Treatment with the CRISPR-based gene therapy exagamglogene autotemcel (exa-cel) has demonstrated significant and sustained improvements in health-related quality of life for patients with severe sickle cell disease and transfusion-dependent beta thalassemia, according to two studies published in Blood Advances. The findings represent among the first to quantify patient-reported quality-of-life changes following CRISPR-based gene editing treatment.
Clinical Trial Results Show Meaningful Improvements
The studies examined participants from the ongoing CLIMB-SCD-121, CLIMB-THAL-111, and CLIMB-131 clinical trials, including adolescents and adults with at least 16 months of follow-up. The median follow-up durations were 33.6 months for the sickle cell disease cohort and 38.4 months for the beta thalassemia cohort.
Patients completed validated assessments measuring emotional, physical, social, and functional wellbeing, along with pain-related impacts. These evaluations included disease-specific instruments such as the ASCQ-Me and PedsQL, as well as general health measures like the EQ-5D-5L.
Sickle Cell Disease Patients Exceed Population Norms
Prior to receiving exa-cel, patients with sickle cell disease reported quality of life below population norms. Following treatment, scores not only improved but exceeded those norms, surpassing thresholds for the minimal clinically important difference (MCID) – a benchmark indicating that patients perceived the change as meaningful.
Adult patients experienced the largest non-pain improvements in social and emotional functioning. Among adolescents, notable gains were observed in school and social functioning, demonstrating the therapy's broad impact across different age groups and life domains.
Beta Thalassemia Outcomes Show Additional Benefits
In the beta thalassemia study, patients began with average or near-average quality of life scores. Nevertheless, exa-cel treatment was associated with additional improvements beyond baseline levels. Adults reported a mean gain of 14.0 points in EQ-5D-5L scores by month 48, while adolescents saw an average gain of 6.1 points by month 24. As with sickle cell disease patients, these gains exceeded the MCID threshold.
CRISPR-Based Treatment Mechanism
Exa-cel is a one-time therapy based on CRISPR-Cas9 gene editing technology. The treatment process involves removing the patient's hematopoietic stem cells, editing the cells ex vivo to restore production of fetal hemoglobin, and reintroducing them after myeloablative conditioning.
The US Food and Drug Administration approved exa-cel for treating sickle cell disease in patients aged 12 years and older in December 2023. Approval for transfusion-dependent beta thalassemia followed in January 2024, marking significant regulatory milestones for CRISPR-based therapeutics.
Study Limitations and Future Directions
The authors acknowledge several limitations in their findings. The results are based on patient-reported outcome measures, some of which were not originally developed for individuals with sickle cell disease or transfusion-dependent beta thalassemia. Additionally, the trials are ongoing and include relatively small cohorts.
The researchers emphasize that continued long-term follow-up in larger populations is needed to confirm these results and better understand the sustained impact of this gene editing approach on patient wellbeing. Despite remaining a costly and complex intervention, these recent results suggest exa-cel's potential for substantial improvements in patient quality of life for these serious inherited blood disorders.
