Combined use of anakinra, etanercept and BETA-2 score linked with improved islet cell transplant outcomes
NEW YORK 27/05 - In a single center's 20-year experience with pancreatic islet cell transplantation, patients with sustained graft survival were more likely to have had combination treatment with anakinra plus etanercept (one or more infusions) and a BETA-2 score of 15 or higher - reflecting insulin independence - within one year, researchers say.
"Our findings with anakinra plus etanercept resonate with evidence from a recent systematic review suggesting that dual anti-inflammatory therapies be considered for routine use in islet transplantation, while the BETA-2 score," a measure of beta cell function, "might help to evaluate engraftment," Dr. Marfil-Garza at the University of Edmonton Alberta in Canada and colleagues wrote in The Lancet Diabetes and Endocrinology.
The data "revealed a comprehensive picture of the robust metabolic impact that could be achieved and maintained with sustained graft survival," they added.
The study included 255 patients with type 1 diabetes who received pancreatic islet cells between March 1999 through September 2019 (58% male, 85% white). Overall, 225 patients (88%) patients received two or more islet infusions, 94 (37%) received three or more infusions, 32 (13%) received at least four infusions, and four (2%) received five infusions. Over a median follow-up of 7.4 years, 230 (90%) patients survived. The mortality incidence during follow-up of 2161.9 patient-years was 11.6 per 1000 person-years.
Median graft survival was 5.9 years; 91 patients (36%) experienced graft failure (incidence rate, 51.6 per 1000 person-years). Seventeen failures (19%) occurred less than a year after the first infusion. The Kaplan-Meier estimate for graft survival was 94% at one year, 75% at five years, 58% at 10 years, 50% at 15 years, and 48% at 20 years after the first transplant.
Patients were stratified into two groups: sustained graft survival, i.e., graft survival for at least 90% of patient follow-up (n=178, 70%) and non-sustained graft survival, i.e., graft survival <90% of patient follow-up (n-77, 30%).
Recipients with sustained graft survival had longer type 1 diabetes duration (median 33.5 years vs 26.2 years; p=0·0003) and were older at first transplant (49.4 years vs 44.2; p=0·0011) than those with non-sustained graft survival. The proportion of patients receiving three or more islet infusions was higher in recipients with sustained graft survival than in those with non-sustained graft survival (42% vs 25%, p=0·0079).
The group with sustained graft survival had a significantly longer time to last infusion (14.3 vs 7 months, p=0.005); they also had more infusions (p=0.014) and greater infused islet mass (p<0·0001).
The combined use of anakinra plus etanercept (one or more infusions) and a BETA-2 score of 15 or higher within 1-year after the first infusion significantly increased the odds of achieving sustained graft survival in univariate and multivariate analyses. The adjusted odds ratios (ORs) for sustained graft survival were 7.5 with use of anakinra plus etanercept (95% CI 2.7-21.0, p<0.0001) and 4.1 with a Beta-2 score of 15 or higher (1.5-11.4, p=0.0066).
Insulin independence occurred in 201 patients (79%) and was more frequent in recipients with vs without sustained graft survival (90% vs 53%; p <0.001) .The insulin independence Kaplan-Meier estimate was 61% at 1 year, at 5 years, 20% at 10 years, 11% at 15 years, and 8% at 20 years from first transplant. The median total duration of insulin independence was 2.3 years and was significantly longer in recipients with sustained graft survival (2.7 vs 1.1 years; p<0.0001). A BETA-2 score of 15 or higher within one year after the first infusion was associated with a longer total duration of insulin independence.
Patient survival was similar in the two groups. The estimated patient survival probability was 74% (95% CI 59-84) at 20 years. Median age at death was 62.3 years (IQR 45·4-68·1). 29 (11%) of 255 patients were older than 60 years at baseline and had higher mortality than younger recipients (9·7 vs 29·1 per 1000 patient-years, p=0·034) and comprised six (24%) of 25 deaths.
Marked improvements in glycemic control were evident following islet transplantation. Both HbA1c levels and fasting plasma glucose showed improvements in recipients with sustained graft survival. Additionally, HbA1c concentrations of less than 7% (53 mmol/mol) during follow-up were significantly more prevalent in these patients.
In an editorial, Dr. Rainer W.G. Gruessner of Downstate Medical Center in Brooklyn, New York notes that graft survival criteria in the study included a fasting C-peptide concentration >0.1 nmol/L, which is almost 60% lower than the >0.17 nmol/L concentration proposed by the widely accepted Igls classification, which most likely increased graft survival rates in their study.
He also points out that only 12% of patients with sustained graft survival received one transplant, and more than 37% received three to five transplants, which may be a major hindrance to widespread application, especially since U.S. health insurance companies do not cover islet cell transplants. Furthermore, he writes, islet cells are considered biological drugs in the U.S., a regulatory distinction that "has impeded patient access" to this treatment.
"The results of the Edmonton group, achieved over a 20-year period, might help to gain more widespread application of islet transplantation," Dr. Gruessner concluded.
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