Listening to patients and parents with sickle cell disease: the totality of gene therapy risks may outweigh the perceived benefits

TO THE EDITOR:

We read with interest the December 2023 article by Sepulveda et al,¹ “Preferences for potential benefits and risks for gene therapy in the treatment of sickle cell disease.” The authors used a discrete choice methodology to assess how differences in a limited set of risk and benefit scenarios might influence an individual patient’s (or parent’s) interest in gene therapy for sickle cell disease (SCD). Using this limited set of choice architecture, the authors concluded that the “appeal of gene therapy is evident in our study results, with respondents accepting gene therapy in most scenarios.”

We are members of the Sickle Cell Disease Gene Therapy Working Group, a multi-institutional, interdisciplinary research collaborative conducting patient-focused research for potentially curative treatments for SCD, with a focus on gene therapy. We have previously reported on the informational needs of patients with SCD and parents surrounding high-risk, high-reward treatments, including gene therapy.² Here, we share vital information about attitudes toward gene therapy from our ongoing work with patient and parent stakeholders.

Although the work by Sepulveda et al¹ is an important addition to the literature on patient attitudes toward gene therapy for SCD, we are concerned that the discrete choice approach fails to adequately capture the totality of risks patient and parent stakeholders consider when evaluating the acceptability of gene therapy as a potential treatment option either for themselves or for their child. Specifically, we are concerned that the discrete choice methodology used in this study overestimates the acceptability of gene therapy among most patient and parent stakeholders by evaluating only 2 risk factors (death within 1 year of treatment and increased lifetime cancer risk). Although significant, we submit that there are many other potential adverse outcomes a gene therapy recipient may experience. Individuals undergoing gene therapy remain at risk of infertility and organ toxicity due to exposure to myeloablative chemotherapy and may continue to experience poor quality of life due to residual organ damage from SCD and its sequalae (such as osteonecrosis, nephropathy, cardiomyopathy, impotence, and stroke). Although many of these potential adverse outcomes are uncommon, they present significant health and psychological burden to the patients and their families.

Further supporting our assertation, we draw upon >2 years of focus group work with a regionally diverse advisory panel of patients and parents of children with SCD, ongoing interviews of a cross-sectional sample of parents of children with SCD (spanning from infancy through adolescent years with varying levels of disease severity), and from patients with SCD who have undergone gene therapy.

Our findings contrast the authors’ conclusions about the appeal of gene therapy in most scenarios. Through a qualitative approach, which we believe might provide a richer insight into patient attitudes about the risks and acceptability of gene therapies than a discrete choice architecture, our findings suggest that adult patients and most parents of children with SCD have serious concerns about the risks of gene therapy, and many do not believe these risks, when taken together, outweigh the potential benefits.

Of the parental interviews we have qualitatively coded, only a few expressed that gene therapy might be right for their child. Many of the parents interviewed said they did not think the benefits of gene therapy outweighed its risks.

Themes that have emerged thus far from our interviews and focus groups show that most respondents do not believe that their (or their child’s) disease is severe enough to accept the treatment-associated morbidities, potential mortality risks, and uncertainty surrounding the long-term risks and efficacy of gene therapy itself. Additional concerns included uneasiness about medical research, the relative novelty of gene therapy, and interventions that “change your genes.”

Regarding treatment-related toxicities, infertility risk is of particular concern for both adult patients and parents of children with SCD. Importantly, Sepulveda et al¹ did not include this risk in their discrete choice experiment, which could have limited the assessment of risk in their study. Unless tangible fertility preservation is offered as part of the treatment plan, we believe that the risk of infertility may be a “deal-breaker” for many patients and parents. Fertility preservation referral alone is insufficient, because fertility preservation procedures must be accessible (ie, adequate insurance coverage for expenses associated with retrieval and long-term storage). In our research, parents have expressed unwillingness to agree to medical treatments that will expose their child to short-term acute toxicity and that may subsequently impair their child’s ability to have children in the future. Given the totality of risks associated with gene therapy, the burden of this decision weighs heavily on parents.

Representative quotations from our ongoing work exemplify these themes:

• “It's this big question about what are the long-term consequences of this [gene therapy]? Is it fixing one thing and opening a Pandora's box to add many issues to the one you are trying to fix?”

• “Basically, the hair loss and then the immune system being weak for 6 months, that’s a lot to take a child through. And the chances of her growing up not being able to have a child, I don’t want to have to make that decision. I want her to make that decision herself.”

• “Some of the patients that already started with the gene therapy, they ended up having leukemia, like what if we put our son in a clinical trial and then he ends up in a worse situation?”

Although gene therapy for SCD is now a Food and Drug Administration-approved intervention, it remains a “high-risk, high-reward therapy.” Many of the risks limiting the acceptability of gene therapy outlined above are also risks of haploidentical hematopoietic cell transplantation. Both interventions may be associated with risks that are unpalatable to many patients, particularly parents of children with SCD who in interviews stated they believe their child should decide for themselves in the future whether those risks are acceptable.

Sepulveda et al reported that <3% of respondents always chose gene therapy in their discrete choice experiment. Our data suggest that, at least for now, most patients will find the potential risks associated with gene therapy to outweigh its potential benefits. We acknowledge that the results of the study conducted by Sepulveda et al and our data might represent 2 extreme ends of the spectrum of SCD patient beliefs and hopes.¹ Nevertheless, we hope that our results will spur additional discussion and studies in this field to truly investigate this nuanced and complicated topic.

We encourage clinicians to offer up-to-date, interactive, and age-appropriate educational materials for patients and parents considering gene therapy, along with dedicated appointment times for additional discussion. For patients for whom gene therapy is strongly recommended, a shared decision-making approach and “checking-in” about treatment options over time may build trust and interest in this treatment. Additionally, conversations that include both a patient’s hematology team and the gene therapy/transplant team may also be helpful in fostering trust while attending to patients’ and parents’ concerns about this promising potentially curative therapy.

Contribution: J.B. and L.-M.J. drafted the first version of the manuscript, which was edited and reviewed by all authors.

Conflict-of-interest disclosure: L.-M.J. has received consultant funding from CSL Behring. A.S. has received consultant fees from Spotlight Therapeutics, Medexus Inc, Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine; research funding from CRISPR Therapeutics; honoraria from Vindico Medical Education; is the St. Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880); the industry sponsors provide funding for the clinical trial, which includes salary support paid to A.S.’s institution; A.S. has no direct financial interest in these therapies. The remaning authors declare no competing financial interests.

Correspondence: Liza-Marie Johnson, Department of Oncology, Bioethics Program, St. Jude Children's Research Hospital, 262 Danny Thomas Pl, MS 260, Memphis, TN 38105; email: liza.johnson@stjude.org.