Tacrolimus After Lung Transplant Cuts Chronic Lung Allograft Dysfunction

MILAN — Once-a-day tacrolimus significantly reduced chronic lung allograft dysfunction (CLAD) in lung transplant patients compared with the standard immunosuppressant, according to the ScanCLAD trial.

Among patients who underwent double lung transplantation, CLAD occurred significantly more often among those who received cyclosporine (cumulative incidence 39%, 95% CI 31-48) versus those who got tacrolimus (13%, 95% CI 8-21, P

While overall survival was similar between the two treatment groups, allograft survival was significantly better among the tacrolimus cohort (HR 0.49, 95% CI 0.26-0.91, log-rank P=0.021), according to the open-label, multi-center trial. Results were simultaneously published in The Lancet Respiratory Medicine.

CLAD, previously defined as chronic rejection of lung allografts, can lead to poor health following transplants and is considered irreversible, according to the researchers. Cyclosporine and tacrolimus are calcineurin inhibitors that “are regarded as primary immunosuppressants after lung transplantation. However, few randomized controlled trials on the choice of calcineurin inhibitor after lung transplantation have been published,” they stated.

Dellgren and colleagues explained that “[a]ll lung transplant centres globally use calcineurin inhibitors after lung transplantation; however, in the past decade, a switch has occurred worldwide from cyclosporine to tacrolimus,” per the International Society for Heart and Lung Transplantation (ISHLT) registry. But that change happened “despite a lack of real proof-of concept studies confirming that tacrolimus is superior to cyclosporine with respect to long-term survival after lung transplantation. Before this study, cyclosporine had been the calcineurin inhibitor of choice in all Scandinavian lung transplant programmes and formed the clinical equipoise for this study,” they said.

The researchers reported that adverse events (AEs) were slightly more common in the cyclosporine cohort at 1,516, compared to 1,459 in the tacrolimus cohort. The majority of both the cyclosporine and tacrolimus groups experienced at least one AE (90% and 87%, respectively). Infection was the most frequently observed AE, followed anemia and acute rejection in both groups.

In an accompanying comment, Michael P. Combs, MD, of the University of Michigan in Ann Arbor, noted that the once daily tacrolimus dosage used in ScanCLAD introduced a new facet to post-transplant treatment.

“Comparisons of tacrolimus dosing once versus twice per day after lung transplantation have thus far been limited to pharmacokinetic and safety studies, which have found that both tacrolimus formulations can be maintained in the target range with similar rates of adverse events. The largest study comparing tacrolimus dosing once versus twice per day in lung transplant recipients found that patients were less likely to take their medication irregularly or miss doses with the once-per-day formulation,” he wrote.

Combs noted that once-a-day dosing has proven successful in patients receiving other solid organ transplants, and is recommended in an ISHLT-endorsed consensus guideline. “These observations raise the question of whether real-world use of once-per-day tacrolimus might result in more efficacious immunosuppression and, thus, lower rates of CLAD and rejection,” he said.

ScanCLAD had 249 patients who underwent de novo double lung transplantation and received at least one of the study drugs. After randomization, 125 patients were on cyclosporine and 124 were on tacrolimus. Average patient age was 55.2, 45% were women, and the vast majority were white. Most were former smokers and around 30% had chronic obstructive pulmonary disease.

Surgeries were conducted at five centers in four countries — Sweden, Norway, Finland, and Denmark — from Nov. 8, 2016, to Sept. 9, 2019. Patients were randomized to receive either cyclosporine or tacrolimus, and follow-up was conducted until 36 months following transplant procedures, concluding in October 2022. Patients also received surveillance bronchoscopies after 1, 3, and 12 months post- transplant. More patients in the tacrolimus group required mechanical circulatory support in the form of cardiopulmonary bypass versus the cyclosporine group. The researchers reported no loss to follow-up.

Immediately prior to the surgery, patients got 2-3 mg/kg oral cyclosporine or 0.05-0.1 mg/kg oral tacrolimus. All study patients received 1.5 mg/kg of an anti-thymocyte globulin induction following the procedure, as well as oral mycophenolate mofetil and corticosteroids.

Dellgreen and colleagues reported that crossover from one calcineurin inhibitor to the other occurred more often in the cyclosporine group than in the tacrolimus group (17% vs 2%), explaining that “[r]escue therapy in some form was the reason for crossover in 15 patients, among whom seven (all in the cyclosporine group) switched due to repeated acute rejection. Eight patients (seven in the cyclosporine group and one in the tacrolimus group) switched due to side-effects.”

Trial limitations included the lack of double blinding, and no details on some secondary outcomes, although that data will be published separately, they said. In addition, “[d]espite no difference in overall survival between groups in the mITT [modified intention-to-treat] population, we observed a higher rate of re-transplantation in the cyclosporine group, which translated into worse allograft survival in the cyclosporin [per protocol] CLAD population. This will be further evaluated in an extended study of the cohort, which has been approved by the ethics review board and is ongoing,” Dellgren’s group said.

But they still said they hope the findings will encourage a change in current practice, as “we found immunosuppression based on the use of tacrolimus once per day reduced the incidence of CLAD significantly compared with use of cyclosporine twice per day, suggesting that tacrolimus should be regarded as the first choice of calcineurin inhibitor after lung transplantation.”