Registry of Transfusion-Dependent Beta-Thalassemia (TDT) Cases in Spain Molecularly Characterized over the Past 20 Months
Authors: Ropero Gradilla Paloma , Menor Gómez María , Fonte Feal Cristina , Hernandez Rivas Jesus Maria , Vagace Valero José Manuel , De La Iglesia Íñigo Silvia , Morado Arias Marta , Senent Peris María Leonor , Salido Fiérrez Eduardo José , Montañés García María Ángeles , López Rubio Montserrat , Recasens Flores Valle , Zamanilllo Herreros Irene , Orbe Jaramillo Irene , Esperanza Marco Josefa , Raya Sanchez Jose Maria , González González Bernardo Javier , Molina Arrebola María Angustias , Linares Garcia Mariano , Lo Riso Laura , Abío Calvete Mariola , Hinojosa Orantos Cristina , Hidalgo Campos Manuela Ines , Hernández García M.ª del Carmen , López López Rosa María , Ugalde Fernández Nazaret , Fernandez Garcia Sergio , Ferre Bermejo Oscar , Herrera Robles Keneth A , Popa Dusacovschi Oana , Vara Míriam , Groiss Buiza Jorge , Palma Vallellano Antonio José , Vidan Estevez Julia Maria , Herrera Esther , Ríos Rull Pablo , Peri Valeria Luciana , Rodríguez Ana , Rodríguez Servan Isabel , Ricard Andrés Pilar , Ferrer Sara , Gómez Álvarez Miguel , Martínez Nieto Jorge , Fernandez Fernando Ataulfo Gonzalez , Villegas Ana , Benavente Cuesta Celina , Sehh Grupo Español de Eritropatología 
Published: December 2024

Introduction: β-thalassemia can be a severe transfusion-dependent disease, also called β-thalassemia major. There are heterozygous mild forms and intermediate forms. In recent years, there has been a clinical tendency to simplify the classification of symptomatic cases according to transfusion requirements into transfusion-dependent thalassemias (TDT) with regular transfusion requirements and non-transfusion-dependent thalassemias (NTDT) with little or no transfusion requirements.

Objective: To register the cases of β-Thalassemia Transfusion Dependent Thalassemia (TDT) in Spain molecularly characterized over the last 20 months.

Material and Methods: Between November 2022 and July 2024, 128 individuals were recruited from various Spanish regions, including native and migrant populations. Seventy-two are TDT and 56 NTDT (not presented in this work). Conventional hemocytometric analysis, HbA2, and HbF determination were performed. Molecular diagnosis, which so far has been performed in 68 TDT cases, included the study of alpha and beta genes by multiplex PCR with hybridization using the globin StripAssay® method, Multiplex Ligation-dependent Probe Amplification (MLPA), and automatic Sanger sequencing.

Results: Thirty-three women (45.8%) and thirty-eight men (52.8%) made up the sample, with a mean age of 35.3 years. Twenty patients are under 30 years old, seven are under 5 years old, and only one has Spanish parents and ancestors.

Of the total, 55.5% were Spanish and 44.5% were immigrants, with Hindus being the majority (12.5%) followed by Maghrebis and Portuguese (5.5% each), and others 4 from different countries were studied. Forty percent were splenectomized at a mean age of 12 years. They received a mean of 28 transfusion units per year. Ferritin had a mean value of 915.5 ng/mL. Sixty-one patients received chelation monotherapy. Seven were treated with two chelators simultaneously, and in four cases, the treatment was unknown. Fourteen were treated with luspatercept. Three patients underwent transplantation from an HLA-identical heterozygous sibling.

Genotype: In the Spanish population, the most prevalent mutations included IVS-1-nt1 (G&gt;A), CD39 (C&gt;T), and IVS-1-nt110 (G&gt;A). Among Hindus, common mutations were IVS-1-nt1 (G&gt;T) and the 619 bp deletion. The Moroccan population showed a high frequency of IVS-1-nt6 (T&gt;C) and CD39 (C&gt;T). The Portuguese population predominantly exhibited IVS-1-nt110 (G&gt;A) and IVS-1-nt1 (G&gt;T) mutations. Two patients had associated structural hemoglobinopathies (Hb Konoss and Hb Monroe with IVS-1-nt1 (G&gt;A) and δβ-thalassemia, respectively) and another two presented the association of β+-thalassemia [IVS-1-nt110 (G&gt;A) and Spanish δβ-thalassemia].

Conclusions: The phenotype of the mutations determines the frequency of transfusions in patients with β-thalassemia TDT, with mutations such as CD39 (C&gt;T) or IVS-1-nt1 (G&gt;A) strongly associated with the need for regular and frequent transfusions due to their disruptive nature. Most patients are treated with iron chelators, mainly deferasirox, though some require a combination of chelators, indicating a high iron load or suboptimal response to standard treatment. The diversity of genotypes and variability in transfusion needs highlight the complexity of managing this condition and the necessity for individualized treatment strategies. This work underlines the importance of molecular characterization in the management of β-thalassemia TDT and the need for a personalized approach based on phenotype and molecular data, which can optimize treatment, adjust transfusion frequency, iron chelator dosage, and monitor ferritin levels, thus improving patients' quality of life.

FUNDING: Agios Pharmaceuticals

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