Dr. Coates: Yes, if a patient has a matched sibling donor, we strongly recommend that approach. However, even if there is a perfectly matched sibling, there remains a 3% to 5% risk of transplant-related mortality. For most parents of young children with beta thalassemia, the only acceptable number is zero percent. Adequate management with transfusion and iron control gives the patient and his family the time and opportunity to discuss options.
Dr. Thompson: Any of these cures has a cost. In addition to the risk of transplant-related mortality, all curative approaches carry the risk of infertility.
No matter what kind of transplant – gene therapy, alloHCT, or autologous hematopoietic cell transplantation – infertility is still a burden we are not able to alleviate. I am encouraged by some of the progress in fertility cryopreservation in young children, but this is still experimental. In our experience, if fertility is a high priority, parents of children with sibling matches have deferred transplant to ensure that they allow the child time to participate in that decision.
Dr. Coates: Another concern about gene therapy are the less-exciting outcomes seen in patients with the ß0 genotype, compared with those in patients with the ß+ genotype. We also have seen that some patients who receive gene therapy are developing thalassemia intermedia instead, when only sporadic or no transfusions are required. These represent some of the most complicated patients to follow, even for physicians with extensive experience in managing thalassemias.
If patients undergo gene therapy and their hemoglobin levels are at 11 or 12 g/dL, I anticipate gene therapy will continue to provide long-term clinical benefit; however, if patients undergo gene therapy and their hemoglobin levels linger at 8 or 9 g/dL, they might develop the same long-term complications seen with thalassemia intermedia. In contrast, after a sibling or unrelated donor alloHCT, patients essentially no longer have thalassemia.
Dr. Thompson: We have managed a fair number of patients who have thalassemia intermedia, and I am struck by how severely their quality of life worsens over time compared with some of our patients with transfusion-dependent thalassemia – irrespective of transplantation. As we look to improve gene therapy, it must be with the intent to normalize hemoglobin and iron homeostasis. Without achieving those goals, we may see improvements in terms of scientific measures, but we will fall short in terms of clinical improvement.
Dr. Coates: Thalassemia intermedia brings me to another topic: the current enthusiasm for luspatercept.3 This drug is thought to work by inhibiting ineffective erythropoiesis. The BELIEVE trial showed that it was efficacious in transfusion-dependent patients, meeting all major transfusion burden–related endpoints. Data from the preliminary studies in non–transfusion-dependent patients also are quite exciting, showing that, while the approach did not cure the disease, it markedly improved disease burden – particularly in those with hemoglobin levels of 8 to 9 g/dL.4
Again, this is a huge problem in the U.S. because patients with non–transfusion-dependent beta thalassemia are often not recognized as having thalassemia by many hematologists or general practitioners. Luspatercept will probably be an exciting option for them, but I wonder what effect luspatercept would have on patients with hemoglobin levels of 8 or 9 g/dL who have received gene therapy.