Lung-Pancreatic Cell Transplant Safe, Effective in CF Patients With CFRD
A lung and pancreatic cell transplant from a single donor to people with end-stage cystic fibrosis (CF) and CF-related diabetes (CFRD) safely and effectively improved their lung function, metabolic control, and quality of life, data from a small Phase 1/2 trial show.
Given that CFRD increases the risk of complications after a lung transplant, these early findings suggest that a combined lung-pancreatic cell transplant may be an effective way of improving life for this group of end-stage CF patients.
Larger and appropriately controlled studies are needed to confirm these findings, the researchers noted.
Findings were detailed in the study, “Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis related diabetes—PIM study: a multicenter phase 1-2 trial,” published in the American Journal of Transplantation.
CF is caused by mutations in the CFTR gene, leading to the buildup of thick mucus in multiple organs, such as the lungs and pancreas, resulting in inflammation and damage. CF-related damage to the pancreas leads to diabetes in about 40–50% of adult patients due to insufficient production of insulin or to insulin resistance.
Notably, CFRD is associated with poorer lung function, poor nutritional status (slower growth and/or weight loss), and a greater risk of death. In addition, for CF patients undergoing a lung transplant, its presence “decreases patient survival, whilst promoting infection and post-transplant pulmonary rejection,” the researchers wrote.
Restoring satisfactory glucose, or sugar, control through a transplant of pancreatic islets — groups of cells that produce insulin and other hormones — may help improve outcomes of a lung transplant in CF patients with CFRD.
Combined lung-pancreas cell transplantation, however, “is technically more complex, carrying a higher risk of complications due to the simultaneous thoracic and abdominal procedures in already very weak patients,” the researchers wrote.
Pancreatic islets can be successfully grown and maintained in the lab for up to 10 days, and transplanted into the liver through the portal vein. This allows implantation to be delayed until the patient’s condition has improved.
To date, only case reports of combined lung-pancreatic islets “have been published, and questions remain as to the efficacy and safety of this procedure in this particular patient population,” the team noted.
Researchers at Strasbourg University Hospital, in France, launched a Phase 1/2 clinical trial, called PIM (NCT01548729), to assess the feasibility and effectiveness of combined double lung-pancreatic islet transplant from a single donor in end-stage CF patients with CFRD and on insulin therapy.
Using the same donor for a combined transplant is thought to reduce the risk of immune responses against the transplanted tissues.
From February 2012 to December 2019, 14 patients were enrolled at four French hospitals, and 10 of them (one teenage girl, three men, and six women) received a double lung transplant followed by a pancreatic islet transplant.
Of the remaining four patients, one withdrew from the transplant waiting list due to improving lung function, and three underwent a double lung transplant alone due to unsuitability of the donor’s pancreas.
Nine of the 10 patients who underwent the combined procedure carried the most common CF-causing mutation, F508del, in at least one copy of the CFTR gene. Their median age was 24 (range, 16–41), and they had been living with CFRD for a median of eight years (range, three to 25 years).
The trial’s main goal was to assess the combined transplant’s metabolic efficacy, measured by a composite score including metabolic and nutritional parameters.
“For the patients enrolled in our study, the purpose of islet transplantation was … to restore satisfactory glucose control, aiming to improve clinical management during the postoperative period and in the medium term,” the researchers wrote.
A transplant was defined as successful if, at one year, three of the following four criteria were met: weight increase of at least 5%; fasting blood-sugar levels lower than 110 mg/dL; a 30% or greater reduction in insulin requirements; and at least a 0.5% drop in HbA1c (a measure of the average blood sugar levels over a period of time).
Secondary goals included changes in these individual measures, insulin production, lung function, and health-related quality of life, as well as safety assessments.
Seven of these 10 patients (70%) had a successful combined transplant. They showed an increase in body-mass index (BMI, a ratio between weight and height), better control of blood-sugar levels, and a 38% drop in daily insulin doses. One person was able to stop taking insulin.
Among the three who failed to achieve satisfactory metabolic control post-transplant, one person was not compliant with treatments, including “repeated discontinuation of insulin therapy,” and another had been transfused with what might have been an insufficient number of islets, the researchers wrote. No evident “events” might explain the inability of the third patient to achieve metabolic control.
Successful lung-pancreatic islet transplant was also associated with better lung function and gains in health-related quality of life, particularly its physical aspects.
Notably, diabetes-related quality of life “was only modestly improved,” suggesting that most quality-of-life improvements were “related to the effects of lung transplantation,” the team wrote.
No one died or rejected their transplanted lungs during the follow-up year, and no complications related to the pancreatic islet injection procedure were reported.
The safety profile of the combined transplant was similar to that of a lung transplant alone, with lung infection as the most common complication and no reports of unexpected adverse events. All serious adverse events, most commonly occurring within the first month post-transplant, were successfully treated.
“In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the [complications] of lung transplantation,” the researchers wrote.
These findings indicate that it is “an efficient and viable therapeutic option for patients with end-stage CF and CFRD, whose numbers are on the rise due to the increased life expectancy of CF patients,” they added.
Researchers noted, however, that larger studies including a group of patients undergoing lung transplant alone are needed to confirm these findings and to determine whether the observed benefits relate to pancreatic islet transplant.
Such trials, while “challenging … will be of utmost importance in defining the long-term benefits of this treatment and identifying the best suited candidates, in turn, allowing to optimize clinical outcomes,” the researchers concluded.