Editor's Note:At the EBMT 2026 Annual Meeting, Professor Franco Locatelli from Bambino Gesù Children’s Hospital presented long-term follow-up data for exagamglogene autotemcel (exa-cel), a CRISPR/Cas9-based gene-editing therapy. The study included patients with transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). With a median follow-up of over three years and some patients reaching over six years, the results provide robust evidence for the long-term efficacy and safety of gene editing in hereditary blood disorders. 01 Mechanism of Action: Non-Viral Ex Vivo Editing Targeting BCL11A
Exa-cel is an autologous CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. The mechanism involves non-viral ex vivo CRISPR/Cas9 editing to disrupt the erythroid-specific enhancer region of the BCL11A gene. BCL11A is a key repressor for the switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA). By silencing this enhancer, the synthesis of γ-globin is induced, reactivating HbF production to compensate for β-globin deficiency in TDT or to prevent HbS polymerization in SCD.
02 Long-Term Efficacy: Near-Total Elimination of VOC Risks in SCD
The SCD cohort comprised 46 patients (25% adolescents, 75% adults) with a median follow-up of over three years (up to six years).
- Primary Endpoint: 91.3% of patients remained free of severe VOCs for at least 12 consecutive months following exa-cel infusion.
- Hospitalization Reduction: 97.8% of patients achieved freedom from VOC-related hospitalizations for at least 12 consecutive months.
- Pain Event Analysis: VOC events reported post-infusion were primarily mild acute pain episodes, occurring mostly in adult patients with a history of chronic pain, often triggered by infection or psychosocial stress. Most did not require inpatient hospitalization.
03 Clinical Outcomes: 100% Success in Transfusion Independence for TDT
In the TDT cohort (n=56, 1/3 adolescents), clinical benefits were even more pronounced. These patients, many with β⁰/β⁰ or β⁰-like genotypes, had heavy pre-treatment transfusion burdens.
- Transfusion Independence (TI): Nearly all patients achieved TI (defined as no transfusions for ≥ 12 months with a weighted average Hb ≥ 9 g/dL).
- Success Rate: Although one patient initially took longer to meet the formal TI criteria, they eventually became transfusion-free. At the last evaluation, the success rate for TI in this cohort reached 100%.
- Cell Collection: Adolescents required fewer mobilization cycles (median 1.3 cycles) compared to adults to reach the target CD34+ cell dose.
04 Biomarkers: Sustained High-Level HbF Expression
Biological kinetics showed a rapid rise in HbF levels post-infusion, reaching a plateau at 6–9 months and remaining stable for the duration of the 6-year follow-up.
- Distribution: HbF showed a pancellular distribution. In the SCD cohort, HbF accounted for approximately 40% of total hemoglobin.
- Quality of Life: Stable HbF expression was accompanied by significant improvements in markers of hemolysis, reduction in iron overload, and substantial increases in Health-Related Quality of Life (HRQoL) scores.
05 Safety Profile: Consistent with Myeloablative Conditioning
The long-term safety of exa-cel was consistent with the known profiles of busulfan-based myeloablative conditioning and autologous stem cell transplantation.
- Adverse Events: Seven TDT patients developed veno-occlusive disease (VOD), all of which resolved following treatment with defibrotide.
- Survival: Overall survival (OS) and event-free survival (EFS) were approximately 98% in the SCD cohort and 100% in the TDT cohort. One SCD patient died due to COVID-19 pneumonia, which was judged unrelated to the study drug.
- Clonal Evolution: Long-term monitoring via next-generation sequencing (NGS) of the myeloid compartment showed no evidence of malignant clonal evolution or clonal hematopoiesis.
Conclusion and Outlook:
Professor Franco Locatelli concluded that exa-cel provides a “one-time” functional cure with remarkable durability and safety over a follow-up period exceeding six years. By significantly elevating HbF levels, the therapy eliminates transfusion dependency in TDT and drastically reduces the burden of VOCs in SCD. This represents a clinical milestone for CRISPR technology and offers a critical therapeutic alternative to allogeneic transplantation. Patients in this cohort will continue to be monitored for a total of 15 years to confirm ultra-long-term safety.
