Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance

Author(s):  
Dixon Kaufman ◽  
E. Steve Woodle ◽  
Adele Shields ◽  
John Leone ◽  
Arthur Matas ◽  
...  

Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multi-center study. MethodsAll kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized to 1:1:1 to receive belatacept with alemtuzumab induction, belatacept with rabbit antithymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite endpoint consisted of death, kidney allograft loss, or an MDRD calculated eGFR of <45 ml/min/1.73m2 at 2 years. ResultsThe composite endpoint was observed for 11/107 (10%) participants assigned to belatacept/alemtuzumab, 13/104 (13%) assigned to belatacept /rATG, and 21/105 (21%) assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.99: belatacept/rATG vs tacrolimus/rATG p = 0.66). Patient and graft survival rates were similar between all groups. eGFR <45 ml/min/1.73m2 was observed for 9/107 (8%) participants assigned to belatacept/alemtuzuab, 8/104 (8%) participants assigned to belatacept/rATG, and 20/105 (19%) participants assigned to tacrolimus/rATG (p<0.05 for each belatacept group vs tacrolimus/rATG). Biopsy-proven acute rejection was observed for 20/107 (19%) participants assigned to belatacept/alemtuzuab, 26/104 (25%) participants assigned to belatacept/rATG, and 7/105 (7%) participants assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.006: belatacept/rATG vs tacrolimus/rATG p < 0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin based immunosuppression. ConclusionsOverall two-year outcomes were similar comparing maintenance immunosuppression based on belatacept versus tacrolimus, each protocol with rapid steroid withdrawal. The incidence of eGFR <45 ml/min/1.73m2 was significantly lower but the incidence of biopsy proven acute rejection significantly higher with belatacept compared with tacrolimus.

2002 ◽  
Vol 13 (1) ◽  
pp. 234-241
Author(s):  
Andrew M. Herzenberg ◽  
John S. Gill ◽  
Ognjenka Djurdjev ◽  
Alex B. Magil

ABSTRACT. Peritubular capillary deposition of C4d has been demonstrated to be associated with both acute humoral and vascular rejection and increased graft loss. Whether it is an independent predictor of long-term graft survival rates is uncertain. The biopsies (n = 126) from all patients (n = 93) with a tissue diagnosis of acute rejection that were performed between July 1, 1995, and December 31, 1997, were classified according to Cooperative Clinical Trials in Transplantation (CCTT) criteria. Fresh frozen tissue was immunostained for C4d. There were 58 patients with CCTT type I (interstitial) rejection and 35 with CCTT type II (vascular) rejection. For 34 patients, at least one biopsy exhibited peritubular C4d deposition (C4d+ group). The C4d+ group had proportionately more female patients (P = 0.003), more patients with high (>30%) panel-reactive antibody levels (P = 0.024), more patients with resistance to conventional antirejection therapy (P = 0.010), and fewer patients with postrejection hypertension (P = 0.021) and exhibited a greater rate of graft loss (38 versus 7%, P = 0.001). Peritubular C4d deposition was associated with significantly lower graft survival rates in the CCTT type I rejection group (P = 0.003) and the CCTT type II rejection group (P = 0.003). Multivariate analyses demonstrated that peritubular C4d deposition (P = 0.0002), donor age (P = 0.0002), cold ischemic time (P = 0.0211), and HLA matches (P = 0.0460) were significant independent determinants of graft survival rates. Peritubular C4d deposition is a significant predictor of graft survival rates and is independent of histologic rejection type and a variety of clinical prognostic factors.


Author(s):  
David Wojciechowski ◽  
Alexander Wiseman

The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5–8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor–based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.


2020 ◽  
Vol 104 (11) ◽  
pp. 2403-2414
Author(s):  
Alicia B. Lichvar ◽  
Simon Tremblay ◽  
Abbie D. Leino ◽  
Adele R. Shields ◽  
Michael A. Cardi ◽  
...  

2012 ◽  
Vol 94 (10S) ◽  
pp. 979
Author(s):  
D. J. Conti ◽  
B. J. Conti ◽  
R. Dellehunt ◽  
N. Chandolias ◽  
N. Siparsky ◽  
...  

2012 ◽  
Vol 15 (1) ◽  
pp. 4 ◽  
Author(s):  
David M. Holzhey ◽  
William Shi ◽  
A. Rastan ◽  
Michael A. Borger ◽  
Martin H�nsig ◽  
...  

<p><b>Introduction:</b> The goal of this study was to compare the short- and long-term outcomes after aortic valve (AV) surgery carried out via standard sternotomy/partial sternotomy versus transapical transcatheter AV implantation (taTAVI).</p><p><b>Patients and Methods:</b> All 336 patients who underwent taTAVI between 2006 and 2010 were compared with 4533 patients who underwent conventional AV replacement (AVR) operations between 2001 and 2010. Using propensity score matching, we identified and consecutively compared 2 very similar groups of 167 patients each. The focus was on periprocedural complications and long-term survival.</p><p><b>Results:</b> The 30-day mortality rate was 10.8% and 8.4% (<i>P</i> = .56) for the conventional AVR patients and the TAVI patients, respectively. The percentages of postoperative pacemaker implantations (15.0% versus 6.0%, <i>P</i> = .017) and cases of renal failure requiring dialysis (25.7% versus 12.6%, <i>P</i> = .004) were higher in the TAVI group. Kaplan-Meier curves diverged after half a year in favor of conventional surgery. The estimated 3-year survival rates were 53.5% � 5.7% (TAVI) and 66.7% � 0.2% (conventional AVR).</p><p><b>Conclusion:</b> Our study shows that even with all the latest successes in catheter-based AV implantation, the conventional surgical approach is still a very good treatment option with excellent long-term results, even for older, high-risk patients.</p>


2011 ◽  
Vol 14 (4) ◽  
pp. 237 ◽  
Author(s):  
Ferdinand Vogt ◽  
Anke Kowert ◽  
Andres Beiras-Fernandez ◽  
Martin Oberhoffer ◽  
Ingo Kaczmarek ◽  
...  

<p><b>Objective:</b> The use of homografts for aortic valve replacement (AVR) is an alternative to mechanical or biological valve prostheses, especially in younger patients. This retrospective comparative study evaluated our single-center long-term results, with a focus on the different origins of the homografts.</p><p><b>Methods:</b> Since 1992, 366 adult patients have undergone AVR with homografts at our center. We compared 320 homografts of aortic origin and 46 homografts of pulmonary origin. The grafts were implanted via either a subcoronary technique or the root replacement technique. We performed a multivariate analysis to identify independent factors that influence survival. Freedom from reintervention and survival rates were calculated as cumulative events according to the Kaplan-Meier method, and differences were tested with the log-rank test.</p><p><b>Results:</b> Overall mortality within 1 year was 6.5% (21/320) in the aortic graft group and 17.4% (8/46) in the pulmonary graft group. In the pulmonary graft group, 4 patients died from valve-related complications, 1 patient died after additional heterotopic heart transplantation, and 1 patient who entered with a primary higher risk died from a prosthesis infection. Two patients died from non-valve-related causes. During the long-term follow-up, the 15-year survival rate was 79.9% for patients in the aortic graft group and 68.7% for patients in the pulmonary graft group (<i>P</i> = .049). The rate of freedom from reoperation was 77.7% in the aortic graft group and 57.4% in the pulmonary graft group (<i>P</i> < .001). The reasons for homograft explantation were graft infections (aortic graft group, 5.0%; pulmonary graft group, 6.5%) and degeneration (aortic graft group, 7.5%; pulmonary graft group, 32.6%).</p><p><b>Conclusion:</b> Our study demonstrated superior rates of survival and freedom from reintervention after AVR with aortic homografts. Implantation with a pulmonary graft was associated with a higher risk of redo surgery, owing to earlier degenerative alterations.</p>


2015 ◽  
Vol 156 (45) ◽  
pp. 1824-1833 ◽  
Author(s):  
Árpád Illés ◽  
Ádám Jóna ◽  
Zsófia Simon ◽  
Miklós Udvardy ◽  
Zsófia Miltényi

Introduction: Hodgkin lymphoma is a curable lymphoma with an 80–90% long-term survival, however, 30% of the patients develop relapse. Only half of relapsed patients can be cured with autologous stem cell transplantation. Aim: The aim of the authors was to analyze survival rates and incidence of relapses among Hodgkin lymphoma patients who were treated between January 1, 1980 and December 31, 2014. Novel therapeutic options are also summarized. Method: Retrospective analysis of data was performed. Results: A total of 715 patients were treated (382 men and 333 women; median age at the time of diagnosis was 38 years). During the studied period the frequency of relapsed patients was reduced from 24.87% to 8.04%. The numbers of autologous stem cell transplantations was increased among refracter/relapsed patients, and 75% of the patients underwent transplantation since 2000. The 5-year overall survival improved significantly (between 1980 and 1989 64.4%, between 1990 and 1999 82.4%, between 2000 and 2009 88.4%, and between 2010 and 2014 87.1%). Relapse-free survival did not change significantly. Conclusions: During the study period treatment outcomes improved. For relapsed/refractory Hodgkin lymphoma patients novel treatment options may offer better chance for cure. Orv. Hetil., 2015, 156(45), 1824–1833.


2020 ◽  
Vol 16 (8) ◽  
pp. 1022-1043
Author(s):  
Imran Khan ◽  
Sadaf Mahfooz ◽  
Mustafa A. Hatiboglu

Background: Glioblastoma is one of the most aggressive and devastating tumours of the central nervous system with short survival time. Glioblastoma usually shows fast cell proliferation and invasion of normal brain tissue causing poor prognosis. The present standard of care in patients with glioblastoma includes surgery followed by radiotherapy and temozolomide (TMZ) based chemotherapy. Unfortunately, these approaches are not sufficient to lead a favorable prognosis and survival rates. As the current approaches do not provide a long-term benefit in those patients, new alternative treatments including natural compounds, have drawn attention. Due to their natural origin, they are associated with minimum cellular toxicity towards normal cells and it has become one of the most attractive approaches to treat tumours by natural compounds or phytochemicals. Objective: In the present review, the role of natural compounds or phytochemicals in the treatment of glioblastoma describing their efficacy on various aspects of glioblastoma pathophysiology such as cell proliferation, apoptosis, cell cycle regulation, cellular signaling pathways, chemoresistance and their role in combinatorial therapeutic approaches was described. Methods: Peer-reviewed literature was extracted using Pubmed, EMBASE Ovid and Google Scholar to be reviewed in the present article. Conclusion: Preclinical data available in the literature suggest that phytochemicals hold immense potential to be translated into treatment modalities. However, further clinical studies with conclusive results are required to implement phytochemicals in treatment modalities.


Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.


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