Editor's Note: At the 2026 European Hematology Association (EHA) Annual Meeting, Professor Giuseppe De Franceschi from the University of Verona, Italy, representing the joint working group of the European Society for Blood and Marrow Transplantation (EBMT) and EHA, delivered an in-depth interpretation of the latest update to the "Guidelines for Patient Selection for Gene Therapy in Transfusion-Dependent β-Thalassemia (TDT)." This guideline update aims to integrate the latest clinical evidence from gene addition and gene editing technologies to provide standardized patient screening and follow-up pathways for hematologists worldwide. 01 Methodology Update: The Joint Effort of EBMT and EHA
Professor Giuseppe De Franceschi pointed out that this guideline represents a significant upgrade from the 2021 consensus version. The consensus was achieved through close collaboration between EBMT and EHA, fully integrating the professional expertise of both societies in the fields of hematopoietic stem cell transplantation (HSCT) and hematology. During the development process, the writing group was divided into a Writing Group (Writers) and a Reviewing Group (Reviewers). The Writing Group conducted a literature search based on predefined key academic questions, covering keywords such as gene addition, gene editing, iron overload, and liver fibrosis. As the evidence base in the field of thalassemia gene therapy is still rapidly expanding, some answers to key questions took the form of expert consensus (Panel Position). Professor De Franceschi emphasized that all academic disagreements were resolved through in-depth discussion to ensure the authority and consistency of the recommendations.
02 Evolution of the Gene Therapy Landscape: From Gene Addition to Gene Editing
With the rapid development of biotechnology, treatment strategies for TDT have expanded from simple gene addition to the field of gene editing. Professor De Franceschi cited information from the guideline supporting materials (Table 1S) regarding gene therapy labels approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Currently, gene therapies for TDT patients primarily include: • Gene Addition Therapy: Such as lentiviral vector-mediated β-globin gene replacement. • Gene Editing Therapy: Such as utilizing CRISPR/Cas9 technology to knock out the erythroid-specific enhancer of BCL11A to restore the production of fetal hemoglobin (HbF). The guidelines note that, unlike traditional allogeneic hematopoietic stem cell transplantation (allo-HSCT), gene editing methods demonstrate broader applicability across β-thalassemia genotypes and are no longer limited to specific types of gene mutations.
03 Liver Health: The Key Determinant for Gene Therapy Access
In the patient screening algorithm, the degree of liver organ damage is listed as a core evaluation metric. Professor De Franceschi presented a highly academic metaphor: Liver Iron Concentration (LIC) is like the “Portrait of Mona Lisa (Snapshot),” while Liver Stiffness Measurement (LSM) tells the “Life Story of St. Francis (Story).” This expression emphasizes that LIC only reflects cross-sectional iron load, whereas LSM reflects the evolutionary process of liver structural damage caused by long-term iron overload. The guidelines explicitly set 8 kPa as the critical cut-off value for LSM, with logical support derived from the European Association for the Study of the Liver (EASL) diagnostic standards for liver fibrosis under different pathological states: • LSM < 8 kPa: Suggests a lower probability of advanced liver fibrosis. Such patients are in a relatively safe zone for liver risk assessment. • LSM ≥ 8 kPa: Suggests the possible presence of advanced liver fibrosis or cirrhosis. These patients must undergo an in-depth investigation of liver status. Notably, Professor De Franceschi cited recent research data published in the American Journal of Hematology. The data show that when LSM < 8 kPa, there is a good linear correlation between LIC and LSM; however, once LSM exceeds 8 kPa, this linear relationship disappears, suggesting that liver damage has entered a more complex pathological stage.
04 Liver Biopsy Standards: Transitioning from Qualitative Assessment to Precision
Quantification For patients with LSM ≥ 8 kPa, the guidelines strongly recommend performing a liver biopsy. Professor De Franceschi referred to recommendations from authoritative bodies such as the British Society of Pathology to set rigorous technical requirements for liver biopsy: • Needle Specification: An 18G needle must be used. • Specimen Length: The length of the biopsy tissue should be at least 20 mm. • Pathological Evaluation Criteria: The specimen should contain at least 10 portal spaces to ensure the accuracy of fibrosis staging. • Detection Dimensions: In addition to histological fibrosis grading, liver iron concentration should be determined directly through the biopsy specimen whenever possible to validate imaging data.
05 Patient Stratification Strategy: High Priority and Restrictive Factors
The guidelines construct a rigorous patient access model, classifying TDT patients into three categories:
- High Priority Patients: Patients with good liver reserve (LSM < 8 kPa), no serious organ complications, and meeting gene therapy indications.
- Patients Requiring Intensive Management: Patients with high liver iron load who have not yet reached the fibrosis threshold, or those requiring high-intensity iron chelation therapy before gene therapy.
- Ineligible Patients: Patients already diagnosed with advanced liver fibrosis (Stage F3-F4), decompensated cirrhosis, or other contraindications to gene therapy. Professor De Franceschi particularly emphasized that precise assessment of liver status is not only for screening gene therapy candidates but also for comprehensively improving the clinical management level of thalassemia patients.
06 Follow-up Paradigm Upgrade: Life-cycle Monitoring Beyond Regulatory Requirements
Regarding monitoring after gene therapy, the guidelines propose follow-up protocols that exceed the official recommendations of the EMA. Professor De Franceschi pointed out that while some short-to-medium-term follow-up data are already available clinically, gene therapy—as a treatment that changes the natural history of the disease—still requires rigorous long-term observation. Focus areas of follow-up include: • Hematological Reconstruction: Assessing the duration of Transfusion Independence and hemoglobin levels. • Iron Load Metabolism: The impact of restored endogenous erythropoiesis on existing iron load and iron metabolic balance after gene therapy. • Clonal Evolution and Safety: Long-term monitoring of insertional mutagenesis risks and off-target effects of gene editing. • Changes in Natural History: Observing whether gene therapy can reverse or slow down long-term organ damage related to thalassemia.
Expert Summary and Clinical Outlook
Professor Giuseppe De Franceschi concluded that the update of the EBMT-EHA joint guidelines marks the entry of thalassemia diagnosis and treatment into the “Era of Precise Gene Therapy.” By introducing LSM ≥ 8 kPa as a decision threshold and standardizing liver biopsy technical criteria, clinicians can more scientifically identify patient groups that will achieve maximal benefit. In the future, as more clinical research data from gene editing are released, this consensus will continue to evolve, providing full-chain academic guidance from screening and treatment to long-term management for TDT patients worldwide.
