What are the treatment options for sickle cell disease?

Treatment of Sickle Cell Disease

Hydroxyurea should be offered to every child with HbSS or Sβ⁰-thalassemia starting at 9 months of age, regardless of symptoms, and remains the first-line disease-modifying therapy for most individuals with sickle cell disease. 1

Disease-Modifying Therapies

Hydroxyurea (First-Line)

• Mechanism and efficacy: Increases fetal hemoglobin production, reduces red blood cell sickling, and decreases vaso-occlusive complications including pain crises (44% reduction), acute chest syndrome, hospitalizations, and transfusion requirements 1, 2, 3
• Dosing: Administered once daily orally as capsule, fast-dissolving tablet, or compounded liquid 1
• Monitoring requirements: CBC and reticulocyte count every 1-3 months depending on duration of therapy and dose stability; primary concern is myelosuppression 1, 4
• Safety profile: Long-term follow-up shows no increased risk of birth defects, infection, stroke, or neoplasia 4
• Do not discontinue when initiating antibiotics like doxycycline for concurrent infections 4

L-Glutamine (FDA-Approved Adjunctive Therapy)

• Indication: Reduction of pain events in patients with sickle cell disease, can be used in combination with hydroxyurea 5, 6
• Efficacy: Reduces median number of sickle cell crises from 4 to 3 per year, decreases hospitalizations (median 3 to 2), and reduces cumulative hospital days (median 11 to 6.5 days) 5
• Dosing: Weight-based at 1 g/kg divided into two daily doses, mixed with 8 oz of cold/room temperature beverage or 4-6 oz of food 5
• Clinical benefit: Observed irrespective of concurrent hydroxyurea use 5

Crizanlizumab (Second-Line Agent)

• Mechanism: Anti-P-selectin monoclonal antibody that reduces vaso-occlusive episodes 6, 7
• Efficacy: Reduces pain crises from 2.98 to 1.63 per year compared to placebo 6

Voxelotor (Second-Line Agent)

• Mechanism: Increases hemoglobin oxygenation by stabilizing oxygenated hemoglobin 6, 7
• Efficacy: Increases hemoglobin by at least 1 g/dL in 51% of patients versus 7% with placebo 6

Chronic Transfusion Therapy

Indications

• Primary stroke prophylaxis: Children at high risk based on abnormal transcranial Doppler velocities 1
• Secondary stroke prevention: Patients with history of stroke 1
• Refractory complications: Select patients with recurrent complications unresponsive to other disease-modifying therapies 1

Administration and Monitoring

• Monthly red blood cell transfusions to suppress bone marrow and decrease HbS percentage 1
• Extended antigen matching required (at minimum C, E, Kell antigens) 1
• Iron chelation therapy mandatory after 12-20 transfusions to prevent iron overload 1

Risks

• Febrile and allergic reactions, pathogen transmission, alloimmunization, iron overload, central line complications (infection, thrombosis) 1

Curative Therapies

Hematopoietic Stem Cell Transplantation

• Best outcomes: HLA-matched sibling donor with procedure before 16 years of age 1, 6
• Major complications: Infection, graft rejection, graft-versus-host disease, and infertility (especially with myeloablative regimens) 1
• Current standard: Recommended for severe disease when matched sibling donor available 6

Gene Therapy

• Three approaches under investigation: gene addition, gene correction, and gene editing 1
• Represents emerging curative option for this single-gene disorder 1

Supportive Care Essentials

Infection Prevention

• Prophylactic penicillin: Penicillin V potassium 125 mg orally twice daily from 2 months to at least 5 years of age 1
• Continue after age 5 in select patients with history of invasive pneumococcal infection or surgical splenectomy 1
• Complete pneumococcal vaccine series 1

Acute Pain Management

• PCA (patient-controlled analgesia) preferred for severe pain requiring parenteral opioids 8
• Comprehensive approach includes adequate hydration, warmth maintenance, incentive spirometry, and nonpharmacologic methods 8
• Close monitoring with continuous SpO2 to detect acute chest syndrome early 1, 8

Chronic Kidney Disease Management

• For patients with worsening anemia and chronic kidney disease, combination therapy with hydroxyurea and erythropoiesis-stimulating agents is suggested 1
• Critical safety threshold: Do not exceed hemoglobin of 10 g/dL (hematocrit 30%) to reduce risk of vaso-occlusive complications, stroke, and venous thromboembolism 1

Common Pitfalls to Avoid

• Never discontinue hydroxyurea for concurrent antibiotic therapy unless severe myelosuppression develops 4
• Avoid hypothermia in perioperative settings as this triggers sickling through shivering and peripheral stasis 1
• Do not delay iron chelation therapy once transfusion threshold (12-20 transfusions) is reached 1
• Maintain high index of suspicion for acute chest syndrome in postoperative period with continuous SpO2 monitoring 1, 8
• Recognize that patients with HbSC disease may require exchange transfusion more frequently due to higher baseline hemoglobin 1