What are the new modalities in the management of thalassemia in children?

New Modalities in Thalassemia Management in Children

The most significant new modalities for children with thalassemia include gene therapy with lentiviral vectors (approved for patients ≥12 years), CRISPR-Cas9 gene editing targeting BCL11A, luspatercept for erythroid maturation, and optimized hematopoietic stem cell transplantation protocols, with gene therapy representing the first potentially curative option beyond transplantation. 1, 2, 3

Gene Therapy: The Transformative Curative Option

Lentiviral Vector Gene Addition Therapy

• Betibeglogene autotemcel (LentiGlobin BB305) was approved in 2019 for transfusion-dependent thalassemia patients ≥12 years old with non-β0/β0 genotypes who lack a matched sibling donor, representing the first successful gene therapy approach for thalassemia. 2
• Gene therapy using self-inactivating lentiviral vectors to add a functional beta-globin gene into autologous hematopoietic stem cells has achieved transfusion independence in the majority of transfusion-dependent thalassemia patients across different age groups and genotypes, with multi-year follow-up data now available. 3
• This approach is limited to industrialized countries with longstanding experience and remains unavailable to the majority of thalassemia patients globally. 1

CRISPR-Cas9 Gene Editing

• Gene editing with CRISPR-Cas9 technology targeting erythroid BCL11A expression (a key regulator of fetal-to-adult hemoglobin switching) has achieved high levels of fetal hemoglobin production, allowing discontinuation of transfusions in treated patients. 3
• This represents a newer approach compared to gene addition therapy, with promising early results but less long-term safety data. 3

Critical Limitations and Safety Concerns

• A major safety concern emerged in 2021 regarding the risk of secondary hematological malignancies following gene therapy, which is complex and multifactorial in origin and not limited solely to insertional mutagenesis risk. 3
• The prohibitive cost has led to arrest of commercialization in Europe of the first gene therapy medicinal product for transfusion-dependent thalassemia, despite conditional approval by the European Medicines Agency. 3

Hematopoietic Stem Cell Transplantation: Optimized Protocols

HLA-Matched Sibling Donor Transplantation

• Modern HSCT approaches in young, low-risk children transplanted from HLA-matched sibling donors achieve transplantation-related mortality of ≤5%, with overall survival of 91% and disease-free survival of 83%. 1
• Optimal results require transplantation before age 14 years (96% disease-free survival vs. 74% for older patients) and before iron-related complications develop. 1
• Patient status at transplantation according to the Pesaro risk score (assessing hepatomegaly, portal fibrosis, and adequacy of chelation) is the critical element predicting outcome. 1

Alternative Donor Sources

• Cord blood from HLA-identical siblings shows decreased risk of acute and chronic graft-versus-host disease (10% and 5% respectively) compared to bone marrow (20% and 12%), with overall survival of 96% and disease-free survival of 81%. 1
• Peripheral blood stem cell transplantation from matched sibling donors is feasible but carries increased risk of chronic graft-versus-host disease in most studies. 1
• HSCT from HLA-mismatched family members should be considered experimental and conducted only within well-designed controlled trials, as results remain inferior to matched sibling donors. 1

Timing Recommendations

• For patients with an HLA-identical sibling donor or well-matched related/unrelated donor, HSCT should be performed as soon as possible to avoid transfusion-associated complications. 1
• HSCT in adults who have been well-chelated since infancy should be offered only within controlled trials. 1

Erythroid Maturation Agents

• Luspatercept, the first erythroid maturation agent, was approved for beta-thalassemia adult patients in the last decade, though pediatric approval data is not yet available. 2
• This represents a novel mechanism targeting ineffective erythropoiesis rather than simply managing its consequences. 2

Enhanced Iron Chelation Strategies

Modern Chelation Regimens

• Deferasirox (oral chelator) requires careful monitoring in pediatric patients, as those receiving >25 mg/kg/day (tablets for oral suspension) equivalent to >17.5 mg/kg/day (tablets) when serum ferritin is <1000 mcg/L have a 6-fold greater rate of renal adverse events and 2-fold greater rate of dose interruptions. 4
• A 26% increased risk of acute kidney injury occurs with each 5 mg/kg increase in daily deferasirox dosage starting at 20 mg/kg/day, and a 25% increased risk occurs with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L. 4
• Deferiprone may increase neutropenia risk and should be used with caution, particularly during concurrent antiviral therapy. 5, 6, 7

Combination Chelation Therapy

• For acute decompensated heart failure from cardiac iron overload, initiate continuous intravenous deferoxamine at 50 mg/kg/day plus deferiprone 75 mg/kg/day for combined chelation therapy. 5
• Switching to deferoxamine during hepatitis C antiviral treatment is recommended rather than continuing deferiprone or deferasirox, as safety data for deferasirox with combination antiviral therapy is lacking. 6

Optimized Transfusion Protocols

• Maintain pre-transfusion hemoglobin at 9-10 g/dL and target post-transfusion hemoglobin of 13-14 g/dL to suppress ineffective erythropoiesis, with regular transfusions every 3-4 weeks. 5
• Monitor hemoglobin levels every 2 weeks, especially during antiviral treatment periods. 5

Comprehensive Monitoring Strategies

Cardiac Surveillance

• Annual echocardiography and cardiac MRI T2 are required to detect early iron-related cardiomyopathy*, as cardiac iron overload is a leading cause of death and can present with seizures. 5
• Transfer to specialized thalassemia centers with integrated cardiology and hematology expertise is necessary if cardiac complications develop, as this represents a medical emergency with 50% one-year mortality if untreated. 5

Hepatic and Endocrine Monitoring

• Liver function tests should be performed every 3 months, with liver iron concentration monitoring via MRI to guide chelation therapy intensity. 5
• Annual screening for diabetes, thyroid dysfunction, and hypogonadism is required to detect endocrine complications. 5

Critical Pitfalls to Avoid

• Never supplement iron in thalassemia patients based on low hemoglobin alone, as anemia results from ineffective erythropoiesis and hemoglobin production defects, not iron deficiency. 8
• Avoid vitamin C supplementation above 500 mg daily, as it enhances iron absorption and can mobilize iron from reticuloendothelial stores, potentially accelerating cardiac deterioration. 8
• Do not delay cardiac assessment when seizures occur, as cardiac iron overload can present with neurological symptoms. 5
• Avoid valproic acid for seizure management due to potential hepatotoxicity in patients with underlying liver disease from iron overload or viral hepatitis. 5
• Avoid aggressive diuretic therapy in heart failure, as thalassemia patients require adequate preload; use minimal diuretics only. 5