INSIDE BLOOD ADVANCES - Sickle cell disease and thalassemia go to the PROm

Sep 29, 2026

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Gene addition and editing strategies targeting sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have progressed into clinical trials, including CRISPR-Cas9 enhancer editing of BCL11A to raise fetal hemoglobin and support transfusion independence in TDT while reducing vaso-occlusive episodes in SCD. Blood Advances reports patient-reported outcomes and health-related quality of life improvements with Exa-Cel across adolescents and adults. The text explains the concept of a functional cure and the selection and evaluation of pain, affect, and functioning domains, highlighting clinically meaningful gains and the importance of preventing long-term organ dysfunction.

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Sickle cell disease and thalassemia clinical gene editing

BCL11A enhancer editing and Exa-Cel therapy

Functional cure concept and study endpoints

Patient-reported outcomes (PROs) and quality of life (HRQoL)

Interpretation of results in adolescents and adults

Importance of PROs and future directions

INSIDE BLOOD ADVANCES Sickle cell disease and thalassemia go to the PROm Miguel R. Abboud 1 and Biree Andemariam2 1 Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; and 2 New England Sickle Cell Institute, Department of Medicine, University of Connecticut Health, Farmington, CT Comment on de la Fuente et al, XXX, and Sharma et al, page XXX 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 TDT 1 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 inmost 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 al

FAQs

What gene-editing approach is described for SCD and TDT?

CRISPR-Cas9 editing of the BCL11A enhancer reduces BCL11A expression, suppressing fetal hemoglobin production and leading to rapid, sustained increases in endogenous fetal hemoglobin.

How is a “functional cure” defined in the text?

It is defined as completely suppressing disease-related complications and costs while restoring life expectancy and HRQoL to that of an unaffected comparable individual.

Which patient-reported outcome domains were emphasized in the reported studies?

The studies evaluate PROs across pain, affect (including fatigue and sleep patterns), and functioning (including social, physical, cognitive, and self-efficacy), alongside additional tools related to bone marrow transplantation.

Sep 29, 2026

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