Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation

doi:10.1016/j.healun.2012.03.008

The Journal of Heart and Lung Transplantation

Volume 31, Issue 8, August 2012, Pages 797-804

https://doi.org/10.1016/j.healun.2012.03.008 Get rights and content

Background

Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS.

Methods

Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events.

Results

Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09).

Conclusions

Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

Section snippets

Study design

This 3-year prospective, randomized (1:1), open-label, multicenter, investigator-driven superiority study in two parallel groups of adult lung transplant recipients was conducted in compliance with the provisions of the Declaration of Helsinki and good clinical practice guidelines. The study protocol was accepted by each local hospital research ethics committee. All patients provided written informed consent and were free to withdraw from the study at any time-point. The trial was proposed and

Patients

From January 2001 until June 2003, a total of 274 patients from 14 centers in 6 countries were assessed for eligibility, of whom 265 were randomized and transplanted (Figure 1). Fifteen patients did not receive study drug and 1 patient was retransplanted within 3 days, leaving 249 patients in the intent-to-treat population.

The groups were well-balanced with respect to patient demographics, etiology of end-stage lung disease and type of transplantation (Table 1). Of note, 26% patients in the

Synopsis of the key findings

Calcineurin inhibitors are commonly used in combination with anti-proliferative agents and steroids for the prevention of acute and chronic rejection in patients undergoing lung transplantation. This is the first prospective, randomized, controlled, multicenter trial to demonstrate superiority of tacrolimus over cyclosporine in combination with MMF and steroids for the development of BOS, the surrogate for chronic rejection and the main reason for death in long-term follow-up after lung

Disclosure statement

The authors have no conflicts of interest to disclose. The study was funded by Astellas Pharma (formerly Fujisawa Pharmaceuticals) and Roche. The funding companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Cited by (95)

Once-per-day tacrolimus to reduce chronic lung transplant rejection
2024, The Lancet Respiratory Medicine
Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial
2024, The Lancet Respiratory Medicine
Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation.
ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18–70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2–3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05–0·1 mg/kg before transplantation and 0·1–0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27).
Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31–48]) in the ciclosporin group and 16 patients (13% [8–21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15–0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65–81] for ciclosporin vs 79% [70–85] for tacrolimus; HR 0·72 [95% CI 0·41–1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26–0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event.
Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation.
Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.
Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients
2023, Transplantation Proceedings
This retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application.
Overall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan–Meier analysis.
The use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF.
The real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.
Chronic lung allograft dysfunction in 2022, past and updates
2023, Revue des Maladies Respiratoires
Les résultats à court terme de la transplantation pulmonaire se sont améliorés mais la survie à long terme reste en deçà de celle observée dans les autres transplantations d’organes solides.
La principale cause de mortalité tardive est la dysfonction chronique du greffon pulmonaire (DCG) qui affecte près de la moitié des receveurs à 5 ans de la greffe. Des facteurs de risques immunologiques et non immuns ont été identifiés. Ces facteurs vont activer le système immunitaire inné et adaptatif entraînant des processus lésionnels et de réparations altérées aboutissant à une fibrose touchant les petites voies aériennes ou le tissu interstitiel. Plusieurs phénotypes de DCG sont maintenant identifiés en fonction du profil fonctionnel respiratoire et de l’imagerie. En dehors de la retransplantation, uniquement possible pour une minorité de patients, il n’existe pas à ce jour de traitement permettant d’inverser le processus de la DCG.
Des espoirs thérapeutiques existent, comme les traitements anti-fibrosants ou la photophérèse. Les travaux de recherche ont par ailleurs permis d’identifier de nombreux biomarqueurs qui pourraient s’avérer être pertinents comme cibles thérapeutiques.
Les mécanismes physiopathologiques de la DCG sont mieux compris aujourd’hui mais le défi thérapeutique reste entier.
While short-term results of lung transplantation have improved considerably, long-term survival remains below that achieved for other solid organ transplants.
The main cause of late mortality is chronic lung allograft dysfunction (CLAD), which affects nearly half of the recipients 5 years after transplantation. Immunological and non-immune risk factors have been identified. These factors activate the innate and adaptive immune system, leading to lesional and altered wound-healing processes, which result in fibrosis affecting the small airways or interstitial tissue. Several phenotypes of CLAD have been identified based on respiratory function and imaging pattern. Aside from retransplantation, which is possible for only small number of patients, no treatment can reverse the CLAD process.
Current therapeutic research is focused on anti-fibrotic treatments and photopheresis. Basic research has identified numerous biomarkers that could prove to be relevant as therapeutic targets.
While the pathophysiological mechanisms of CLAD are better understood than before, a major therapeutic challenge remains.
Conventional and Novel Approaches to Immunosuppression in Lung Transplantation
2023, Clinics in Chest Medicine
Critical Care of the Lung Transplant Patient
2022, Clinics in Chest Medicine

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Featured clinical trialTacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation

Background

Methods

Results

Conclusions

Section snippets

Study design

Patients

Synopsis of the key findings

Disclosure statement

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Unilateral lung transplantation for pulmonary fibrosis

N Engl J Med

Featured clinical trial
Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation