Targeted liver assessment and the role of biopsy prior to gene therapy and HSCT in transfusion-dependent β-thalassemia: Addressing an unmet need in the absence of standardized protocols Free

Introduction Liver assessment plays a pivotal role in pre-transplant work up in gene therapy and Hematopoietic Stem Cell Transplant (HSCT) in patients with transfusion dependent β-thalassemia (TDT). Due to the high risk of transplant related morbidity and mortality such as veno-occlusive disease, there are established exclusion criteria including a history of cirrhosis, bridging fibrosis or advanced liver disease. The absence of widely accepted standardised protocol for liver assessment in adults with TDT undergoing HSCT or gene therapy presents a significant clinical challenge, especially given the crucial role of hepatic status in determining treatment outcomes. Our experience with non-invasive techniques including Acoustic Radiation Force Impulse (ARFI) elastography and transient elastography highlights their utility as reliable methods for liver assessment. Despite the invasive nature of liver biopsy, it remains a reference standard in evaluation of liver pathology.

Methods All patients undergoing matched related HSCT or gene therapy had a comprehensive liver assessment. This included review of previous and current MRI based liver iron quantification, ferritin and viral hepatitis serology (hepatitis A, B and C). Liver impairment and synthetic functions were monitored through serum ALT, AST, conjugated bilirubin and prothrombin time to identify the presence of advanced liver disease. Non-invasive liver stiffness assessment was performed using liver stiffness assessment modalities like ARFI elastography and transient elastography. Patients with abnormal elastography results or a significant history of liver disease underwent liver biopsy for histopathological confirmation. In addition, MRI liver imaging was also utilised to improve liver disease characterization.

Results A total of eight patients were included in the study. Their ages ranged from 17 to 37 years, with a median age of 28.5 years (interquartile range 21.5–31.5 years). The cohort included five males and three females. Three patients with normal elastography values proceeded directly to apheresis, while five were referred for liver biopsy. Among the biopsy group, four patients had abnormal elastography values ranging from 6.5 kPa to 8.6 kPa (consistent with fibrosis stage ≥F2). One patient, despite having a normal elastography result, is currently awaiting an appointment for liver biopsy due to significant liver iron overload and hepatitis C in preparation for matched sibling donor HSCT. All cases were reviewed by the UK National Haemoglobinopathy Panel (NHP) or Cellular Therapy Group (CTG). Liver enzymes and coagulation profile were within normal range in all the patients. To date, two biopsies in patients with liver stiffness of 6.5 kPa and 8.6 kPa have excluded significant bridging fibrosis or advanced liver disease. Both patients have proceeded for gene therapy stem cell collection. Liver histology in the remaining two patients, with liver stiffness of 6.5 kPa and 7.1 kPa, confirmed Ishak fibrosis stage 3. Of these, one patient was deemed ineligible for gene therapy, while the other is currently under review by the NHP/CTG for eligibility assessment.

ConclusionFor patients with TDT undergoing gene therapy or HSCT, liver biopsy continues to play a crucial role in risk stratification and clinical decision-making, especially with abnormal elastography results. In cases where clinical history indicates increased hepatic risk such as prolonged period of poor iron control, inadequate documentation of iron control or co-existing risk factors for liver cirrhosis or fibrosis, biopsy offers critical histopathological confirmation to allow safe therapeutic progression. In our experience, results of liver biopsy supported informed decision-making for both patients and clinicians, particularly in the context of the risk of veno-occlusive disease. With the growing adoption of advanced cellular therapies for patient with TDT, incorporating targeted liver biopsy into pre-treatment assessment pathway is likely to enhance patient safety and improve clinical outcomes, especially where non-invasive modalities demonstrate abnormal or inconclusive results.