Optimising Transplant in Haemoglobinopathies: EHA 2026 Perspectives

Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative option for many patients with severe haemoglobinopathies, such as beta-thalassaemia major and sickle cell disease. However, the procedure is associated with significant morbidity and mortality, primarily due to transplant-related toxicity and graft-versus-host disease (GVHD). Optimising the transplant process requires careful consideration of several factors, including patient selection, conditioning regimen, graft source, and post-transplant management. Discussions at EHA 2026 focused on refining these elements based on clinical experience and emerging evidence, aiming to improve long-term survival and quality of life for patients.¹

Patient stratification is critical in determining transplant eligibility and tailoring treatment. For beta-thalassaemia, the Pesaro classification, which considers liver fibrosis, hepatomegaly, and portal fibrosis, has historically guided risk assessment. Patients classified as Pesaro Class 1 generally have superior outcomes with standard myeloablative conditioning. However, for higher-risk patients (Pesaro Class 2 and 3), reducing transplant-related mortality while maintaining engraftment remains a challenge. Similarly, in sickle cell disease, transplant indications are typically reserved for patients with severe complications, such as recurrent vaso-occlusive crises, acute chest syndrome, or stroke, who have suitable donors. The global burden of haemoglobinopathies is substantial, with millions affected worldwide, particularly in regions like the Mediterranean, Middle East, and Southeast Asia for thalassaemia, and sub-Saharan Africa for sickle cell disease. This widespread prevalence underscores the urgent need for effective and safe curative strategies.²

Optimising Conditioning Regimens and Graft Sources

The choice of conditioning regimen is paramount. Myeloablative conditioning (MAC), typically involving busulfan and cyclophosphamide, has been the standard for many years, particularly for younger patients with beta-thalassaemia. MAC regimens aim to eradicate host haematopoiesis and create sufficient space for donor cells. However, MAC is associated with significant organ toxicity, including hepatic veno-occlusive disease and cardiac complications. Reduced-intensity conditioning (RIC) regimens, which use lower doses of chemotherapy or radiation, have been explored to mitigate toxicity, particularly in older patients or those with comorbidities. RIC regimens aim for sufficient immunosuppression to allow engraftment without complete myeloablation. Data presented at EHA 2026 highlighted that while RIC can reduce acute toxicity, the risk of graft rejection may be higher in some haemoglobinopathy cohorts, necessitating careful patient selection and potentially different immunosuppressive strategies. The mechanism of action for these regimens involves targeting rapidly dividing cells, including both host hematopoietic stem cells and immune cells, to prevent rejection of the donor graft.³

The source of haematopoietic stem cells also significantly impacts transplant outcomes. Matched sibling donors (MSD) are considered the optimal source due to lower rates of GVHD and improved engraftment. However, only a minority of patients have an MSD. For patients without an MSD, alternative donor sources include matched unrelated donors (MUD), umbilical cord blood (UCB), and haploidentical donors. Each alternative source presents distinct advantages and disadvantages. MUD transplants offer comparable outcomes to MSD transplants if a highly matched donor is identified, but the search process can be lengthy. UCB transplantation is associated with a lower incidence of chronic GVHD but carries a higher risk of graft failure and slower engraftment due to lower cell doses. Haploidentical transplantation, using a partially matched family member, has become increasingly feasible with advancements in post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. PTCy has significantly reduced the incidence of severe acute and chronic GVHD, making haploidentical HSCT a viable option for many patients lacking other donor types. Real-world data from EHA 2026 indicated that haploidentical HSCT with PTCy is increasingly being adopted for haemoglobinopathies, demonstrating encouraging engraftment rates and acceptable toxicity profiles, particularly in centres with extensive experience.^4,5

Post-transplant management, including immunosuppression and monitoring for complications, is also critical. Prophylaxis against infections, particularly viral infections such as cytomegalovirus (CMV), is standard. Long-term follow-up is essential to monitor for late complications, including chronic GVHD, secondary malignancies, and endocrine dysfunction. The ongoing challenge is to refine these protocols to minimise long-term sequelae while maintaining disease-free survival. The discussions at EHA 2026 underscored the need for multicentre collaborations to gather more comprehensive real-world data, enabling further optimisation of HSCT for haemoglobinopathies. Limitations in current transplant approaches often include the availability of suitable donors, the high cost of the procedure, and the long-term management of potential complications, which can impact patient quality of life.⁶

For an in-depth exploration of haemoglobinopathies, transplant considerations, and comprehensive clinical haematology, consult the definitive Oxford Handbook of Clinical Haematology.