Duffy Antigen Status, Hydroxyurea Dosing, and Phenotype Severity in Pediatric Patients with Sickle Cell Disease

Background: Individuals whose red blood cells lack the Duffy antigen (“Duffy null”) are immune to P. vivax infection but have lower measured ANC in the bloodstream despite normal total-body ANC. The Duffy null phenotype is seen in more than 80% of people of sub-Saharan ancestry and thus a majority of patients with sickle cell disease (SCD). Hydroxyurea treatment for SCD is dose-escalated to maximum tolerated dose (MTD) based on degree of myelosuppression, particularly neutropenia, with the goal of increasing HbF levels. To our knowledge, no studies have assessed hydroxyurea MTD or HbF levels in pediatric patients with SCD based on Duffy antigen status. Moreover, our study uniquely evaluated complications of SCD based on Duffy antigen status in patients who have been on hydroxyurea for both short periods and chronically.

Methods: This was a single-center, retrospective chart-review study of patients with HbSβ₀ and HbSS disease who were > 2 years old as of January 1, 2023 and were prescribed hydroxyurea. Patients were excluded if they had a different form of SCD, were not on hydroxyurea, or were on chronic transfusions for the entirety of 2023. Duffy antigen status, attainment of MTD, HbF at MTD, and metrics of disease severity were assessed for calendar year 2023.

Results: Data from 68 patients with HbSS disease and 4 patients with HbSβ₀ were analyzed. Duffy antigen status was available for 70 patients: 15 (21%) were Duffy positive, and 55 (79%) were Duffy null.

There was no difference in achievement of MTD by Duffy antigen status (Duffy positive: 66.7%, Duffy null: 65.5%, p = 1). Mean MTD in Duffy positive patients was 24.8 mg/kg and in Duffy null patients was 21.4 mg/kg (p = 0.16). In patients who achieved MTD, mean HbF at MTD was 21.7% (range: 11.0-33.0%) in Duffy positive patients vs 25.0% (range: 7.2-35.8%) in Duffy null patients (p = 0.49). In all patients, regardless of achievement of MTD, there was no difference in attainment of HbF > 20% (p= 0.71).

Among all patients, there was no difference in the total number of: vaso-occlusive episodes (VOE), VOE requiring hospitalization, splenic sequestration episodes, acute chest syndrome episodes, hospitalizations related to SCD, or emergency room (ER) visits related to SCD based on Duffy antigen status (p = 0.18, 0.74, 0.61, 0.37, 0.92, 0.10). Likewise, in patients who achieved MTD, no differences based on Duffy antigen status were seen in the same metrics (p= 0.06, 0.54, 0.61, 0.61, 0.79, 0.08). In patients who did not attain MTD, there were no splenic sequestration events in either group. For the other above metrics, there were no differences based on Duffy status (p = 0.49, 0.74, 0.46, 0.85, 0.79).

Conclusion: There were no detected differences in hydroxyurea MTD, HbF at MTD, attainment of HbF > 20%, or metrics of disease severity based on Duffy antigen status in our study population with sickle cell disease. In patients who attained MTD, both total VOE and total ER visits approached significance. Although not statistically significant, Duffy positive patients required, on average, higher hydroxyurea doses than Duffy null patients to reach MTD. With dose adjustments typically made in 5 mg/kg increments, Duffy positive patients may clinically require more dose escalations to reach MTD.

No relevant conflicts of interest to declare.