Breve actualización
Determinar la gravedad de la anemia falciforme es un reto. Cualquier estimación debe tener en cuenta el nivel de hemoglobina fetal (la hemoglobina más prevalente en los dos últimos trimestres de gestación en humanos), la presencia de alfa-talasemia y la edad. El tratamiento con hidroxiurea (HU) ha demostrado su eficacia clínica y de laboratorio para mejorar los signos y síntomas de la anemia falciforme y, en consecuencia, reducir la tasa de mortalidad, principalmente mediante el aumento del nivel de hemoglobina fetal (HbF) hasta un intervalo del 10 al 40%. Prácticamente todos los pacientes tratados obtendrán el beneficio asociado a la gravedad de la enfermedad. Sin embargo, existe una variabilidad significativa entre pacientes, incluso si se administra la dosis máxima tolerada de HU, y algunos pacientes presentarán una mielosupresión excesiva a dosis relativamente bajas.

Some authors (McDade, J and Ware, R.E.) hypothesised in 2009 that "genetic polymorphisms may play an important role in the observed inter-patient variability for both Hydroxyurea response and toxicity".

En 2016, Habara, A. y Steinberg, M.H. afirmaron que la heterogeneidad fenotípica de la anemia falciforme solo se explicaba parcialmente por la variabilidad genética de la expresión de la hemoglobina fetal y la coherencia de la alfa-talasemia. Trabajos realizados por otras personas propusieron y posteriormente demostraron la inesperada asociación del papel de BCL11A en la expresión del gen HbF.

In 2022, Sales RR. et al. published a systematic review to assess whether genetic polymorphisms affect HbF levels in patients with Sickle Cell Anaemia treated with HU. In addition, pathway analysis of single nucleotide polymorphisms (SNPs) was performed. The study was conducted at the Federal University of Minas Gerais, Belo Horizonte, Brazil. Of 1,597 articles initially identified, only seven cohort studies were included in the systematic review (five from the US and two from Brazil).

Of 1,597 articles initially identified, only seven cohort studies were included in the systematic review (five from the US and two from Brazil). The sample mean age ranged from 8.1 to 21 years. The mean dose of HU ranged from 19 to 27.1 +/- 4.3 mg/Kg, and the mean duration of treatment with HU ranged from 13.4 to 102 months.



The authors comment that "a complex regulation environment determines the HbF concentration in the blood as well as chromosome remodelling, transcription factors, erythropoiesis modulation, gene regulatory elements linked to the beta- globin gene cluster and the kinetics of erythroid cell differentiation and differential red cell survival. Consistent with this complex regulation apparatus, even with the restricted number of studies, our systematic review suggests that there is huge heterogeneity in genetic elements modulating the HbF levels in response to HU treatment". After extensive analysis, the authors concluded: "Changes in HbF levels in response to HU therapy are likely to be regulated by genetic variations on multiple loci, and there is evidence that the BCL11A gene affects HbF changes in patients with Sickle Cell Anaemia treated with Hydroxyurea". The induction of HbF is a powerful mechanism of action of HU; however, further research is needed to predict the success of treatment.

Teniendo en cuenta que la respuesta al tratamiento con HU es variable y parece ser un rasgo hereditario, y que alrededor del 25% de los pacientes no responden al tratamiento con HU o se consideran malos metabolizadores, estudios muy recientes que evalúan los determinantes genéticos de la respuesta a la Hidroxiurea junto con la presencia de variantes en genes responsables no sólo del metabolismo de la HU sino también de regular la expresión de HbF y la proliferación de progenitores eritroides podrían ser la respuesta a las diferencias en las respuestas de los pacientes a la HU.

Ginette, C. et al. (2023) from Portugal have published that using HU in children with Sickle Cell Anaemia should be considered safe and beneficial. "Even in children considered non/poor responders, using HbF as the main criteria, significant changes were registered in almost the same parameters identified in responders, which also denotes clinical improvement in these patients".

Again, their conclusion was: "Several polymorphisms seem to be associated with response to Hydroxyurea treatment in Sickle Cell Anaemia patients as previously reported in other studies". On the other hand, apart from the co-inheritance of alfa-thalassaemia and phenotype elements determining HbF levels, environmental factors are undoubtedly crucial with socioeconomics and access to basic medical care explaining the considerable differences in outcomes between countries. In addition, studies indicate that the inflammatory profile can vary according to the genetic polymorphisms of the patient. The healthcare system should provide the necessary infrastructure to confirm new-borns’ diagnoses and provide appropriate counselling and treatment. The early diagnosis and treatment, as well as the follow-up with a multidisciplinary team, are fundamental to the survival rate and patients' quality of life.

As a final comment, the responsible healthcare provider should not withhold safe and effective therapy with Hydroxyurea from people with the disease while awaiting a better model to predict who will be the sickest of the sick. Every person with HbSS, as young as six to nine months of age, deserves disease-modifying therapy (Hydroxyurea); However, it can now be argued that every child with an HLA-matched sibling donor is a potential candidate for haematopoietic stem cell transplantation.

The mission of Masters Speciality Pharma, a empresa farmacéutica mundial, is to improve the lives of patients by facilitating access to life-saving medications. We work alongside life science partners and knowledgeable pharmaceutical drug suppliers to the healthcare industry. Our primary goal is to supply people in emerging markets with essential medicines.

Referencias McDade,J. et.al. (2009). http://doi.org/10.1182/blood.V114.22.820.820 Habara,A. and Steinberg, MH.(2016). http://doi.org/10.1177/1535370216636726 Sales,RR. et.al. (2022). http://doi.org/10.3389/fphar.2021.779497 Ginete,C. et.al.(2023). http://doi.org/10.3390/ijms24108792 Written by: Enrique Blanco, MD. FCP.