Clinical Pearls & Morning Reports
Published January 20, 2021
Esrick et al. conducted a single-center, open-label pilot study that assessed whether BCL11A inhibition was an effective target for fetal hemoglobin induction in patients with severe sickle cell disease. Read the NEJM Original Article here.
Q: What pathophysiological effects are caused by the abnormal hemoglobin in sickle cell disease?
A: Sickle hemoglobin (HbS) is a variant of normal adult hemoglobin (HbA) that is produced when the β-globin gene (HBB) contains a single E6V missense mutation. On deoxygenation, HbS polymerizes, leading to abnormally shaped red cells and protean downstream clinical sequelae, including painful vaso-occlusive crises, chronic hemolytic anemia, progressive and irreversible organ damage, decreased quality of life, and early death.
Q: How does BCL11A affect fetal hemoglobin levels in erythrocytes?
A: The transcription factor BCL11A has been validated as a repressor of fetal hemoglobin (HbF) levels in model systems. Inactivation of BCL11A in a transgenic humanized sickle cell mouse model resulted in correction of the hematologic and pathologic defects associated with sickle cell disease. BCL11A plays key roles outside the erythroid lineage, including a role in the development and function of hematopoietic stem cells and B-lymphocytes, so clinical translation of a BCL11A-targeting therapy requires lineage specificity to selectively reduce the BCL11A protein in erythrocytes.
A: In utero and during infancy, the abnormal HbS protein is produced at very low levels in those with sickle cell disease because the erythrocytes have not yet shifted from expression of the γ-globin gene, which encodes the developmentally regulated component of HbF, to expression of the HBB gene, a phenomenon known as hemoglobin switching. Thus, infants with sickle cell disease are typically free of clinical symptoms, owing to the potent antisickling properties of HbF combined with the lower levels of HbS. In older children and adults, a higher level of HbF is associated with lower disease severity in sickle cell disease, as has been observed in persons with hereditary persistence of HbF and in those who have a good response to hydroxyurea. The overall percentage of HbF is important, but equally critical is the level of HbF within each red cell. To exert a beneficial effect, HbF must be distributed broadly enough to protect a high proportion of cells from intracellular HbS polymerization. Prior studies have shown that a 20% HbF level in whole blood is associated with amelioration of sickle cell disease symptoms. On an individual cell basis, although less well studied, a level of 10 pg of HbF per F-cell, or approximately one third of the cellular hemoglobin content, is likely to be sufficient to prevent HbS polymerization.
A: Six patients (7 to 25 years of age at enrollment) received the investigational gene therapy between February 2018 and March 2020, and the patients had a median follow-up of 18 months (range, 7 to 29) after infusion. The primary end point was neutrophil engraftment, as measured by an absolute neutrophil count of at least 0.5×109 per liter for 3 sequential days during the 7 weeks after infusion. All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction, with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell.