based immunosuppression. Cumulative rates of biopsy-proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for Belatacept more-intensive, Belatacept less-intensive, and cyclosporine, respectively (Belatacept more-intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47-1.92; P = .89; Belatacept less-intensive vs cyclosporine: HR = 1.61; 95% CI 0.85-3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for Belatacept 4-weekly, Belatacept 8-weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (Belatacept 4-weekly vs cyclosporine: HR = 1.06, 95% CI 0.35-3.17, P = .92; Belatacept 8-weekly vs cyclosporine: HR = 2.00, 95% CI 0.75-5.35, P = .17). Renal function trends were estimated using a repeated-measures model. Estimated mean GFR values at year 10 for Belatacept 4-weekly, Belatacept 8-weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m2, respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2-fold higher in patients administered Belatacept every 8 weeks vs every 4 weeks.

  • retrospective evaluation of the efficacy and safety of Belatacept with thymoglobulin induction and maintenance everolimus a single center clinical experience
    Clinical Transplantation, 2017
    Co-Authors: David Wojciechowski, Sindhu Chandran, Minnie M Sarwal, Joshua Y C Yang, Flavio Vincenti
    Abstract:

    Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that Belatacept with low dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post-transplant ± corticosteroids would improve efficacy and maintain safety. Retrospective single center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1 year eGFR was 61.4 (SD 18.4) mL/min/1.73 m2. There were 5 acute cellular rejections (11.4%) and occurred in patients who had changed from everolimus to mycophenolate mofetil due to side effects. 32% developed BK viremia and 12% developed CMV viremia. There were no cases of PTLD. A novel Belatacept regimen with rATG induction and maintenance everolimus demonstrated a low acute rejection rate and maintained an excellent 1-year eGFR. This article is protected by copyright. All rights reserved.

Allan D Kirk - One of the best experts on this subject based on the ideXlab platform.

  • optimization of de novo Belatacept based immunosuppression administered to renal transplant recipients
    American Journal of Transplantation, 2021
    Co-Authors: Allan D Kirk, Christian P. Larsen, Flavio Vincenti, Antoine Durrbach, David Wojciechowski, Mandy L Ford, Andrew B Adams, David A Hildeman, Steve E Woodle
    Abstract:

    Kidney transplant recipients administered Belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved Belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo Belatacept-based maintenance regimens. Steroid-sparing, Belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with Belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative Belatacept-based regimen for minimizing early cellular AR occurrence.

  • kidney transplantation using alemtuzumab Belatacept and sirolimus five year follow up
    American Journal of Transplantation, 2020
    Co-Authors: Robin Schmitz, Aneesh K Mehta, Antonio Guasch, Ada Ghali, Zachary W Fitch, Allan D Kirk
    Abstract:

    Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by Belatacept and sirolimus maintenance therapy. Patients were offered weaning to Belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to Belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naive cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naive cells susceptible to control with CoB, and permits control of rejection with Belatacept monotherapy in selected patients.

  • tailored use of Belatacept in adolescent kidney transplantation
    American Journal of Transplantation, 2020
    Co-Authors: Kathryn H Blew, Allan D Kirk, Annabelle N Chua, John W Foreman, Rasheed Gbadegesin, Annette M Jackson, Shashi Nagaraj, Rebecca E Sadun, Del Wigfall, Eileen Tsai Chambers
    Abstract:

    Adolescent transplant recipients are at risk for nonadherence, development of de novo donor-specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor-based regimens in adults; however, its use in children is scant. Three adolescents were initiated on Belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid-free Belatacept and sirolimus for two patients. One patient was initially maintained steroid-free on Belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy-proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m2 at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid-responsive acute cellular rejection. Belatacept-based regimens can be tailored for adolescent recipients with good short-term clinical outcomes.

  • Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long term renal allograft function
    American Journal of Transplantation, 2017
    Co-Authors: Andrew B Adams, Antonio Guasch, Nicole A Turgeon, J Goldstein, Cristen Garrett, Rebecca Zhang, Rachel E Patzer, Kenneth A Newell, Ashtar Chami, Allan D Kirk
    Abstract:

    Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of Belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized Belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with Belatacept (n = 535) with a historical cohort receiving a tacrolimus-based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low-intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with Belatacept was associated with superior estimated GFR (Belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade-based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor-free immunosuppression.

  • postdepletion lymphocyte reconstitution during Belatacept and rapamycin treatment in kidney transplant recipients
    American Journal of Transplantation, 2016
    Co-Authors: Kannan P Samy, Allan D Kirk, Aneesh K Mehta, Antonio Guasch, Sue I Mead, Ada Ghali, Linda Stempora
    Abstract:

    Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when Belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, Belatacept and rapamycin (ABR) regimen controls Belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naive cells, notably diminished in Belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with Belatacept monotherapy.

Antoine Durrbach - One of the best experts on this subject based on the ideXlab platform.

  • optimization of de novo Belatacept based immunosuppression administered to renal transplant recipients
    American Journal of Transplantation, 2021
    Co-Authors: Allan D Kirk, Christian P. Larsen, Flavio Vincenti, Antoine Durrbach, David Wojciechowski, Mandy L Ford, Andrew B Adams, David A Hildeman, Steve E Woodle
    Abstract:

    Kidney transplant recipients administered Belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved Belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo Belatacept-based maintenance regimens. Steroid-sparing, Belatacept-based immunosuppression (following T cell-depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with Belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative Belatacept-based regimen for minimizing early cellular AR occurrence.

  • outcomes at 7 years post transplant in black vs nonblack kidney transplant recipients administered Belatacept or cyclosporine in benefit and benefit ext
    Clinical Transplantation, 2018
    Co-Authors: Sander Florman, Flavio Vincenti, Antoine Durrbach, Lionel Rostaing, Barbara A Bresnahan, V D Garcia, Marwan S Abouljoud, Laura L Mulloy, Kim Rice, Carlos Zayas
    Abstract:

    Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to Belatacept more intense-based, Belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, Belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); Belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for Belatacept-treated vs cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for Belatacept, but declined for cyclosporine. Outcomes were similar in Belatacept-treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.

  • ten year outcomes in a randomized phase ii study of kidney transplant recipients administered Belatacept 4 weekly or 8 weekly
    American Journal of Transplantation, 2017
    Co-Authors: Flavio Vincenti, Gilles Blancho, Antoine Durrbach, G Grannas, J Grinyo, H U Meierkriesche, M Polinsky, L Yang, Christian P. Larsen
    Abstract:

    In the phase II IM103-100 study, kidney transplant recipients were first randomized to Belatacept more-intensive-based (n = 74), Belatacept less-intensive-based (n = 71), or cyclosporine-based (n = 73) immunosuppression. At 3-6 months posttransplant, Belatacept-treated patients were re-randomized to receive Belatacept every 4 weeks (4-weekly, n = 62) or every 8 weeks (8-weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine-based immunosuppression. Cumulative rates of biopsy-proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for Belatacept more-intensive, Belatacept less-intensive, and cyclosporine, respectively (Belatacept more-intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47-1.92; P = .89; Belatacept less-intensive vs cyclosporine: HR = 1.61; 95% CI 0.85-3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for Belatacept 4-weekly, Belatacept 8-weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (Belatacept 4-weekly vs cyclosporine: HR = 1.06, 95% CI 0.35-3.17, P = .92; Belatacept 8-weekly vs cyclosporine: HR = 2.00, 95% CI 0.75-5.35, P = .17). Renal function trends were estimated using a repeated-measures model. Estimated mean GFR values at year 10 for Belatacept 4-weekly, Belatacept 8-weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m2, respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2-fold higher in patients administered Belatacept every 8 weeks vs every 4 weeks.

  • long term outcomes in Belatacept versus cyclosporine treated recipients of extended criteria donor kidneys final results from benefit ext a phase iii randomized study
    American Journal of Transplantation, 2016
    Co-Authors: Antoine Durrbach, Sander Florman, M Polinsky, Thomas Wekerle, Lionel Rostaing, Arthur J Matas, Jose Osmar Medina Pestana, M Del Carmen Rial, Dirk Kuypers, H U Meierkriesche
    Abstract:

    In the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), extended criteria donor kidney recipients were randomized to receive Belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, Belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 Belatacept MI-treated, 138 of 175 Belatacept LI-treated and 108 of 184 cyclosporine-treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625-1.339; p = 0.65) for Belatacept MI versus cyclosporine and 0.927 (95% CI 0.634-1.356; p = 0.70) for Belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for Belatacept MI, Belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m2 were 0.754 (95% CI 0.536-1.061; p = 0.10) for Belatacept MI versus cyclosporine and 0.706 (95% CI 0.499-0.998; p = 0.05) for Belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of Belatacept- and cyclosporine-based treatment were similar. De novo donor-specific antibody incidence was lower for Belatacept (p ≤ 0.0001). Relative to cyclosporine, Belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.

  • survenue d un cas de lemp chez un patient greffe renal traite par Belatacept
    Revue Neurologique, 2016
    Co-Authors: Marion Quirins, Antoine Durrbach, Celine Labeyrie, Manon Dekeyser, Helene Francois, Jacques Gasnault, D L Adams
    Abstract:

    Introduction La leucoencephalopathie multifocale progressive [LEMP] est une infection opportuniste rare redoutee chez les patients traites par natalizumab. Nous decrivons le cas d’une LEMP survenue chez un patient traite par Belatacept. Observation Un patient de 68 ans, transplante renal en 2013 et traite par Belatacept, mycophenolate mofetil (MM) et prednisone aux posologies habituelles, presenta en mai 2015 un changement progressif de comportement avec une apathie et des episodes confusionnels transitoires. Il presenta le mois suivant une faiblesse du membre superieur droit d’installation brutale et une amputation du champ visuel droit sans anomalie visible a priori sur un premier scanner cerebral. L’IRM cerebrale realisee quelques jours plus tard mis en evidence une lesion de substance blanche, fronto-parietale gauche sans systematisation vasculaire, en hypersignal diffusion et Flair et en hyposignal T1, non rehaussee par le gadolinium. Le diagnostic LEMP fut confirme par une PCR JC positive dans le LCR. Le Belatacept fut immediatement arrete et deux echanges plasmatiques furent rapidement realises. Le patient presentait alors 275 CD4+ circulants. Le MM fut arrete le 22/06 et devant l’evolution progressivement defavorable, 3 injections d’interleukine-7 furent administrees. La fonction renale resta stable tout au long de l’hospitalisation mais le patient s’aggrava progressivement sur le plan neurologique et deceda 10 semaines apres le diagnostic. Discussion Le Belatacept est un anticorps humanise anti-CTLA4 non nephrotoxique qui inhibe l’activation lymphocytaire T en inactivant la co-stimulation lymphocytes T/cellule presentatrice d’antigene. Sous ce traitement, seuls deux cas de LEMP ont ete decrits dans la base de donnees anglo-saxonnes de pharmacovigilance. Les patients recevaient des posologies superieures a celles actuellement recommandees contrairement a notre patient. Conclusion La survenue d’une LEMP reste rare sous Belatacept mais sa gravite et l’absence de ressource therapeutique, doivent la faire rechercher en cas de survenue de signes neurologiques rapidement progressifs.

Josep M Grinyo - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy outcomes 3 years after switching to Belatacept from a calcineurin inhibitor in kidney transplant recipients results from a phase 2 randomized trial
    American Journal of Kidney Diseases, 2017
    Co-Authors: Josep M Grinyo, Flavio Vincenti, Steven M Steinberg, Josefina Alberu, Georgy Nainan, M Rial, R C Manfro, Charlotte Jonesburton, Nassim Kamar
    Abstract:

    Background In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to Belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. Study Design 36-month follow-up of the intention-to-treat population. Setting & Participants CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m 2 ). Interventions At 6 to 36 months posttransplantation, patients were randomly assigned to switch to Belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). Outcomes Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. Measurements Treatment exposure−adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. Results Serious adverse events occurred in 33 (39%) Belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure−adjusted incidence rates for serious infections (Belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the Belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m 2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for Belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P =0.2). HR for the comparison of Belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P =0.9). Limitations Exploratory post hoc analysis with a small sample size. Conclusions Switching patients from a CNI to Belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

  • long term Belatacept exposure maintains efficacy and safety at 5 years results from the long term extension of the benefit study
    American Journal of Transplantation, 2013
    Co-Authors: Lionel Rostaing, Flavio Vincenti, Josep M Grinyo, K M Rice, Barbara A Bresnahan, Steven M Steinberg, S Gang, L E Gaite, Mariechristine Moal, G Mondragonramirez
    Abstract:

    The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of Belatacept or cyclosporine A (CsA). The 5-year results of the long-term extension (LTE) cohort are reported. A total of 456 (68.5% of intent-to-treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of Belatacept MI, Belatacept LI and CsA patients, respectively; graft loss occurred in 0% Belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero Belatacept MI, one Belatacept LI and one CsA. Rates for infections and malignancies for Months 36–60 were generally similar across Belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m2) at Month 60 was 74 for Belatacept MI, 76 for Belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in Belatacept-treated patients in the early posttransplant period was sustained through 5 years.

  • improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to Belatacept 2 year results from the long term extension of a phase ii study
    Transplant International, 2012
    Co-Authors: Josep M Grinyo, Flavio Vincenti, Steven M Steinberg, Josefina Alberu, F L C Contieri, Roberto Ceratti Manfro, Guillermo Mondragon, Georgy Nainan, M Rial, Yuping Dong
    Abstract:

    Summary Kidney transplant recipients who switched from a calcineurin inhibitor (CNI) to Belatacept demonstrated higher calculated glomerular filtration rates (cGFRs) at 1 year in a Phase II study. This report addresses whether improvement was sustained at 2 years in the long-term extension (LTE). Patients receiving cyclosporine or tacrolimus were randomized to switch to Belatacept or continue CNI. Of 173 randomized patients, 162 completed the 12-month main study and entered the LTE. Two patients (n = 1 each group) had graft loss between Years 1–2. At Year 2, mean cGFR was 62.0 ml/min (Belatacept) vs. 55.4 ml/min (CNI). The mean change in cGFR from baseline was +8.8 ml/min (Belatacept) and +0.3 ml/min (CNI). Higher cGFR was observed in patients switched from either cyclosporine (+7.8 ml/min) or tacrolimus (+8.9 ml/min). The frequency of acute rejection in the LTE cohort was comparable between the Belatacept and CNI groups by Year 2. All acute rejection episodes occurred during Year 1 in the Belatacept patients and during Year 2 in the CNI group. There were more non-serious mucocutaneous fungal infections in the Belatacept group. Switching to a Belatacept-based regimen from a CNI-based regimen resulted in a continued trend toward improved renal function at 2 years after switching.

  • Belatacept from rational design to clinical application
    Transplant International, 2012
    Co-Authors: Thomas Wekerle, Josep M Grinyo
    Abstract:

    Gradually improved immunosuppression has contributed significantly to the progress achieved in transplantation medicine so far. Nevertheless, current drug regimens are associated with late graft loss--in particular as a result of immunologic damage or drug toxicity--and substantial morbidity. Recently, the costimulation blocker Belatacept (marketed under the name Nulojix®) has been approved for immunosuppression in renal transplantation. Belatacept (a mutated version of CTLA4Ig) is a fusion protein rationally designed to block CD28, a critical activating receptor on T cells, by binding and saturating its ligands B7-1 and B7-2. In phase II and III trials, Belatacept was compared with cyclosporine (in combination with basiliximab, MMF, and steroids). Advantages observed with Belatacept include superior graft function, preservation of renal structure and improved cardiovascular risk profile. Concerns associated with Belatacept are a higher frequency of cellular rejection episodes and more post-transplant lymphoproliferative disorder (PTLD) cases especially in EBV seronegative patients, who should be excluded from Belatacept-based regimens. Thus, after almost three decades of calcineurin inhibitors as mainstay of immunosuppression, Belatacept offers a potential alternative. In this article, we will provide an overview of Belatacept's preclinical development and will discuss the available evidence from clinical trials.

  • Belatacept based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients benefit and benefit ext studies
    Transplantation, 2011
    Co-Authors: Yves Vanrenterghem, Christian P. Larsen, Antoine Durrbach, Josep M Grinyo, Philippe Lang, Barbara A Bresnahan, Josep M Campistol, Hanshellmut Neumayer, Eduardo Mancillaurrea, Jose Osmar Medina Pestana
    Abstract:

    Background. Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants. Methods. Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of Belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed Belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT). Results. A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P≤0.002) across both studies at month 12. Non-HDL cholesterol was lower in the Belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the Belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the Belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA). Conclusions. At month 12, Belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of Belatacept will continue to be assessed over the 3-year trials.