Introduction

In recent years, the clinical classification of beta thalassemia has been based on transfusion needs. Non-transfusion dependent beta-thalassemias (NTDT), previously referred to as thalassemia intermedia, do not require regular transfusions or may not need them at throughout the patient's life, only receiving transfusions in specific clinical situations such as pregnancy, infections, or surgery, etc. These patients represent a very heterogeneous and complex group with various associated Hb abnormalities.

Objective

Molecular characterization and registry of the cases of non-transfusion dependent thalassemia detected in Spain in the last 20 months.

Material and Methods

Between November 2022 and July 2024, 54 individuals from different Spanish regions, including native and migrant populations, were studied. Conventional hemocytometric analysis, determination of HbA2 and HbF by ion exchange HPLC were performed. Molecular diagnosis included multiplex PCR with hybridization using the α-globin StripAssay® method, Multiplex Ligation-dependent Probe Amplification (MLPA), and automated Sanger sequencing.

Results

Twenty-two women (40.7%) and 32 men (59.3%) comprised the sample, with a mean age of 41.7 years. Twenty-two percent were splenectomized at a mean age of 11 years. Of the patients, 85.2% did not receive transfusions, 14.8% (8) received a transfusion, 2 sporadically and the other 6 needed at least 1.5 units per year. All patients presented with variable moderate anemia, with hemoglobin levels between 7.9 and 12.1 g/dL, accompanied by microcytosis (MCV (fL) = 67.5 ± 10.5); (MCH (pg) = 19.9 ± 3.2) and increased RDW (%) (22.6 ± 4.6). Hb A2 (%) levels were also elevated (4.8 ± 0.9) and Hb F levels ranged from 0.6% to 25%. Reticulocytes were moderately elevated.

Ferritin was at a mean value of 304.9 ng/mL. Fifteen patients received chelation monotherapy the rest the treatment was unknown.

The most common HBB gene genotypes were CD39 (C>T) (50% of patients) and IVS-1-nt6 (T>C) (11%), with the predominant alpha genotype being ααα/αα (65% of patients). Six patients had 2 mutations in the HBB gene, 2 were carriers of Hb Lepore Baltimore and IVS-1-nt1 (G>A), and another with an IVS-1-nt110 (G>A); the first of them also had an associated -α3.7/αα. Three patients presented with homozygous Spanish δβ-thalassemia, and 2 patients were carriers of an Hb C associated with a β0-thalassemia [CD39 and IVS-1-nt1 (G>A)]. Finally, 2 patients were carriers of heterozygous beta-thalassemia [IVS-1-nt6 (T>C) and IVS-1-nt110 (G>A)] and 6 alpha genes (ααα/ααα and αααα/αα, respectively).

Conclusions

NTDT patients in Spain represent a very heterogeneous group both genetically and clinically. This is evidenced by the diversity of mutations and combinations of mutations found, as well as the variability in clinical presentations, such as hemoglobin levels and transfusion requirements.

Splenectomized patients tend to have higher ferritin levels, especially those with the CD39 genotype (514 ng/mL) compared to those who have not been splenectomized (140.5 ng/mL).

This study contributes to understanding the complex molecular foundations of NTDT in Spain, emphasizing the need for personalized management strategies based on genetic profiles and clinical phenotypes.

FUNDING: Agios Pharmaceuticals

CONFLICT OF INTEREST: The authors declare that they have no conflict of interest

Disclosures

Villegas:Agios: Consultancy.

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2024
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