Autologous umbilical cord blood mononuclear cell therapy for hypoplastic left heart syndrome: a nonrandomized control trial of the efficacy and safety of intramyocardial injections

Abstract

Background

Preliminary phase I clinical trial results revealed that autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) preserved right ventricular cardiac function. To establish the efficacy of intramyocardial injections of an autologous UCB-MNC product at the time of stage II palliation surgery in patients with hypoplastic left heart syndrome (HLHS).

Methods

A phase IIb, multicenter, open-label, nonrandomized study was conducted. Ninety-five children (fifty treated and forty-five controls) with HLHS and its variants, a history of stage I palliation surgery, and planned stage II palliation surgery at less than thirteen months were enrolled. We assessed coprimary efficacy endpoints for changes in right ventricular cardiac function through fractional area changes and longitudinal and circumferential strain, both in the short term (three months) and long term (twelve months). Second, we assessed changes in biomarkers of cardiac injury. Safety endpoints included severe adverse events (SAEs), changes in overall health through vital signs, and cumulative hospitalization.

Results

Assessment of our coprimary efficacy endpoints revealed an unfavorable change in longitudinal cardiac strain in the treatment group compared with an improvement in strain in the control group (unadjusted p =.032) in the short term. No differences were observed between the groups in terms of other coprimary efficacy endpoints in the short or long term. A secondary assessment of biomarkers of cardiac injury revealed higher troponin T levels in the treatment group at three and six hours postsurgery. Regarding safety, no deaths related to the administered product or delivery procedure were reported. The treatment group presented a greater incidence (20%) of at least one SAE than the control group at three months (p =.048). Additionally, no statistically significant differences were found for the other safety endpoints.

Conclusion

Intramyocardial injections of autologous UCB-MNC products into the right ventricular myocardium during stage II palliation surgery failed to enhance cardiac function in patients with hypoplastic left heart syndrome.

Registered on ClinicalTrials.gov

Registered on ClinicalTrials.gov (NCT03779711) on 12/04/2018; URL: https://clinicaltrials.gov/ct2/show/NCT0377971.

Novelty and significance

What is known?

• To date, no prior efficacy studies have examined the use of autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) in patients with hypoplastic left heart syndrome following stage palliation surgeries.

• A preliminary phase I clinical trial noted that early follow-up (six months) after the administration of autologous UCB-MNC enhanced right ventricular cardiac function relative to that of controls, alongside greater weight percentiles [19].

What new information does this article contribute?

• Largest worldwide stem cell phase IIb clinical trial on congenital heart disease, specifically investigating the efficacy and safety of an autologous UCB-MNC product in patients with hypoplastic left heart syndrome.

• The autologous UCB-MNC product depicted a favorable safety profile, with no severe adverse events or fatalities related to the product or product administration.

• Despite the favorable safety profile observed, intramyocardial injections of the autologous UCB-MNC product did not yield improvements in cardiac function in the short or long term.

The preservation of right ventricular cardiac function remains a critical challenge in HLHS, as evidenced by several studies documenting a decline in right ventricular contractility over time at various stages of surgical palliation. The use of stem cells is effective in regenerating, remodeling, and renewing injured myocardium. Although preliminary clinical trials reported improved cardiac function following the administration of autologous UCB-MNC in HLHS patients, this study failed to demonstrate the preservation of cardiac function while maintaining safety. The multicenter nature and magnitude of this dataset are substantial and should not be understated; however, we must also acknowledge the limitations of our study, underscoring the need for further research to address them and optimize the therapeutic potential of UCB-MNC therapy for HLHS. We are committed to continuing our efforts to provide more bases and insights into the mechanisms and a better understanding of regenerative medicine to find solutions for congenital heart disease.