What are the treatment options for sickle cell anemia?

Treatment of Sickle Cell Anemia

Hydroxyurea is the first-line disease-modifying therapy for sickle cell anemia and should be offered to all patients with HbSS or HbSβ0-thalassemia genotypes starting at 9 months of age, as it reduces pain crises, acute chest syndrome, hospitalizations, and transfusion requirements by 44% and improves survival. 1, 2

Primary Disease-Modifying Therapy: Hydroxyurea

Hydroxyurea works by increasing fetal hemoglobin (HbF) production, which reduces red blood cell sickling and prevents vaso-occlusive complications. 2, 3 The mechanism involves inhibition of ribonucleotide reductase, leading to DNA synthesis blockade without interfering with RNA or protein synthesis 3.

Dosing and Administration

• Start at 15-20 mg/kg/day orally once daily (available as capsules, fast-dissolving tablets, or compounded liquid) 2
• Titrate to maximum tolerated dose, typically 25-30 mg/kg/day, targeting hemoglobin ≥9 g/dL and HbF ≥20% 4
• Do not discontinue hydroxyurea when initiating antibiotics like doxycycline for concurrent infections 5

Monitoring Requirements

• Complete blood count with reticulocyte count every 2-4 weeks during initial dose titration 5
• Once stable, monitor CBC every 1-3 months 1, 2
• The primary concern is myelosuppression, which typically resolves within 2 weeks of temporary discontinuation if needed 5
• Only discontinue temporarily if severe bone marrow suppression develops (decreased counts in one or more cell lines); resume at lower dose after resolution 5

Long-Term Safety and Efficacy

Hydroxyurea has demonstrated a strong safety profile with no increased risk of birth defects, infection, stroke, or malignancy in long-term follow-up 5. A 17-year single-center trial showed 10-year survival of 86% in hydroxyurea-treated patients versus 65% in untreated patients, with 100% survival in HbSS patients on hydroxyurea 6.

Additional Disease-Modifying Therapies

L-Glutamine (Endari)

• Approved for patients ≥5 years old to reduce pain events 1
• Reduces hospitalization rates by 33% and mean length of stay from 11 to 7 days compared to placebo 7
• Mechanism involves reducing oxidative stress in red blood cells 1

Chronic Transfusion Therapy

Chronic transfusion therapy is indicated for specific high-risk situations, not as routine first-line therapy. 8

Specific Indications:

• Primary stroke prevention in children with abnormal transcranial Doppler velocities >200 cm/second 8, 2
• Secondary stroke prevention in patients with history of stroke 2
• Recurrent acute chest syndrome unresponsive to hydroxyurea 1

Administration Details:

• Monthly red blood cell transfusions to suppress bone marrow and decrease HbS percentage to <50% 8, 2
• Target hemoglobin 10-12 g/dL 8
• Requires extended antigen matching (D, C, E, Kell) to reduce alloimmunization risk (11% incidence) 8
• Mandatory iron chelation therapy after 12-20 transfusions to prevent iron overload 2

Evidence for Stroke Prevention:

The STOP trials demonstrated chronic transfusion therapy significantly reduced stroke rate (1% vs 12%; odds ratio 0.10,95% CI 0.02-0.58) in high-risk children, though no mortality benefit was shown 8.

Management of Specific Complications

Pulmonary Hypertension

For patients with confirmed pulmonary hypertension (TRV >2.5 m/s, NT-pro-BNP >160 pg/ml, or RHC-confirmed PH), hydroxyurea is strongly recommended. 8, 1

Chronic Kidney Disease

• Combination therapy with hydroxyurea and erythropoiesis-stimulating agents is recommended for worsening anemia associated with chronic kidney disease 1, 2
• Critical safety threshold: hemoglobin must not exceed 10 g/dL (hematocrit 30%) to reduce risk of vaso-occlusive complications 8, 2, 5
• Blood pressure goal ≤130/80 mmHg for adults with SCD 1

Dose Adjustment in Renal Impairment

Reduce hydroxyurea dose by 50% in patients with creatinine clearance <60 mL/min or ESRD, as drug exposure increases by 64% in these patients. 3

Infection Prevention

Penicillin V potassium prophylaxis is mandatory starting at 2 months of age for all infants with HbSS and Sβ0-thalassemia. 1, 2

• Dosing: 125 mg orally twice daily from 2 months to at least 5 years of age 2
• Continue after age 5 in select high-risk patients 2

Curative Therapies

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation is the only currently available curative option and should be considered for severe disease, with best outcomes achieved using HLA-matched sibling donors in children <16 years old. 2, 7

Gene Therapy

Gene therapy represents an emerging curative option with three approaches under investigation: gene addition, gene correction, and gene editing 2.

Critical Pitfalls to Avoid

• Never withhold hydroxyurea due to concurrent antibiotic use - continue both medications simultaneously 5
• Never exceed hemoglobin 10 g/dL when using erythropoiesis-stimulating agents - this increases vaso-occlusive risk 8, 1, 2, 5
• Never use live vaccines in patients taking hydroxyurea 3
• Caregivers must wear disposable gloves when handling hydroxyurea capsules and never open capsules due to cytotoxic risk 3

Peri-operative Considerations

Patients with sickle cell disease are at increased risk of both sickle-related complications (acute chest crisis, painful crisis, stroke) and non-sickle-related complications (infection, thrombosis) during surgery 8. Careful planning with multidisciplinary team involvement and assessment of comorbidities can mitigate many complications 8.