Gene-edited autologous cell therapy in patients with TDT or SCD

Exagamglogene autotemcel (exa-cel) demonstrated durable clinical benefits with >6 years of follow-up in patients with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD). The safety profile was consistent with myeloablative busulfan conditioning and autologous transplantation, with no malignancies reported [1]. These data suggest that exa-cel has the potential to provide a one-time functional cure for TDT and SCD.

Exa-cel is a one-time, ex vivo CRISPR/Cas9 gene-edited autologous cell therapy approved for patients aged ≥12 years with TDT or SCD who have recurrent vaso-occlusive crises (VOCs). Prof. Franco Locatelli (University of Pavia, Italy) reported long-term efficacy and safety results from 3 phase 3 trials: CLIMB THAL-111 (NCT03655678), CLIMB-121 (NCT03745287), and the extension study CLIMB-131 (NCT04208529). Participants were aged between 12 and 35 years, with a mean age of approximately 21 years.

In CLIMB THAL-111, 56 participants with TDT received exa-cel. TDT was defined as a history of ≥100 mL/kg/year or ≥10 units/year of red blood cell (RBC) transfusions in the previous 2 years. The primary endpoint is transfusion independence (TI12), defined as maintaining a weighted average haemoglobin ≥9 g/dL without RBC transfusion for ≥12 consecutive months. In the combined CLIMB THAL-111 and CLIMB-131 analysis, 55 of 56 patients (98.2%) achieved TI12 after a median follow-up of 49.6 months. Transfusion independence was sustained for a median of 3.9 years. All participants achieved neutrophil and platelet engraftment.

In CLIMB-121, 46 participants with severe SCD and a history of ≥2 severe VOCs per year in the previous 2 years received exa-cel. The primary endpoint was the proportion of participants free of severe VOCs for ≥12 consecutive months (VF12). After a median follow-up of 44.7 months, all 46 evaluable participants achieved VF12 in CLIMB-121 and CLIMB-131 analysis. All participants also achieved neutrophil and platelet engraftment.

The safety of exa-cel was consistent with that expected for myeloablative busulfan conditioning and autologous transplantation in both TDT and SCD. In CLIMB THAL-111, 16 patients (28.6%) experienced adverse events (AEs) related to exa-cel, and 55 (98.2%) experienced AEs related to busulfan. In CLIMB-121, 13 patients (28.3%) and 46 patients (100%) experienced AEs related to exa-cel and busulfan, respectively. No malignancies were reported during follow-up in CLIMB-131.

“Long-term follow-up continues to demonstrate that exa-cel has the potential to provide a one-time, durable treatment benefit for patients with SCD and TDT,” concluded Prof. Locatelli.

Locatelli F, et al. Durable clinical benefits with exagamglogene autotemcel for greater than 6 years of follow-up in transfusion-dependent thalassemia and sickle cell disease with recurrent vaso-occlusive crises. GS2-5, EBMT congress 2026, 22–25 March, Madrid, Spain.