Therapeutic approaches in patients with β-thalassemia

Beta-thalassemia (β-thal) is a congenital hemoglobinopathy explained by a decreased level (β+) or absence (βο) of β-globin gene expression. Microcytic hypochromic anemia and various clinical symptoms comprising severe anemia to clinically nonsymptomatic features. Treatment with an ordered blood transfusion and iron chelator agents can decrease transfusion iron overload that causes normal maturation. These patients also are at high risk for secondary iron overload because of erythropheron (GF15–TWSG1) release from erythroblasts resulting in erythroid hyperplasia. Based on the previous studies, chemicals such as hydroxyurea and 5-azacytidine are useful in treating β-hemoglobinopathy, including β-thal and sickle cell disease (SCD). Regarding both side effects and lifelong treatment of these chemical components, researchers have recently regarded gene-based treatments. These techniques, such as micro RNA gene silencing, viral-mediated gene editing, and clustered regulatory interspaced short palindromic repeats (CRISPR)-CAS9 systems, are the most commonly used gene therapy methods. Nowadays, ɣ-globin (fetal globin) gene reactivation is one of the most popular treatments for β-thal. Researches showed that these gene modification methods for γ-globin gene reactivation are also useful in increasing hemoglobin F (HbF) and helping patients with β-thal. In this review study, new therapeutic approaches to manage this disorder are regarded.

Investigating the Efficacy and Safety of Thalidomide for Treating Patients With ß-Thalassemia: A Meta-Analysis

At present, the main therapies for ß-thalassemia patients include regular blood transfusion and iron chelation, associating with a number of limitations. Thalidomide, a fetal hemoglobin (HbF) inducer that promotes γ-globin gene expression, has been reported to be effective for ß-thalassemia. Thus, this meta-analysis was conducted to assess the efficacy and safety of thalidomide for treating patients with ß-thalassemia. We searched the related studies from eight databases published from inception until December 1, 2021. The R 4.0.5 language programming was used to perform meta-analysis. After screening of retrieved articles, 12 articles were included that enrolled a total of 451 patients. The Cochrane Collaboration risk assessment tool was used to evaluate the quality and the bias risk of the randomized controlled trials (RCTs), and non randomized trials were assessed using Newcastle-Ottawa Scale (NOS). After treatment with thalidomide, the pooled overall response rate (ORR) was 85% (95% confidence interval (CI): 80–90%), and the pooled complete response rate (CRR) was 54% (95% confidence interval: 31–76%). Compared with the placebo group, the thalidomide group had higher odds of overall response rate (odds ratio = 20.4; 95% CI: 6.75–61.64) and complete response rate (odds ratio = 20.4; 95% CI: 6.75–61.64). A statistically significant increase in hemoglobin level and HbF level after treatment, while there was no statistically significant difference in adult hemoglobin (HbA) level, spleen size, and serum ferritin. According to the results of ORR and CRR, transfusion-dependent thalassemia (TDT) patients showed remarkable efficacy of thalidomide, 83 and 52% respectively. So we analyzed 30 transfusion-dependent thalassemia patients from three studies and found that the most frequent ß-globin gene mutations were CD41-42 (-TCTT), while response to thalidomide did not show any statistically significant relationship with XmnI polymorphism or CD41-42 (-TCTT) mutation. About 30% of patients experienced mild adverse effects of thalidomide. Collectively, thalidomide is a relatively safe and effective therapy to reduce the blood transfusion requirements and to increase Hb level in patients with ß-thalassemia.

THE EFFECT OF ALPHA THALASSEMIA, HBF and HBC ON HAEMATOLOGICAL PARAMETERS OF SICKLE CELL DISEASE PATIENTS IN IBADAN, NIGERIA.

Background: Sickle cell disease is a protean disease with limited data on the phenotypic and genetic variants in Nigeria. This study was conducted to provide baseline data on these variants by characterizing the existing forms of sickle cell disease and correlating these with basic hematological parameters. Methods: Adult and pediatric patients with SCD were recruited from a tertiary health centre in Nigeria. Patients were age and sex matched with healthy controls. Blood samples were obtained for Full Blood Count, phenotyping by High Performance Liquid Chromatography and genotyping for alpha thalassemia by multiplex gap polymerase chain reaction. Data analysis was done using IBM SPSS statistics version 23. Results: A total of 130 patients with sickle cell disease and 117 controls were studied. Alpha thalassemia in the study population was due to a 3.7kb deletion in the alpha globin gene cluster at a prevalence of 45.4% in the patients and 47% in controls. The prevalence of the various existing forms of SCD genotype was: Homozygous S without alpha gene deletion (HbSS)- 39.2%; HbSC - 10.8%; HbSα+1- 35.4%; HbSα+2 - 6.9% and HbSF- 7.7%. HbA2 was significantly elevated in individuals with two alpha gene deletions (HbSα+2). HbF and HbA2 were negatively correlated with each other (r= -0.587, p < 0.001). Individuals with the HbSC genotype followed by HbSα+2 had the best hematological parameters. Conclusions: Hematological parameters varied with hemoglobin genotype. The C hemoglobin and homozygous alpha thalassemia deletion had better ameliorating effect on SCD hematological parameters than the F hemoglobin in this population.

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Introduction: The β-thalassemias are due to autosomal mutations of the β-globin gene, inducing absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that high production of fetal hemoglobin (HbF) is beneficial for β-thalassemia patients. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus found to be a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular and clinical results of the sirolimus-based NCT03877809 clinical trial (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial: Sirthalaclin). Methods: Accumulation of γ-globin mRNA was analyzed by reverse-transcription-quantitative PCR and the hemoglobin pattern by HPLC. The immunophenotype was analyzed by FACS using antibodies against CD3, CD4, CD8, CD14, CD19, CD25. Results: The results were obtained in 8 patients with β+/β+ and β+/β0 genotypes, treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of the study was that expression of γ-globin mRNA was increased in blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. A second important conclusion of our trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated to ineffective erythropoiesis (I.E.) (excess of free α-globin chains, bilirubin, soluble transferrin receptor and ferritin). In most (7/8) of the patients a decrease of the transfusion index was observed. The drug was well tolerated with minor effects on immunophenotype, the only side effect being frequently occurring stomatitis. Conclusions: The data obtained indicate that sirolimus given at low doses modifies hematopoiesis and induces increased expression of γ-globin genes in a sub-set of β-thalassemia patients. Further clinical trials are warranted, considering the possibility to test the drug in patients with less severe forms of the disease and exploring combination therapies.

Advances in the management of α-thalassemia major: reasons to be optimistic

α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.

β-Thalassemia: evolving treatment options beyond transfusion and iron chelation

After years of reliance on transfusion alone to address anemia and suppress ineffective erythropoiesis in β-thalassemia, many new therapies are now in development. Luspatercept, a transforming growth factor–β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading. However, many patients do not respond to luspatercept, so additional therapeutics are needed. Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis. Genetically modified autologous hematopoietic stem cell transplantation offers the potential for lifelong transfusion independence. Through a gene addition approach, lentiviral vectors have been used to introduce a β-globin gene into autologous hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400, respectively. Results from the many clinical trials for these agents will yield results in the next few years, which may end the era of relying on transfusion alone as the mainstay of thalassemia therapy.