What is the recommended treatment for sickle cell disease?

Recommended Treatment for Sickle Cell Disease

Hydroxyurea is the first-line disease-modifying therapy for sickle cell disease and should be offered to all patients with HbSS or HbSβ0-thalassemia genotypes starting at 9 months of age, regardless of symptoms. 1, 2

Primary Disease-Modifying Therapy: Hydroxyurea

Dosing and Administration

• Start hydroxyurea at 15-20 mg/kg/day orally once daily, with subsequent titration to achieve maximum tolerated dose of 20-35 mg/kg/day based on hematologic response 3
• Available formulations include capsules, rapid-dissolving tablets, or compounded liquid to facilitate administration across all age groups 3, 1
• The dose of 15 mg/kg/day appears adequate for most patients, balancing clinical benefit with minimal side effects, though some may require escalation to 20 mg/kg/day for optimal fetal hemoglobin response 4

Clinical Benefits

• Reduces vaso-occlusive pain crises, acute chest syndrome episodes, hospitalizations, and transfusion requirements by approximately 50% 3, 1
• Prolonged therapy for ≥5 years is necessary to achieve mortality benefit, with 17-year data showing 30.4% mortality in those receiving ≥5 years versus 51.1% in those receiving <5 years 3
• Increases fetal hemoglobin production, which reduces red blood cell sickling and decreases vaso-occlusive complications 1

Monitoring Requirements

• Complete blood count and reticulocyte count every 1-3 months 1, 2
• Myelosuppression is the most common dose-limiting toxicity but typically resolves within 2 weeks after temporary suspension 3
• Severe neutropenia (absolute neutrophil count <500/mm³) is rare and has not been complicated by infection in clinical trials 5, 3

Special Populations

• For patients with pulmonary hypertension confirmed by right heart catheterization, hydroxyurea is strongly recommended 5, 2
• For patients with chronic kidney disease and worsening anemia, consider combination therapy with hydroxyurea and erythropoiesis-stimulating agents, maintaining hemoglobin ≤10 g/dL to reduce vaso-occlusive complications 1, 2

Additional Disease-Modifying Therapies

Crizanlizumab (Adakveo)

• FDA-approved selectin blocker to reduce frequency of vaso-occlusive crises in adults and pediatric patients ≥16 years 6
• Dosing: 5 mg/kg intravenous infusion over 30 minutes at Week 0, Week 2, then every 4 weeks 6
• Reduced pain crises from 2.98 to 1.63 per year compared with placebo 7
• Monitor for infusion-related reactions (occurring in 7% of patients), which present as pain, nausea, vomiting, fatigue, dizziness, pruritis, diarrhea, and pyrexia 6
• Most infusion reactions occur during first and second infusions; discontinue for severe reactions 6

L-Glutamine (Endari)

• Approved for patients ≥5 years to reduce pain events 2
• Mechanism: reduces oxidative stress in red blood cells 2
• Reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo 7

Voxelotor

• Increases hemoglobin by at least 1 g/dL in 51% of patients versus 7% with placebo 7
• Used as adjunctive or second-line therapy 7

Chronic Transfusion Therapy

Indications

• Primary stroke prophylaxis in children with abnormal transcranial Doppler velocities (>200 cm/second) 5, 1
• Secondary stroke prevention in patients with history of stroke 5, 1
• Recurrent acute chest syndrome unresponsive to hydroxyurea 2

Administration

• Monthly red blood cell transfusions to suppress bone marrow and decrease HbS percentage to <50% 5, 1
• Goal hemoglobin concentration of 10-12 g/dL 5
• Extended antigen matching required to minimize alloimmunization 1
• Iron chelation therapy mandatory after 12-20 transfusions to prevent iron overload 1

Evidence

• Chronic transfusion significantly reduced stroke rate (1% vs 12%; odds ratio 0.10) in high-risk children, though no mortality benefit was demonstrated in the trials 5

Curative Therapies

Hematopoietic Stem Cell Transplantation

• Curative option for severe sickle cell disease, with best outcomes achieved with HLA-matched sibling donor and procedure before 16 years of age 1, 7
• Currently the only established curative therapy 7

Gene Therapy

• Emerging curative option with three approaches under investigation: gene addition, gene correction, and gene editing 1

Essential Supportive Care

Infection Prevention

• Prophylactic penicillin V potassium 125 mg orally twice daily starting at 2 months of age for all infants with HbSS and Sβ0-thalassemia, continuing to at least 5 years of age 1, 2
• Continue after age 5 in select patients 1

Management of Acute Complications

• Adequate hydration, warmth maintenance, and incentive spirometry 1
• Continuous SpO2 monitoring to detect acute chest syndrome early 1
• Comprehensive pain management including nonpharmacologic methods 1
• Patients with sickle cell disease are not more likely to develop addiction to pain medications than the general population 7

Blood Pressure Management

• Target blood pressure ≤130/80 mmHg for adults with sickle cell disease 2

Important Caveats

Pulmonary Hypertension Management

• For patients with RHC-confirmed marked elevation of pulmonary vascular resistance and normal pulmonary artery wedge pressure, phosphodiesterase-5 inhibitor therapy is NOT recommended as first-line treatment due to increased risk of hospitalization for vaso-occlusive crisis 5
• For patients with elevated tricuspid regurgitant velocity (TRV) alone or elevated NT-pro-BNP alone, targeted pulmonary arterial hypertension therapy is NOT recommended 5

Anticoagulation

• For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional bleeding risk factors, indefinite anticoagulant therapy is suggested over limited duration 5