What are alternative treatments for patients with sickle cell disease who are unable to tolerate hydroxyurea (hydroxycarbamide) or have not responded to it?

Hydroxyurea Alternatives for Managing Sickle Cell Disease

For patients with sickle cell disease who cannot tolerate or have not responded to hydroxyurea, chronic transfusion therapy is the recommended alternative, with hematopoietic stem cell transplantation reserved for select candidates with suitable donors. 1

Primary Alternative: Chronic Transfusion Therapy

Chronic red blood cell transfusion therapy is the first-line alternative when hydroxyurea fails or cannot be used. 1 The American Thoracic Society provides a weak recommendation for chronic transfusion therapy in patients with increased mortality risk who are not responsive to or not candidates for hydroxyurea, though this is based on low-quality evidence. 1

Key Implementation Points:

• Target post-transfusion hemoglobin levels of 10-11 g/dL to minimize vaso-occlusive complications while providing therapeutic benefit 2
• Consider exchange transfusion rather than simple transfusion when baseline hemoglobin exceeds 9-10 g/dL to avoid hyperviscosity 2
• Monitor for iron overload, which is an established complication requiring chelation therapy 1

Evidence for Transfusion Efficacy:

The TWiTCH trial demonstrated that patients on chronic transfusion therapy maintained stable TCD velocities and avoided stroke, though iron burden increased significantly (P ≤0.001). 1 This underscores both the efficacy and the burden of long-term transfusion therapy.

Curative Option: Hematopoietic Stem Cell Transplantation

For patients with matched sibling donors, hematopoietic stem cell transplantation offers a curative alternative. 1, 3 However, less than 25% of patients have suitable donors, limiting widespread applicability. 3

Transplant Outcomes:

• In the Creteil newborn cohort, 24 patients with normalized TCD velocities post-transfusion underwent bone marrow transplantation from genoidentical sibling donors with no strokes or silent cerebral infarctions during mean follow-up of 3.5 years 1
• A comparative study of 67 children showed bone marrow transplantation resulted in fewer silent cerebral infarctions and greater TCD velocity reduction compared to chronic transfusion at 3-year follow-up 1
• Approximately 1,000 people (mostly children) have been cured through hematopoietic stem cell transplantation to date 4

Combination Therapy for Specific Scenarios

Hydroxyurea Plus Erythropoiesis-Stimulating Agents

For patients with chronic kidney disease and progressive anemia who cannot tolerate full-dose hydroxyurea alone, combination therapy with erythropoiesis-stimulating agents may allow continued hydroxyurea use. 1, 5

Critical Safety Parameters:

• Maintain hemoglobin ≤10 g/dL to reduce risk of vaso-occlusive complications, stroke, and venous thromboembolism 1, 6, 2, 5
• This combination allows more aggressive hydroxyurea dosing by counteracting treatment-related anemia 1, 6
• Only 1 of 56 patients (1.8%) experienced worsening sickle cell symptoms with combination therapy 1

Important caveat: The American Society of Hematology notes this recommendation is based on very low certainty evidence from small case series (n=52) without direct comparison studies. 1 The hemoglobin ceiling of 10 g/dL is essential to prevent hyperviscosity complications. 6

Newer FDA-Approved Agents

While not traditional "alternatives" to hydroxyurea, three additional disease-modifying drugs are now FDA-approved and may be used when hydroxyurea is insufficient:

• L-glutamine (approved by FDA) 4, 7
• Crizanlizumab (P-selectin inhibitor) 7
• Voxelotor (hemoglobin polymerization inhibitor) 7

These agents are increasingly being considered for combination therapy rather than monotherapy alternatives, as individual agent efficacy is limited and combinations will likely be required for optimal outcomes. 7

Therapies to Avoid in Specific Contexts

Pulmonary Hypertension Considerations:

For patients with elevated TRV or NT-pro-BNP alone without right heart catheterization-confirmed pulmonary hypertension, targeted PAH therapy is strongly contraindicated. 1 This includes prostacyclin agonists, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. 1

For most patients with right heart catheterization-confirmed pulmonary hypertension, targeted PAH therapy is also not recommended (strong recommendation, moderate-quality evidence). 1

The only exception is select patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary artery wedge pressure, and related symptoms, who may receive a trial of prostacyclin agonist or endothelin receptor antagonist (weak recommendation, very low-quality evidence). 1 Phosphodiesterase-5 inhibitors should not be used as first-line agents even in this select group (strong recommendation). 1

Clinical Decision Algorithm

1. First-line: Attempt hydroxyurea optimization (15-20 mg/kg/day titrated to MTD of 20-35 mg/kg/day) 6

2. If hydroxyurea fails or is not tolerated:

   • Without chronic kidney disease: Initiate chronic transfusion therapy targeting hemoglobin 10-11 g/dL 1, 2
   • With chronic kidney disease and worsening anemia: Consider combination hydroxyurea + erythropoiesis-stimulating agents (maintain hemoglobin ≤10 g/dL) 1, 5

3. If matched sibling donor available: Evaluate for hematopoietic stem cell transplantation 1, 3

4. If transfusion therapy inadequate: Consider adding newer FDA-approved agents (L-glutamine, crizanlizumab, voxelotor) 7

5. Gene therapy: Remains investigational with limited follow-up data 4