S, Beta-Thalassemia · Hb S/β-Thal

Description

Hemoglobin S beta-thalassemia is a form of sickle cell disease produced by compound heterozygosity in HBB. One allele carries the sickle variant, HbS, a glutamic acid to valine substitution at codon 6. The other allele carries a beta-thalassemia variant that reduces or abolishes normal beta-globin production. The phenotype tracks the residual output of the thalassemia allele.

HbS beta-zero thalassemia produces no normal adult hemoglobin. Its clinical course resembles homozygous HbSS, with chronic hemolytic anemia, recurrent vaso-occlusive crises, acute chest syndrome, stroke risk, and progressive end-organ damage across the kidneys, brain, lungs, and bones. HbS beta-plus thalassemia produces a small amount of normal HbA, in a range that varies by variant. The clinical course is generally milder, with fewer crises and longer survival, although retinopathy and avascular necrosis remain meaningful risks.

Detection is by newborn screening using isoelectric focusing or high-performance liquid chromatography, with a confirmatory second method. The neonatal pattern of HbS beta-zero is FS and is often indistinguishable from HbSS at birth, so HBB sequencing or family studies are required to resolve the genotype. The HbS beta-plus pattern shows FSA, with HbA below the level expected in sickle trait. Annual dilated retinal examination is recommended for adults given retinopathy risk.

Treatments to date

The therapeutic landscape mirrors HbSS for severe genotypes. Hydroxyurea is used in HbS beta-zero and in symptomatic HbS beta-plus. Droxia, the adult hydroxyurea formulation, was approved by the FDA in March 1998. Siklos, the pediatric hydroxyurea formulation, was approved in December 2017 for children ages 2 and older.

L-glutamine oral powder, marketed as Endari, was approved by the FDA in July 2017 for sickle cell disease ages 5 and older to reduce acute complications. Crizanlizumab, marketed as Adakveo, was approved by the FDA in November 2019 to reduce vaso-occlusive crisis frequency in patients 16 and older with sickle cell disease. Voxelotor, marketed as Oxbryta, was approved by the FDA in November 2019. Pfizer voluntarily withdrew Oxbryta from worldwide markets in September 2024 after post-marketing data raised concerns about excess vaso-occlusive crises and deaths.

Two cell and gene therapies expanded the curative-intent menu in late 2023 and early 2024. Casgevy, exagamglogene autotemcel, was approved by the FDA in December 2023 for sickle cell disease in patients 12 and older with a history of recurrent vaso-occlusive crises, and in January 2024 for transfusion-dependent beta-thalassemia in patients 12 and older. The transfusion-dependent beta-thalassemia label covers people on a chronic transfusion program for that diagnosis and is the relevant indication for some HbS beta-zero phenotypes managed as transfusion-dependent disease. Lyfgenia, lovotibeglogene autotemcel, was approved by the FDA in December 2023 for sickle cell disease in patients 12 and older with a history of recurrent vaso-occlusive crises. Both therapies require myeloablative conditioning and autologous hematopoietic stem cell collection.

Allogeneic hematopoietic stem cell transplant remains an option for severe disease. Chronic transfusion programs are standard for primary and secondary stroke prevention and for transfusion-dependent thalassemia phenotypes. Supportive care covers acute pain crises, transfusion for acute chest syndrome, iron chelation for transfusion burden, and surveillance for end-organ complications.