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Milan — Liver transplantation Interim clinical results from the large international CHANCE study showed that the drug improves survival in patients with acute onset of chronic liver failure (ACLF).
Results to date have shown that the 3-month mortality rate after liver transplantation in patients with ACLF grades 2 and 3 is only 9%, which is not significantly different from that in decompensated patients. CirrhosisThe mortality rate is 7%.
“Treatment of ACLF represents an unmet medical need,” said Rajiv Jalan, MD, Professor of Hepatology and Honorary Consultant in Hepatology at University College London Hospital in London, UK.
These findings highlight “the inadequacy of current transplant allocation criteria for ACLF 2 and 3 patients,” which leads to excess mortality on the waiting list, he added.
Jalan presented the interim results at the 2024 European Association for the Study of the Liver (EASL) Congress.
If confirmed in a full analysis, these results make a strong case for increasing access to liver transplants and revising organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Based on the Model for End-Stage Liver Disease (MELD) Score
ACLF occurs in hospitalized patients with cirrhosis and acutely decompensated liver disease and is associated with a high short-term risk of mortality. ACLF 2 and 3 have a 28-day mortality risk of 30% to 90% and are characterized by multiple organ failure.
As seen in previous data, even patients with low MELD scores who are on the transplant waiting list have a 20% to 30% risk of death with ACLF 2 and 3, Dr. Jalan said.
The MELD score does not take into account the risk of death from extrahepatic organ failure, he added. Current organ allocation systems around the world are based primarily on a patient's MELD score, or changes in it, resulting in many patients dying on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival after liver transplantation in patients with ACLF 2 or 3 at the time of liver transplantation and in patients with decompensated cirrhosis without ACLF, as well as transplant-free survival in patients with ACLF 2 or 3 who were not candidates for liver transplantation.
A multicenter observational study of 66 Liver transplantation Centers from 21 countries and more than 500 investigators participated. Recruitment closed when 1,000 patients had been enrolled.
Patients were aged 54-56 years, 31-35% were female, 48-70% had alcohol-related cirrhosis, and 19-24% had metabolic dysfunction-related steatohepatitis. MELD scores ranged from 25-36.
In their interim results, Jalan and colleagues assessed waiting list mortality and mortality three months after liver transplantation.
Secondary outcomes included quality of life and healthcare costs.
The 823 patients included in the study were grouped as follows: 376 patients with ACLF 2 or 3 and listed as liver transplant candidates (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 and listed as liver transplant candidates (group 2), and 134 patients with ACLF 2 or 3 and not listed as liver transplant candidates (group 3).
Overall, patients in group 1 had very severe ACLF, and 177 patients in ACLF 3 had three or more organ failures, Jalan noted.
“The excess of alcohol-related cirrhosis in group 3 is intriguing, but may reflect a bias in transplantation,” he added.
Jalan highlighted geographic differences: US patients were younger, which could be important when interpreting post-transplant outcomes. In Asia, the majority of patients were male and primarily from India, where living donor transplants are common. In Latin America, only 33% of study participants had alcohol-related cirrhosis, compared with 67% in North America.
But “comorbidities were similar across the world, and MELD scores were similar,” Jalan said.
Death or delisting
Between listing and transplant, 28% of patients in group 1 died or were removed from the list, compared with 16% in group 2. In group 3, 85% of patients who were never on the transplant list in the first place died.
Similar to what has been seen in other studies, about 50% of patients on the waitlist who had ACLF 3 but a MELD score below 25 died or were taken off the list, Jalan noted, suggesting that these patients are at a disadvantage under the current waitlist priority system.
Geographically, waiting list mortality was significantly higher in Latin America (40%) than in North America, Europe, and Asia (20%, 18%, and 13%, respectively).
“This is likely due to low blood donation rates in Latin America,” Jalan said.
Regarding mortality at 3 months after transplantation, the mortality rates in groups 1 and 2 were 9% and 7%, respectively.
“This very well illustrates the clear benefit of transplant,” Jaran said. “The risk of death after transplant is not that different from patients with decompensated cirrhosis, even if they have ACLF 2 or 3.”
Patients with ACLF3 had a slightly higher risk of death than those with ACLF2, at 14%, but without transportation, these patients had a 70% to 80% risk of death, he said.
Looking at three-month post-transplant mortality rates by continent, Jalan highlighted that Asia, Europe and North America showed a risk of 12%, 7% and 3%, respectively, while Latin America showed a risk of 16%.
“This is likely multifactorial and influenced by a variety of factors, including time on the waiting list, the quality of organs available, and patient demographics,” Jalan said. If seriously ill patients undergo transplants, “they are at higher risk of death.”
The patients in this study had to wait a long time, “which makes their situation worse,” Jalan said, strengthening his argument for changes to the international organ distribution system to allow these patients to access organs more quickly.
“The organ distribution situation is extremely complex”
Co-moderator Anna Liao, MD, Professor of Internal Medicine and Hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is enormous,” and that the issue of waiting list mortality is of major clinical concern.
“The organ distribution situation is extremely complicated,” she added.
The liver transplant system considers a multitude of clinical conditions with very diverse benefit profiles, she explained.
“We would like to offer every patient a liver transplant with every benefit, but current donations are not enough to meet the request,” Leo said, “so prioritization remains important.”
“The findings of this study demonstrate the inadequacy of current transplant allocation criteria for patients with ACLF2 and 3,” said Debbie Shawcross, MD, professor of hepatology and chronic liver failure at King's College Hospital, London, UK, and vice secretary of the EASL board of directors.
But “this must be balanced with the recognition that the global donor pool of available organs is a finite resource,” she said, echoing Leo's comments.
This calls for a broader ethical discussion to ensure that more stable, often younger, patients with cirrhosis who are candidates for transplant are not penalized, she added.
Jalan declared that he is the inventor of ornithine phenylacetate, licensed from UCL to Mallinckrodt Pharma, a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit Ltd, and founder of Yaqrit Ltd, Hepyx Ltd, CyberLiver Ltd, and Gigabiome. Lleo declared that he has no conflicts of interest relevant to this study but has received speaking fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen, and serves as a consultant for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Shawcross declared that he serves on advisory boards/consultants for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
