What are the treatment options for sickle cell disease?

Treatment Options for Sickle Cell Disease

Hydroxyurea is the first-line disease-modifying therapy for most patients with sickle cell disease and should be offered to every child with HbSS or HbSβ0-thalassemia starting at 9 months of age, even without clinical symptoms. 1

Disease-Modifying Therapies

Hydroxyurea (First-Line)

• Hydroxyurea increases fetal hemoglobin (HbF) production, which reduces red blood cell sickling and prevents hemoglobin S polymerization. 1, 2
• Strongly recommended for adults with 3 or more severe vaso-occlusive crises during any 12-month period, with pain or chronic anemia interfering with daily activities, or with severe/recurrent acute chest syndrome. 3
• Moderate strength recommendation to offer treatment to infants, children, and adolescents without regard to symptom presence. 3
• Administered once daily orally as capsule, fast-dissolving tablet, or compounded liquid. 1
• Requires monitoring with CBC and reticulocyte count every 1-3 months due to potential myelosuppression. 1
• Patients with HbF levels >8% tend to have milder disease phenotype with fewer symptoms. 1

Voxelotor (FDA-Approved Second-Line)

• FDA-approved hemoglobin S polymerization inhibitor for adults and pediatric patients ≥4 years of age. 4
• Dosing for adults and children ≥12 years: 1,500 mg orally once daily. 4
• Dosing for children 4 to <12 years: weight-based (600 mg for 10-<20 kg; 900 mg for 20-<40 kg; 1,500 mg for ≥40 kg). 4
• In clinical trials, increased hemoglobin by ≥1 g/dL in 51% vs 7% with placebo. 2
• Approved under accelerated approval based on hemoglobin increase; continued approval contingent on confirmatory trials demonstrating clinical benefit. 4
• Reduce dose to 1,000 mg daily in severe hepatic impairment (Child-Pugh C) for adults and children ≥12 years. 4

L-Glutamine (FDA-Approved Adjunctive)

• FDA-approved for reduction of pain events in patients with SCD. 1
• Reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. 2
• Used as adjunctive or second-line agent. 2

Crizanlizumab (FDA-Approved Adjunctive)

• Reduced pain crises from 2.98 to 1.63 per year compared with placebo. 2
• Used as adjunctive or second-line agent. 2

Chronic Transfusion Therapy

Indications for Long-Term Transfusion

• Primary stroke prophylaxis in children with abnormal transcranial Doppler velocity (≥200 cm/s). 3
• Secondary stroke prevention in patients who have already developed stroke. 1
• Select children with recurrent complications not responding to other disease-modifying therapies. 1
• Monthly red blood cell transfusions suppress bone marrow and decrease HbS percentage. 1

Transfusion Management

• Red blood cells must be matched for extended blood antigens (at least C, E, Kell) to reduce alloimmunization risk. 1
• Maintain sickle hemoglobin levels <30% prior to next transfusion during long-term therapy (moderate strength recommendation). 3
• After 12-20 transfusions, iron chelation therapy required to treat iron overload. 1
• Assess iron overload regularly and begin chelation when indicated. 3

Peri-Operative Transfusion Strategy

• High-risk surgery: Exchange transfusion aiming for Hb 100 g/L regardless of genotype. 1
• HbSS/HbSβ0 with baseline Hb <90 g/L undergoing low/medium-risk surgery: Top-up transfusion to Hb 100 g/L. 1
• HbSS/HbSβ0 with baseline Hb ≥90 g/L undergoing low/medium-risk surgery: Partial exchange transfusion to Hb 100 g/L. 1
• HbSC undergoing medium-risk surgery: Top-up or partial exchange transfusion to Hb 100 g/L. 1
• Preoperative transfusion to increase hemoglobin to 10 g/dL strongly recommended in sickle cell anemia. 3

Curative Therapy

Hematopoietic Stem Cell Transplantation

• The only curative therapy currently available, with best outcomes when donor is HLA-matched sibling and procedure occurs before 16 years of age. 1, 2
• Standard care for severe disease with matched sibling donor. 2
• Main adverse effects include infection, graft rejection, graft-versus-host disease, and infertility (especially with myeloablative regimens). 1
• Limited by donor availability. 2

Gene Therapy

• SCD is ideal candidate for gene therapy as single-gene disorder. 1
• Three approaches under clinical investigation: gene addition, gene correction, and gene editing. 1

Preventive Care

Infection Prevention

• Daily oral prophylactic penicillin strongly recommended up to age 5 years. 3
• Penicillin V potassium 250 mg orally twice daily after first birthday; continuation may be appropriate in selected patients with history of invasive pneumococcal infection or surgical splenectomy. 1
• Amoxicillin as alternative; erythromycin for penicillin-allergic patients. 1
• Immunizations for functional asplenia required. 1

Stroke Prevention

• Annual transcranial Doppler examinations strongly recommended from ages 2-16 years in sickle cell anemia. 3
• Long-term transfusion therapy strongly recommended for children with abnormal transcranial Doppler velocity (≥200 cm/s). 3

Organ Monitoring

• Begin screening for proliferative retinopathy with annual dilated fundoscopic examinations at 10 years of age. 1
• Urine microalbumin/creatinine ratio screening. 1
• Angiotensin-converting enzyme inhibitor therapy strongly recommended for microalbuminuria in adults. 3
• Echocardiography to evaluate signs of pulmonary hypertension. 3
• Referral to expert specialists for proliferative sickle cell retinopathy for consideration of laser photocoagulation. 3

Acute Pain Management

Pharmacologic Approach

• Rapid initiation of opioids strongly recommended for severe pain associated with vaso-occlusive crisis. 3
• Nonsteroidal anti-inflammatory drugs and opioids are mainstay of pain treatment. 5
• Additional therapies include muscle relaxants and local pain control. 5
• Patients with SCD are not more likely to develop addiction to pain medications than general population. 2

Supportive Measures

• Incentive spirometry strongly recommended in patients hospitalized for vaso-occlusive crisis. 3
• Hydration therapy commonly used, though evidence for optimal IV fluid choice, rate, and volume is limited. 6
• IV hydration can lead to adverse outcomes including fluid overload, pulmonary edema, increased length of stay, and new oxygen requirement. 6

Temperature Management

• Maintaining normothermia is critical; hypothermia directly causes red blood cell sickling through vasoconstriction and peripheral stasis. 7
• Active warming measures should be implemented routinely: increase ambient room temperature, use warm blankets, administer warmed IV fluids, apply active warming devices. 7
• Avoid all cold applications including ice packs and cold environments. 7

Chronic Complications Management

Avascular Necrosis

• Analgesics and physical therapy strongly recommended for treatment. 3

Pregnancy Management

• Epidural analgesia ideal for labor, particularly with opioid tolerance or sickle-related lower body pain. 1
• Regional anesthesia preferred for caesarean section over general anesthesia. 1
• Prophylactic transfusion not routinely offered except for high-risk patients or multiple pregnancies. 1
• Post-partum low molecular weight heparin prescribed for 6 weeks after caesarean section. 1

Organizational Considerations

Multidisciplinary Care Structure

• Planned surgery should ideally be undertaken in centers with experience caring for SCD patients. 1
• Nominated lead haematologist (or paediatrician/paediatric haematologist for children) required when patient undergoes surgery. 1
• In emergency, seek advice from specialists through haemoglobinopathy network arrangements. 1
• Around-the-clock access to facility providing urgent care must be ensured. 1

Common Pitfalls to Avoid

• Do not delay hydroxyurea initiation—offer to all children with HbSS/HbSβ0-thalassemia by 9 months regardless of symptoms. 1
• Do not undertransfuse or overtransfuse—unnecessary transfusion increases alloimmunization risk. 1
• Do not assume room temperature is adequate—actively warm patients rather than relying on passive measures. 7
• Do not apply cold therapy for pain management. 7
• Do not fail to match red blood cells for extended antigens (C, E, Kell) when transfusion required. 1