The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease

Global Blood Therapeutics, former employee, stockholder.

The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease To the Editor: Leg ulcers are a common, painful, and debilitating chronic complication of sickle cell disease (SCD). 1 The prevalence of this complication varies by geography, genotype, and age. 1 In the United States, 14% to 18% of patients with SCD may develop leg ulcers at some point, and an estimated 1% to 5% of patients with SCD have active ulcers. [1][2][3][4] The incidence of leg ulcers in SCD remains steady despite advances in preventive strategies and supportive care. 2 Patients typically develop their first leg ulcer in the second decade of life, and are at an increased risk for leg ulcers with increasing age and severity of anemia. 1,5 However, the true incidence of leg ulcers in SCD may be underestimated given the paucity of registries and large prospective trials for this complication. 1 Leg ulcers in SCD tend to develop in areas with poor blood flow and limited subcutaneous tissue, such as the medial and lateral malleoli (ankles), and when untreated, can progress from epidermal skin loss to extensive tissue destruction and necrosis. 6 The pain that results from ulcers is excruciating and markedly different from the pain associated with sickle cell crises. 1,7 Sharp pain often precedes the formation of new ulcers, and the severity of pain is often unrelated to the size of the formed ulcer. 1 The intense, irregular pain, associated gait abnormalities, and lower limb deformities result in substantial physical and emotional impairment in these patients. 6,7 No standardized protocol for the care of these wounds exists. 8 While nearly all patients with SCD have anemia, those with more severe hemolytic anemia are more prone to developing leg ulcers. 9 Leg ulcers are almost exclusively found in SCD patients with a severe genotype (HbSS/HbSβ 0 ) and are rarely found in milder forms of SCD (HbSC/HbSβ + ). 10 The SCD patients with a severe genotype are also at risk of developing other hemolysis-related complications, including stroke, pulmonary hypertension, and renal dysfunction.  pared with those of patients whose ulcers did not resolve (Table S3).
No new safety signals were observed among patients with leg ulcers, and treatment with voxelotor was well tolerated.
In While the pathophysiology of ulcer formation in SCD remains incompletely understood, it is likely caused by a combination of systemic and local factors, including chronic inflammation, hemolysis, and venostasis. 1 Patients with leg ulcers have also been noted to have impaired red blood cell deformability and altered rheology that was associated with increased intravascular hemolysis. 1 Patients with SCD presenting with leg ulcers should be screened for end-organ complications, given the risk for other forms of organ damage. 9 As a HbS-polymerization inhibitor, voxelotor has been demonstrated to improve parameters of red blood cell health and attenuate intravascular hemolysis in patients. 11  Global Blood Therapeutics, former employee, stockholder.

ETHICS STATEMENT
This trial was conducted in accordance with the principles of the Declaration of Helsinki International Conference on Harmonization, Good Clinical Practice guidelines in clinical trials, and all applicable countryspecific regulatory guidelines. The study protocol was reviewed and approved by institutional review boards and independent ethics committee of each of the participating trial sites.

PATIENT CONSENT STATEMENT
Written informed consent was obtained from patients prior to study.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.