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Reference: N Engl J Med 2018 Apr 19;378(16):1479 (level 3 [lacking direct] evidence)
- Management of beta-thalassemia includes lifelong red blood cell transfusions when bone marrow transplant is not an option.
- Ex vivo gene therapy for the beta globin gene was evaluated in 22 patients with transfusion-dependent beta-thalassemia. Autologous CD34+ cells were transduced with the LentiGlobin BB305 vector carrying a functional HBB gene and reintroduced with a single infusion.
- Red blood cell transfusions were no longer required in 12 out of 13 patients with a less severe form of disease and 3 out of 9 patients with a more severe form of disease at a median follow-up of 26 months.
Beta-thalassemia is a hereditary anemia caused by a point mutation in the beta globin gene leading to decreased or absent beta globin chain synthesis. Beta0 mutations prevent beta-globin synthesis; other mutation types impair but do not completely prevent synthesis. Recommended treatment for patients with a severe form of the disease is blood transfusions every few weeks to maintain pre-transfusion hemoglobin levels of at least 9-10.5 g/dL and chelation therapy to prevent iron toxicity (Thalassemia International Federation 2014). Bone marrow transplant may be considered if a compatible donor is available. A pooled analysis of data from two uncontrolled trials evaluated ex vivo gene therapy for the beta globin gene in 22 patients aged 12-35 years with transfusion-dependent beta-thalassemia of any genotype. CD34+ cells obtained from each patient were transduced with the LentiGlobin BB305 vector carrying a functional HBB gene. After myeloablation with busulfan, the patients were treated with a single infusion of the autologous gene-modified cells. Exclusion criteria included advanced organ damage, infection with human immunodeficiency virus or hepatitis B or C, chronic kidney disease, white blood cell or platelet suppression, and pulmonary hypertension. The median follow-up was 26 months.
Among 13 patients with a non-beta0/beta0 genotype (impaired beta-globin synthesis), 12 no longer required red blood cell transfusions. At the end of follow-up, the total level of hemoglobin ranged from 8.2 to 13.7 g/dL. Among 9 patients with the more severe beta-thalassemia (beta0/beta0 genotype or homozygosity for the IVS1-110 mutation,) 3 no longer required red blood cell transfusions. The annual number of transfusions was reduced by a median of 74% (range 7%-100%) and annual transfusion volume was reduced by a median of 73% (range 19%-100%). At the end of follow-up, the total hemoglobin level ranged from 8.3 to 11.3 g/dL. Serious adverse events in all the patients included veno-occlusive liver disease in 2, Klebsiella infection in 1, cardiac ventricular thrombosis in 1, cellulitis in 1, hyperglycemia in 1, and gastroenteritis in 1 patient. No replication competent lentivirus was detected.
All but one patient with a less severe form, and one-third of those with a more severe form of beta-thalassemia were able to stop receiving red blood cell transfusions. Long-term follow-up is necessary to evaluate continued benefit and potential delayed adverse effects such as malignant transformation or other unpredictable events. The LTF-303 study of some of these and other patients plans to provide follow-up of at least 15 years to address these questions. In the meantime, these early results are promising in that they suggest a potential treatment option to replace supportive care in patients with transfusion-dependent beta-thalassemia and that gene therapy may be a viable therapeutic strategy to pursue for other genetic disorders.
For more information, see the topic Beta-thalassemia major and intermedia in DynaMed Plus. DynaMed users click here.