Baseline symptoms of sickle cell disease (SCD) drive patient acceptance of gene therapy, according to the first study of adult patient and patient parent preferences for outcomes associated with this emerging SCD treatment, published in Blood Advances. Adults and parents of patients with milder symptoms may prefer other treatment options, but an expectation of deteriorating symptoms triggers a strong reassessment of the acceptable benefit-risk balance of this technology.
Noting long-standing concerns about what patients truly understand during the informed consent process, study researcher Marilyn Telen, MD, of Duke University School of Medicine in North Carolina said investigators aimed to better understand patient and family preferences regarding emerging SCD gene therapies after carefully developing and delivering related education materials. The study was an opportunity to get input from patients and families in a setting “where they had the best possible chance of understanding what is truly involved in gene therapy treatments,” Dr. Telen said.
Current pharmacologic treatments for SCD may alleviate symptoms but offer no cure. Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative option that requires a matched donor and may have serious immune-related complications, such as life-threatening graft-versus- host disease. A haploidentical HCT may occur without a matched donor but involves a higher risk of rejection.
Meanwhile, gene therapy approaches under clinical investigation are emerging as a potential disease-modifying treatment for SCD. They neither require a matched donor nor carry risk of the immune-related complications associated with allogeneic transplants. Before gene therapy for SCD becomes widely available, the researchers wanted to understand how adult patients and the parents of children with SCD would accept gene therapy and what relative value they would place on the potential benefits and risks associated with this technology. Researchers also sought to understand how disease severity affected these views.
The researchers surveyed 174 adult patients and 109 parents at three clinical sites and through one patient organization. Respondents selected their preferred treatment alternatives from a series of experimentally controlled pairs of hypothetical gene therapies and a “no gene therapy” option in the survey. It described gene therapy alternatives based on their chances of eliminating SCD symptoms, expected increases in life expectancy, treatment-related risk of death, and potential increases in lifetime cancer risk. Respondents made selections based on their current disease severity and in the context of expectations of worsened disease.
Adult and parent respondents were generally willing to choose gene therapies, but the adult patients required higher expected levels of efficacy — such as chance of eliminating symptoms — than parents to choose gene therapies that conferred mortality risks of 10% or more, researchers reported.
When adults and parents of children with less severe symptoms were asked to consider scenarios involving greater disease severity, their risk tolerance increased. The lowest acceptable level of efficacy for gene therapies with mortality risks dropped by more than 50%, researchers found.
“The patients who were sicker were willing to take more risk and required less promise of benefit than patients with milder symptoms,” Dr. Telen said. She added that the study helps determine what different patients with SCD would consider as viable treatment choices.
Limitations noted by the authors include the fact that choices made based on hypothetical scenarios do not carry the same consequences as real-world choices, the difficulty of imagining worsened health for participants, and their self-reports of symptom severity. Additional limitations are that the survey included information about gene therapy that may change as understanding of its outcomes evolves.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Gonzalez Sepulveda JM, Yang JC, Reed SD, et al. Preferences for potential benefits and risks for gene therapy in the treatment of sickle cell disease [published online ahead of print, 2023 October 31]. Blood Adv. doi: 10.1182/bloodadvances.2023009680.
Perspectives
It is indeed an exciting time in the care of patients with SCD because of new therapeutic options that could significantly improve their quality of life and life expectancy. The idea of a potentially curative therapy for an often debilitating condition like SCD has brought a new wave of optimism for patients and their families.
This article highlights that significant mortality risks accompany the obvious potential benefits of gene therapy. Patients and parents of patients must be thoroughly informed of these risks, especially as they relate to the chemotherapy preparative regimen. Also, the uncertainty regarding the degree of success and improvement of baseline symptoms post-gene therapy is challenging; this is where shared decision-making between the physician and the patient or caregiver is extremely valuable.
The survey results are mostly expected. Patients with milder disease are less likely to accept the potential mortality risk than patients who are more severely affected. Also, if symptoms are expected to worsen over time, it makes sense that affected individuals or parents of children with SCD would tolerate more risks in hopes of preventing this deterioration. As a predominately pediatric hematologist, I’m not surprised that adult caregivers will accept a lower likelihood of cure in hopes of giving their kids a chance at a normal life.
The one unexpected finding is that adults with moderate symptoms required a higher success rate to choose gene therapy (with its estimated 10% mortality risk) compared to those with mild symptoms. As the first preference study to investigate adult patient and parent preferences for outcomes associated with gene therapy for SCD, these findings shine an important light on the patient and caregiver perspective.
Corey Falcon, MD
Ochsner Hospital for Children
New Orleans, Louisiana
