Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion‐Dependent β‐Thalassemia

Jun 8, 2026American journal of hematology

Improving Red Blood Cell Production and Iron Balance After Gene Therapy in Transfusion-Dependent Beta-Thalassemia

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Abstract

Exagamglogene autotemcel (exa-cel) treatment led to transfusion independence in 91% of participants with transfusion dependent β-thalassemia.

98% of participants maintained transfusion independence for at least 12 months after treatment.
68% of participants discontinued iron removal therapy, with a mean duration off therapy of 19.4 months.
Erythroferrone concentrations decreased and hepcidin levels normalized in all participants following treatment.
Key biomarkers of erythropoiesis showed improvements, including erythropoietin levels and reticulocyte counts.
Iron overload biomarkers, such as ferritin and liver iron concentration, decreased and remained stable post-treatment.

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Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo, CRISPR-Cas9 gene edited cell therapy approved for patients with transfusion dependent β-thalassemia (TDT) aged 12-35 years. In a Phase 3 study (CLIMB THAL-111), exa-cel treatment resulted in reactivation of fetal hemoglobin and increases in total hemoglobin, leading to transfusion independence in 91% of participants. Here, we report on the impact of exa-cel treatment on measures of ineffective erythropoiesis and iron homeostasis, which were secondary and exploratory endpoints in CLIMB THAL-111 and the CLIMB-131 long-term follow-up study. Prior to exa-cel infusion, all participants were receiving regular red blood cell transfusions and iron chelation therapy. At time of data cut (April 2025), 98% of participants (55 of 56) had been transfusion independent for ≥ 12 months and 38 (68%) had discontinued iron removal therapy (mean duration off iron removal therapy 19.4 months). Following transfusion independence and cessation of iron removal therapy, erythroferrone concentrations decreased and hepcidin levels normalized in all participants, indicating correction of ineffective erythropoiesis and restoration of iron homeostasis. Further supporting this finding, improvements and trends toward normalization were seen in key erythropoiesis biomarkers, including erythropoietin levels, reticulocyte counts, and soluble transferrin receptor concentrations. Iron overload biomarkers, including ferritin, liver iron concentration, and cardiac T2*, decreased and then remained stable throughout follow-up, even after cessation of iron removal therapy. These results demonstrate restoration of effective erythropoiesis and iron homeostasis after exa-cel infusion in the setting of transfusion independence following reactivation of fetal hemoglobin. (CLIMB THAL-111 and CLIMB-131; Clinical Trials.gov numbers NCT03655678 and NCT04208529).

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CRISPR gene therapy eliminates blood transfusions in 91% of β-thalassemia patients

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Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion‐Dependent β‐Thalassemia

Abstract

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