Patient and Parent-Reported Outcomes Post-Treatment with Shmir-Based Lentiviral Gene Therapy for Sickle Cell Disease
Authors: Jimenez-Kurlander Lauren , Kao Pei-Chi , Magner Mira , Morris Emily , Federico Amy , Moore Theodore , DeOliveira Satiro , Fernandes Augustine , Kohn Donald B. , London Wendy B. , Williams David A. , Esrick Erica B. 
Published: December 2023

Background: Sickle cell disease (SCD) is among the most common monogenic disorders and causes lifelong complications, including vaso-occlusive events (VOEs) and decreased quality of life (QOL). Gene therapy (GT) has emerged as a potential curative therapy for SCD, but its impact on patients' QOL remains underexplored. We previously reported preliminary safety and efficacy data on 6 patients who received autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector (Esrick et al., NEJM, 2021). Here, we report the first results of parent- and patient-reported outcomes (PROs) for 10 patients treated with BCH-BB694 up to 24 months post-infusion.
Methods: We evaluated the QOL of 10 patients with severe SCD who received GT with BCH-BB694 as part of a single-center, open-label pilot study. Assessment occurred during patients' scheduled visits for safety and efficacy monitoring at baseline and months 3, 6, 12, and 24. QOL was measured using the Pediatric Quality of Life Inventory (PedsQL) self- and parent-reported questionnaires for children &lt; 18-years old and the self-reported 36-Item Short Form Health Survey (SF-36) for adults ≥ 18-years old. Assessed domains included: physical functioning, pain, emotional functioning, social functioning, school functioning, and general health. The percent change from baseline to post-treatment score (last observation carried forward [LOCF]) was calculated with 95% confidence intervals (CI). Clinically significant improvement was defined as a score increase ≥5%. Other laboratory and clinical data collected at study timepoints included fetal hemoglobin (HbF) measured by high-performance liquid chromatography, VOEs (including vaso-occlusive pain, priapism, and acute chest syndrome), and transfusion frequency.
Results: All patients demonstrated elevated HbF levels at LOCF (mean 26.9%, range 11.7-38.2%). Of 10 patients enrolled, 1 was missing baseline data and 9 had sufficient data for analysis. Patients (n=9) were aged 8-27 years at time of BCH-BB694 infusion. Baseline self-reported total scale scores (median 69.6, interquartile range [IQR] 50.1, 77.2) were consistent with baseline PedsQL scores for patients with SCD reported in the literature (median 67.4, IQR 50.0, 83.5) (Panepinto et al., J Pediatr Hematol Oncol, 2008). Average self-reported total scale scores increased at 3 months post-treatment (mean % change from baseline [95% CI]: 21% [3.3% to 38%]) and maintained at LOCF (13% [-10% to 36%]). For the 3 patient/parent pairs, parent-reported total scale scores appeared more variable, with a mean % change from baseline of -1% (95% CI: -40% to 38%) at 3 months and -17% (95% CI: -36% to 1%) at 24 months. Clinically significant self-reported improvement occurred in 8 patients (89%) for at least 1 domain and in 5 (56%) for overall QOL. The patient without baseline data reported a maximum total scale score of 100 at 24-months. Specific domains (mean % change from baseline [95% CI]) demonstrating significant improvement included: general health (7% [-11%, 25%]), physical functioning (30% [-15%, 76%]), and emotional functioning (15% [-9%, 39%]). Excluding 1 patient who had a low HbF induction associated with a low in vivo vector copy number and increase in VOEs from baseline, this cohort demonstrated decreased numbers and/or absence of VOEs post-GT (n=8), and all patients required significantly fewer transfusions.
Conclusion: At most recent study visit up to 24 months post-treatment, SCD patients who had received GT with successful HbF induction (&gt;20% in 8 patients) reported higher QOL than baseline on average. Excluding 1 patient, this cohort demonstrated improvement in at least 1 QOL domain following GT, suggesting a positive impact of GT on QOL in this group of patients with SCD. For patients &lt;18-years, discrepancies between parent-reports and higher self-reports warrant future investigation. Few patients (n=3) did not demonstrate overall QOL total score improvement post-GT. Follow up studies may assess whether this reflects insufficient treatment response, treatment- or pre-existing disease-related morbidity, and/or need for more specific QOL assessments. An understanding of the relationship of change in QOL with VOE and/or transfusion rates will be enriched by more patients, longer follow-up, and PRO tools designed specifically for the SCD population. Larger studies are needed to fully elucidate the impact of GT on QOL in this population.