What is the recommended first-line treatment for a young adult patient with sickle cell disease?

Treatment of Sickle Cell Disease

First-Line Therapy: Hydroxyurea

Hydroxyurea is the recommended first-line disease-modifying therapy for all young adults with sickle cell disease, particularly those with HbSS or HbSβ0-thalassemia genotypes. 1

Dosing and Administration

• Start hydroxyurea at 15-20 mg/kg/day orally once daily 2, 1
• Titrate to maximum tolerated dose (MTD) of 20-35 mg/kg/day based on hematologic response and patient tolerance 2
• Available formulations include capsules, rapid-dissolving tablets, or liquid preparations to facilitate administration 2
• Monitor complete blood count every 1-3 months once on stable dose 1, 3

Critical Duration Consideration

Hydroxyurea must be continued indefinitely as lifelong therapy—mortality benefits only emerge after at least 5 years of continuous treatment. 3 This is a critical pitfall: do not discontinue hydroxyurea after short-term use based on clinical improvement alone, as the survival advantage requires prolonged therapy 3. At 17-year follow-up, patients receiving hydroxyurea for ≥5 years had 40% lower mortality (RR 0.60,95% CI 0.44-0.81) compared to those receiving <5 years of treatment 3.

Expected Clinical Benefits

• Reduces vaso-occlusive pain crises, acute chest syndrome, hospitalizations, and transfusion requirements by approximately 50% 2
• Increases fetal hemoglobin, total hemoglobin, and MCV 4
• Decreases WBC, absolute neutrophil count, reticulocytes, LDH, and bilirubin 4

Managing Toxicity

• Myelosuppression is the primary dose-limiting toxicity but is reversible within 2 weeks after temporary suspension 2, 3
• If severe myelosuppression occurs (decrease in one or more cell lines), temporarily suspend hydroxyurea and resume at lower doses 2
• Severe neutropenia (ANC <500/mm³) is rare and has not been complicated by infection in clinical trials 2
• Long-term safety is established: no increased risk of congenital defects, infections, stroke, or neoplasias 2, 3

Second-Line and Adjunctive Therapies

L-Glutamine (Endari)

For patients ≥5 years old, L-glutamine is FDA-approved to reduce acute pain events and can be used as adjunctive therapy with hydroxyurea. 5

• Mechanism: reduces oxidative stress in red blood cells by improving NAD redox potential 5
• Reduces hospitalizations by 33% and mean length of stay from 11 to 7 days compared to placebo 6
• Administered orally twice daily 5
• Most common adverse effects (>10%): constipation (21%), nausea (19%), headache (18%), abdominal pain (17%) 5
• 63.4% of patients in clinical trials were receiving hydroxyurea at baseline, demonstrating safety of combination therapy 5

Chronic Transfusion Therapy

For patients with increased mortality risk who are not responsive to or not candidates for hydroxyurea, chronic transfusion therapy is recommended. 7

Specific indications include:

• Primary or secondary stroke prevention 1
• Recurrent acute chest syndrome unresponsive to hydroxyurea 1
• Patients with RHC-confirmed pulmonary hypertension who fail hydroxyurea 7

Management of High-Risk Patients

Identifying Increased Mortality Risk

Risk stratification guides clinical decision-making. Increased mortality risk is defined as: 7

• Tricuspid regurgitant velocity (TRV) ≥2.5 m/second on echocardiography
• NT-pro-BNP level ≥160 pg/ml
• Right heart catheterization-confirmed pulmonary hypertension (mean PAP >25 mmHg)

Treatment Algorithm for High-Risk Patients

1. First-line: Hydroxyurea (strong recommendation, moderate-quality evidence) 7
2. Second-line: Chronic transfusion therapy if hydroxyurea fails or is contraindicated (weak recommendation, low-quality evidence) 7

Pulmonary Hypertension-Specific Considerations

For patients with elevated TRV alone or elevated NT-pro-BNP alone, targeted PAH therapy (prostacyclin agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors) is NOT recommended. 7

For most patients with RHC-confirmed pulmonary hypertension, targeted PAH therapy is NOT recommended (strong recommendation, moderate-quality evidence). 7

Exception: For select patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary artery wedge pressure, and related symptoms, consider a trial of either prostacyclin agonist or endothelin receptor antagonist (weak recommendation, very low-quality evidence) 7

Avoid phosphodiesterase-5 inhibitors as first-line agents in this population due to increased risk of hospitalization for vaso-occlusive crisis (strong recommendation, moderate-quality evidence). 7

Special Populations and Additional Considerations

Renal Disease

• For patients with chronic kidney disease and progressive anemia, consider combination therapy with hydroxyurea and erythropoiesis-stimulating agents 1
• Maintain hemoglobin ≤10 g/dL to reduce risk of vaso-occlusive complications 2, 1
• Blood pressure goal of ≤130/80 mmHg for adults with SCD 1

Infection Prevention

• Penicillin V potassium prophylaxis starting at 2 months of age for all infants with HbSS and Sβ0-thalassemia 1
• Do not suspend hydroxyurea when initiating doxycycline or other antibiotics 2

Important Drug Interactions

• Hydroxyurea should be suspended ≥72 hours before CAR-T cell infusion if the patient is on a transplant protocol 2

Common Pitfalls to Avoid

1. Discontinuing hydroxyurea prematurely: The mortality benefit requires ≥5 years of continuous therapy 3
2. Using targeted PAH therapy inappropriately: Most patients with SCD and pulmonary hypertension should NOT receive PAH-specific medications 7
3. Allowing hemoglobin to exceed 10 g/dL in patients on erythropoiesis-stimulating agents: This increases vaso-occlusive risk 2, 1
4. Stopping hydroxyurea during antibiotic therapy: Continue hydroxyurea when starting antibiotics 2