Voices of patients with hemophilia: Life‐changing gene therapy

Dear Editor, In a 2021 forum published in Research and Practice in Thrombosis and Haemostasis, Professor Cedric Hermans, an opinion leader in the field, introduced the concept of the "hemophilia-free mind" as a guiding ambition for future hemophilia care and research.1 Since then, this concept has been embraced by groundbreaking innovative therapies such as hemophilia gene therapy2 and ultra-long acting factor VIII (FVIII), which promise patients a "hemophilia-free life" by providing significantly improved FVIII activity levels compared to previous therapies.3 While the medical community has largely embraced this vision, patient feedback has been limited to occasional presentations at industry symposia or publication4 and an academic publication featuring interviews with three patients from Germany.5 Recognizing the importance of gathering a broader patient perspective, a national survey was launched by representatives of the French hemophilia society (AFH) and the French Hemophilia Reference Center. The survey was developed by a working group that included healthcare professionals, patients, and patients' families. It aims to capture the views of all hemophilia A and B patients participating in phase 1/2 or 3 gene therapy studies in France, focusing on their experiences with gene therapy and its impact on their daily lives. This survey was conducted via an online questionnaire available on the Skezia platform (https://skezia.io/fr/) from March 3 to June 4, 2024, after obtaining institutional approval. Hematologists at French hemophilia care centers were contacted by the investigators to distribute the survey link to their patients who had participated in gene therapy studies. All respondents were volunteers, remained anonymous, received no compensation, and consented to participate. The study was conducted in compliance with French and European protection laws. The survey included 18 participants, representing 78% of French patients with severe or moderately severe hemophilia who participated in gene therapy clinical trials in France. These patients came from four comprehensive hemophilia care centers located in Lyon, Paris, Lille, and Marseille. Of these participants, 16 had severe hemophilia A and two had hemophilia B. The respondents spanned different age groups: one patient was 18–25 years old, five were 26–35 years old, 11 were 36–50 years old, and one patient was over 50 years old. Four patients received their doses in 2019, two in 2020, one in 2022, and eleven in 2023. The survey comprised 28 questions (Supporting Information), each designed to cover different stages of the patients' experience with gene therapy. Fourteen out of eighteen patients answered all the questions, while four provided incomplete responses. Our results indicate that the primary motivation for patients to choose gene therapy was to reduce the number of factor injections and thereby reduce the burden of the disease (86.7%). Other motivating factors included the desire to be free and healthy and the belief that gene therapy was the best available treatment. Fifty-nine percent of patients took more than 3 months to make their decision, while 29% decided in less than 1 month. All patients reported being satisfied with the support they received from healthcare professionals at hemophilia centers during the decision-making process. They all reported that they received adequate and realistic information about follow-up care during the 1st year after gene therapy. However, 38.5% of patients wished they had received more information about potential side effects, adverse effects of corticosteroid therapy and the unpredictability of results. The organization implemented on the day of gene therapy administration was appreciated by all patients, and 61.5% reported having an overnight hospital stay for clinical monitoring after gene therapy injection for dizziness, fever, or itching all over the body. After gene therapy, more than 100 IU/dL of FVIII or factor IX (FIX) was expressed in 38.5% of patients, between 40 and 100 IU/dL in 30.8%, between 10 and 40 IU/dL in 23%, and less than 10 IU/dL in 7.7% of patients. Currently, FVIII or FIX levels exceed 100 IU/dL in 23% of patients, range between 40 and 100 IU/dL in 23%, between 10 and 40 IU/dL in 31%, and are less than 10 IU/dL in 23% of patients. All patients reported satisfactory efficacy of gene therapy on bleeding. In addition, 92% reported very good or good efficacy of gene therapy for pain, joint health, and participation in leisure activities. All patients (100%) reported a very good or good effect of gene therapy on their daily activities. Some patients added free comments such as "It's a revolution. A new life" or "A new world has opened up for me." However, three patients (15%) reported that they had not stopped drinking alcohol. Of those who did quit, 55% abstained completely for at least 6 months. All patients reported that they were in compliance with their doctor's recommendations for contraception. Regarding regular clinical follow-up during the 1st year after gene therapy, only 23% of patients complained about the burden of follow-up, which was difficult to manage alongside their professional lives. In addition, 12% of patients reported difficulties with their families or caregivers due to the side effects of corticosteroid therapy. Despite 96% of patients reporting that gene therapy did not alter their relationships with family and colleagues at work, 69% emphasized that it significantly improved their self-perception. It enabled them to be less vigilant in daily activities, like walking in a crowded street with a target joint without worrying about its protection from the sudden movements of others, feeling less vulnerable and fatalistic, and envisioning a brighter future. Moreover, 62% noted an enhancement in self-confidence post gene therapy. Importantly, every patient surveyed expressed no regrets about their decision to undergo gene therapy, and none reported encountering new disease-related burdens afterward. Ten patients among 18 responders (55%) still experience some anxiety about the future, particularly about the unpredictable duration of gene therapy efficacy, the inability to receive a second dose of gene therapy, and the "theoretical" risk of cancer (Figure 1). Despite these concerns, they all emphasize the positive aspects of gene therapy, including freedom, happiness, self-confidence, the ability to live life fully as a normal person, psychological relief, and the elimination of prophylaxis. Finally, 13 patients among 14 responders (92.9%) said they would recommend gene therapy to other hemophilia patients. When asked if gene therapy has allowed them to achieve a "hemophilia-free mind," 13 patients among 14 responders (92.9%) answered yes, and one (7.1 %) stated, "Gene therapy has allowed me to temporarily have a hemophilia free mind." The primary limitations of this study are partial responses of four patients to the questionnaire and the relatively small number of participants, although they represent 78% of French adult hemophilia patients who underwent gene therapy. Since the majority of patients received gene therapy less than 2 years ago, this survey cannot provide additional data on the duration of gene therapy. There may be a bias associated with recruitment through voluntary participation, as volunteers are typically more engaged in their care or may have more favorable clinical outcomes. However, among the participants in the study, there were individuals who showed both high and low levels of FVIII/FIX expression after gene therapy and no association was found between the success or failure of the gene therapy and the participation in the questionnaire. It should be noted that time may influence perceptions of constraints and behaviors, and that the majority of patients in this survey received their gene therapy less than 2 years ago. In addition, there were no mandatory questions and some patients did not answer all questions. In an earlier national survey of severe and moderate hemophilia patients eligible for gene therapy, we found that French patients are still seeking more information about hemophilia gene therapy. Some are eager to adopt gene therapy, while others feel the need to compare it with their current treatments to assess its potential benefits. Concerns about the uncertainties and unknowns associated with gene therapy were also noted in our previous work.6 The results of our current study reinforce the positive feedback from three German patients regarding the transformative potential of gene therapy to enable a "normal life" for people with hemophilia.5 A group of seven patients with hemophilia A or B who had previously undergone gene therapy, and representatives from Bayer also reported that overall patient sentiment shifted from negative before gene therapy to positive after gene therapy.4 Patients who have participated in gene therapy clinical trials underscore the unique value of hemophilia gene therapy and its profound impact on patients' lives. However, the irreversible nature of gene therapy, existing knowledge gaps, and uncertainties highlight the critical importance of promoting shared decision-making, especially given the availability of alternative therapies for hemophilia. Corticosteroid therapy for potential hepatotoxicity and its adverse effects should be thoroughly explained to all patients considered for gene therapy and their caregivers. Our findings also emphasize the critical role of therapeutic education in the success of gene therapy. If 15% of patients fail to abstain in tightly controlled trials, it is conceivable that the percentage could be even higher in real-world scenarios. Ensuring that patients understand the importance of protecting their hepatocytes is critical to improving the success rate of this costly treatment. The uncertainties and challenges associated with gene therapy underscore the need for psychological support for patients, particularly with regard to the unavailability of treatment for those pre-immunized against Adeno associated virus (AAV) with high titer antibodies and those having a progressive decline in efficacy over time. Patient perceptions of gene therapy, along with evidence of its clinical and cost effectiveness, will be critical to its widespread clinical adoption. Genevieve Pietu, Nicolas Giraud, and Yesim Dargaud conceived and designed the project. Laurent Frenzel, Antoine Rauch, Herve Chambost, Anne Lienhart, and Yesim Dargaud are the hematologists in charge of the patients. Genevieve Pietu, Nicolas Giraud, and Yesim Dargaud analyzed the data. Yesim Dargaud produced the first draft of the manuscript which was subsequently finalized by all authors. All authors approved the final manuscript. The authors thank all patients who participated in the survey. L.F. received consulting fees from BioMarin, CSL Behring, Roche/Chugai, SOBI and Pfizer; received research grant from Pfizer, and received support for attending meetings from CSL Behring, NovoNordisk, Pfizer and Roche. A.R. received consulting fees from BioMarin, CSL Behring, Roche/Chugai, SOBI; and received support for attending meetings from Biomarin, CSL Behring, NovoNordisk, Pfizer, Roche and Sobi. H.C. received consulting fees from BioMarin, CSL Behring, NovoNordisk, Pfizer, Roche/Chugai, SOBI; received payment/honoraria for lectures/speakers bureau from BioMarin, CSL, Roche Chugai, and Sobi; received payment for expert testimony from BioMarin; and received support for attending meetings from Biomarin, CSL Behring, NovoNordisk, Octapharma, Pfizer, Roche and Sobi. Y.D. has been a member of the advisory board for Sobi, BioMarin, CSL, Novo Nordisk, Roche, Pfizer; she received research support to institution from Bayer, Pfizer, CSL Behring, Octapharma, Novo Nordisk. G.P. and N.G. stated that they had no interests which might be perceived as posing a conflict or bias. Research ethics committee (REC) approval was not required for the preparation of this manuscript. Data will be made available upon request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.