What are the management options for thalassemia major?

Management of Thalassemia Major

Thalassemia major requires lifelong regular blood transfusions every 3-4 weeks to maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL, combined with immediate initiation of iron chelation therapy to prevent fatal iron-related cardiac complications. 1

Transfusion Protocol

Initiate regular transfusions immediately upon diagnosis to suppress ineffective erythropoiesis and ensure normal growth and development. 1, 2

• Pre-transfusion target: Maintain hemoglobin at 9-10 g/dL 1, 3
• Post-transfusion target: Achieve hemoglobin of 13-14 g/dL 1, 3
• Transfusion frequency: Every 3-4 weeks 1, 3
• Blood product specifications: Use leukoreduced red blood cells universally 2
• Phenotype matching: Perform RBC antigen phenotyping at baseline and prophylactically match for Rh (C, c, E, e) and K antigens to minimize alloimmunization 2

The higher hemoglobin targets (compared to older protocols maintaining 7-9 g/dL) are critical because they suppress the bone marrow's ineffective erythropoiesis, which reduces extramedullary hematopoiesis, skeletal deformities, and cardiac stress from chronic anemia. 1, 4

Iron Chelation Therapy

Start iron chelation immediately when establishing regular transfusions—do not wait for iron overload to develop. 1 Each unit of blood contains 200-250 mg of iron with no physiological mechanism for excretion, making iron overload inevitable without chelation. 3

First-Line Chelation Options:

• Deferasirox (oral): Starting dose 20-30 mg/kg/day based on liver iron concentration (LIC); doses below 20 mg/kg/day fail to consistently lower iron burden 5
• Deferoxamine (subcutaneous): 50 mg/kg/day administered 5-7 nights per week 3
• Deferiprone (oral): 75 mg/kg/day, but use with caution due to neutropenia risk 1

Critical warning: Avoid deferiprone during concurrent antiviral therapy for hepatitis due to additive neutropenia risk. 1 Switch to deferoxamine if neutropenia develops or if the patient requires medications that increase neutropenia risk. 1

Monitoring Chelation Efficacy:

• Liver iron concentration (LIC) via MRI: Primary method to guide chelation intensity; target LIC reduction and maintenance 1, 5
• Serum ferritin: Check every 3 months as a trend marker; target <1000 mcg/L, though MRI is more accurate than ferritin alone 1
• Cardiac MRI T2:* Annually to detect cardiac iron before symptoms develop (T2* values <10 ms indicate severe cardiac iron overload requiring intensified chelation) 1, 5

Surveillance for Complications

Cardiac Monitoring (Leading Cause of Death):

Cardiac iron overload causes dilated cardiomyopathy and remains the primary cause of mortality in thalassemia major. 6

• Cardiac MRI T2 annually:* Values <10 ms indicate severe cardiac iron requiring immediate intervention 1
• Echocardiography annually: Assess left ventricular ejection fraction and detect early cardiomyopathy 1, 3
• Emergency protocol for cardiac decompensation: If acute heart failure develops, initiate continuous IV deferoxamine 50 mg/kg/day PLUS oral deferiprone 75 mg/kg/day for combined chelation, transfer to specialized thalassemia center immediately, and avoid aggressive diuretics (these patients require adequate preload) 1

Critical pitfall: Cardiac iron overload can present with seizures and has 50% one-year mortality if untreated—do not delay cardiac assessment assuming seizures are purely neurological. 1

Hepatic Monitoring:

• Liver function tests: Every 3 months 1
• Hepatitis B and C screening: At baseline and periodically, as chronic viral hepatitis is common in transfused patients 1, 3
• Liver iron concentration via MRI: To guide chelation therapy intensity 1

Endocrine Monitoring:

• Annual screening for: Diabetes mellitus, thyroid dysfunction, hypogonadism, and growth delays 1

Management of Viral Hepatitis Complications

Hepatitis C Treatment:

• Regimen: Pegylated interferon plus ribavirin 7
• Duration: 48 weeks for genotypes 1 or 4; 24 weeks for genotypes 2 or 3 7
• Stopping rule: Withdraw therapy at 12 weeks if HCV-RNA has not decreased by at least 2 log units from baseline 7
• Transfusion adjustment: Expect 30-40% increase in transfusion requirements during treatment to maintain hemoglobin >9 g/dL due to ribavirin-induced hemolysis 7, 1
• Chelation modification: Switch to deferoxamine during antiviral treatment and intensify chelation before starting antivirals in patients with severe iron burden 7, 1

Hepatitis B Treatment:

• Three treatment options: Finite 48-week course with pegylated interferon, finite course with nucleoside/nucleotide analogs (NUCs), or long-term NUCs 7
• HBeAg-positive patients with favorable predictors (high ALT, low HBV DNA, genotype A or B): Finite 48-week course with pegylated interferon or NUCs 7
• HBeAg-negative patients or those failing finite therapy: Long-term NUCs with tenofovir or entecavir as first-line (high barrier to resistance) 7

Curative Treatment

Hematopoietic stem cell transplantation (HSCT) is the only cure and should be performed as early as possible, ideally before age 14 years and before iron-related organ damage develops. 3 Optimize iron chelation before transplant to reduce non-relapse mortality. 1

Common Pitfalls to Avoid

• Undertransfusion: Maintaining hemoglobin at 7-9 g/dL (older protocols) fails to suppress ineffective erythropoiesis and increases complications 8, 4
• Delayed chelation initiation: Waiting for ferritin elevation before starting chelation allows irreversible organ damage 1
• Inadequate monitoring during antiviral therapy: Ribavirin causes significant hemolysis requiring 30-40% more transfusions—monitor hemoglobin every 2 weeks 7, 1
• Using valproic acid for seizures: Avoid due to hepatotoxicity risk in patients with underlying liver disease from iron overload or viral hepatitis 1
• Excluding cardiac assessment in patients with seizures: Cardiac iron can present with neurological symptoms 1