Recently, several gene addition and editing approaches aimed at addressing the underlying cause of both sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have entered clinical trials. One of the more successful approaches uses gene editing with CRISPR-Cas9 of the enhancer of BCL11A to reduce expression of this protein, which is a suppressor of fetal hemoglobin production. This leads to rapid and sustained increases in endogenous fetal hemoglobin production, which results in transfusion independence in patients with beta-thalassemia and a decrease in painful vaso-occlusive episodes requiring health care utilization in patients with SCD.1,2 These results led to the approval of this modality of therapy, labeled exagaglogene autotemcel (Exa-Cel), for the treatment of both TDT and severe SCD.
Although not correcting the underlying genetic defect, this approach has led to what is referred to as potentially a “functional cure” for both disorders. The primary end points in the original studies were hemoglobin level and transfusion independence for 12 months in patients with TDT1 and freedom from painful crises requiring a visit to a medical facility for patients with severe SCD.2 In addition to the primary end points, both studies and the subsequent extension and long-term follow-up studies of treated patients included patient-related outcomes (PROs) and measures of health-related quality of life (HRQoL) as predefined secondary end points evaluated at defined time points during the studies. In this issue of Blood Advances, these results are reported in 2 studies; one by de la Fuente et al3 and the other by Sharma et al4 demonstrating improvements in HRQoL in adolescents and adults with severe SCD and TDT treated with Exa-Cel gene therapy.
A functional or fully effective cure in SCD was recently defined as “one that completely suppresses disease related complications and costs and restores life expectancy and HRQoL to that of a comparable individual unaffected by the disease,”5 a definition that could also apply to TDT. Thus, to determine a functional cure for patients treated with gene therapy, the investigators would also need to demonstrate improved HRQoL in the short, intermediate, and long-term periods of follow-up and suppression of “disease related complications” and prevention of chronic organ dysfunction in the long-term. The evaluation of and selection of PROs is a complex process and involves the selection of generic and disease-specific measures.6-9 The utilization of PROs as end points in SCD was recently evaluated, and recommendations were made by a panel selected by the American Society of Hematology and the Food and Drug Administration to collect PROs8 for the following 3 specific domains: pain, affect (including fatigue and sleep patterns), and functioning (including social, physical, cognitive, and self-efficacy). In both studies published in Blood Advances, the investigators have evaluated each of these domains in addition to using a tool related to PROs of patients undergoing bone marrow transplantation. The tools were validated, and minimal clinically important differences were extensively and appropriately evaluated.3,4 Both studies demonstrated improvement compared with baseline in most measures for adults and adolescents. It is interesting to note that adults with TDT had values close to the unaffected population at baseline which further improved after gene therapy, whereas for adults with SCD, the baseline values were below those of the unaffected population, and these also improved significantly. Another important observation is that adolescents with SCD had greater improvement in measures of pain suggesting that earlier intervention, before chronic pain syndromes appear, may be more effective.
Measuring PROs as part of clinical trials in thalassemia and SCD is of great importance as many of the most common symptoms, such as pain, fatigue, and poor physical functioning,10 which affect the lives of these patients are not evaluable otherwise. The improvement in these PRO measures reported here is very encouraging, and we now look forward to future results on the prevention of chronic end-organ complications in both diseases. After the prom, we expect long and fruitful lives for people with TDT and SCD.
Conflict-of-interest disclosure: M.R.A. reports research support from Agios, Novartis Pharmaceuticals, Pfizer, AstraZeneca, Salix Pharmaceuticals, and Novo Nordisk; serves as a member of the data safety monitoring boards for trials with Vertex and CRISPR Therapeutics; reports direct speaker honoraria from Emmaus and Novo Nordisk;travel support from Roche; and serves as a member on the advisory board of Agios Pharmaceuticals. B.A. served as a consultant of Accordant, Afimmune, Agios, Beam Therapeutics, bluebird bio, Chiesi, Editas, Genentech, GlaxoSmithKline, Hema Biologics, Hemanext, Merck, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanius Health, Sanofi Genzyme, and Vertex; reports research support from Afimmune, Agios, American Society of Hematology, American Thrombosis Hemostasis Network, Centers for Disease Control, Connecticut Department of Public Health, Hemanext, Health Resources and Services Administration, Novo Nordisk, Patient-Centered Outcomes Research Institute, and Pfizer; and served as a member of the data safety monitoring boards for trials with Editas and Fulcrum Therapeutics.
