What is the treatment approach for a patient with sickle cell disease (SCD) who is not currently in crisis?

Treatment of Sickle Cell Disease Outside of Crisis

Yes, patients with sickle cell disease who are not in crisis absolutely require disease-modifying therapy, with hydroxyurea as the cornerstone of treatment for most patients. 1

Primary Disease-Modifying Therapy

Hydroxyurea - First-Line Treatment

The 2014 National Heart, Lung, and Blood Institute guidelines recommend offering hydroxyurea to every child with HbSS or Sβ0-thalassemia starting at 9 months of age, even without clinical symptoms. 1 This represents a paradigm shift from reactive to proactive treatment.

Hydroxyurea works by:

• Increasing fetal hemoglobin production, which reduces red blood cell sickling 1
• Decreasing the frequency and severity of pain crises 1
• Reducing mortality risk in patients with elevated tricuspid regurgitant velocity (TRV) or elevated NT-pro-BNP 1

Monitoring requirements:

• CBC and reticulocyte count every 1-3 months depending on dose stability 1
• Watch for myelosuppression as the primary adverse effect 1

Additional FDA-Approved Disease-Modifying Agents

L-glutamine (Endari):

• FDA-approved for patients ≥5 years of age to reduce acute pain episodes 2
• Reduces sickle cell crises by 25% compared to placebo (median 3 vs 4 crises annually) 2
• Reduces hospitalizations and cumulative hospital days 2
• Dosed at 5-15 grams orally twice daily based on body weight 2
• Can be used as adjunctive therapy with hydroxyurea 3

Crizanlizumab (Adakveo):

• Indicated for patients ≥16 years to reduce vaso-occlusive crises 4
• Reduced pain crises from 2.98 to 1.63 per year in clinical trials 3
• Dosed at 5 mg/kg IV on Week 0, Week 2, then every 4 weeks 4

Voxelotor:

• Increases hemoglobin by ≥1 g/dL in 51% of patients vs 7% with placebo 3
• Used as second-line or adjunctive therapy 3

Chronic Transfusion Therapy

For patients with increased mortality risk who are not responsive to or not candidates for hydroxyurea, chronic transfusion therapy is recommended. 1

Specific indications for chronic transfusion:

• Primary stroke prevention in children with abnormal transcranial Doppler (TCD) 1
• Secondary stroke prevention after overt stroke 1
• Recurrent acute chest syndrome despite optimal medical therapy 1
• Monthly transfusions suppress bone marrow and decrease HbS percentage 1

Transfusion complications to monitor:

• Iron overload requiring chelation after 12-20 transfusions 1
• Alloimmunization 1
• Risk of infection and thrombosis from central lines 1

Risk Stratification and Monitoring

All patients require systematic risk assessment even when asymptomatic:

Cardiovascular monitoring:

• Blood pressure goal of ≤130/80 mm Hg (same as general population) 1
• Routine targeted history for cardiopulmonary symptoms 1
• Echocardiography at steady state (not during acute illness) to assess for pulmonary hypertension 1
• TRV >2.5 m/second or NT-pro-BNP >160 pg/mL indicates increased mortality risk 1

Neurologic monitoring:

• All children <17 years require annual transcranial Doppler screening 1
• Abnormal TCD is an indication for consideration of matched sibling donor transplant 1

Renal monitoring:

• Annual urine microalbumin/creatinine ratio starting at age 10 1
• For worsening anemia with chronic kidney disease, combination hydroxyurea plus erythropoiesis-stimulating agents is suggested 1
• Conservative hemoglobin threshold of ≤10 g/dL to reduce vaso-occlusive complications 1

Ophthalmologic monitoring:

• Annual dilated fundoscopic examination starting at age 10 to screen for proliferative retinopathy 1

Curative Therapies

Hematopoietic stem cell transplantation (HSCT):

The ASH guideline panel suggests HLA-matched related HSCT over standard care for patients with:

• History of overt stroke or abnormal TCD 1
• Frequent pain crises not responding to standard therapy 1
• Recurrent acute chest syndrome despite optimal care 1

Key considerations:

• Best outcomes occur in children <16 years with matched sibling donors 1
• Myeloablative conditioning suggested for children; nonmyeloablative for adults 1
• Alternative donor transplants should only be performed in clinical trials 1
• Barriers include donor availability, graft rejection, graft-versus-host disease, and infertility risk 1

Preventive Care

Infection prevention:

• Penicillin prophylaxis from diagnosis through at least age 5 years 1
• May continue beyond age 5 in selected patients with history of invasive pneumococcal infection or splenectomy 1
• Complete pneumococcal vaccine series 1

Thromboprophylaxis:

• All post-pubertal patients require thromboprophylaxis due to increased VTE risk 1

Common Pitfalls to Avoid

Do not withhold hydroxyurea based on absence of symptoms - the 2014 guidelines explicitly recommend starting at 9 months regardless of clinical manifestations 1

Do not use targeted pulmonary arterial hypertension therapy (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclin agonists) for elevated TRV alone - strong recommendation against this practice 1

Do not exceed hemoglobin of 10 g/dL when using erythropoiesis-stimulating agents - higher levels increase risk of vaso-occlusion, stroke, and VTE 1

Do not assume all patients are on hydroxyurea - despite guidelines, many patients remain untreated and require initiation of disease-modifying therapy 1