Impact of the duffy-null phenotype on hydroxyurea dosing and clinical outcomes in children with sickle cell disease Free

Background: Individuals with Duffy-null phenotype have lower circulating neutrophils without an increased risk of infection. Duffy-null phenotype is present in about 65-70% of African Americans and ≥75% of sickle cell disease (SCD) patients in the US. Hydroxyurea (HU), a disease-modifying therapy, improves the condition by increasing fetal hemoglobin (Hgb F) production and reducing inflammation. The HU dose is escalated to maximum tolerated dose (MTD), guided in part by the absolute neutrophil count (ANC). While some studies suggest lower HU dosing in SCD patients with Duffy-null phenotype (Menell et al., Goldfarb et al.), others report no significant differences in ANC or HU dosing (Goldfarb et al., Oladipupo et al., Zheng et al.). In addition, SCD-related clinical outcomes between Duffy-null and Duffy non-null phenotypes are conflicting (Oladipupo et al., Zheng et al.) and more data is needed to determine the impact of Duffy status on SCD outcomes, including HU dosing.

Objective: To evaluate the impact of Duffy-null phenotype on hydroxyurea dosing and clinical outcomes in children with SCD.

Methods: A retrospective cohort study was performed on SCD patients (genotype SS, SC, Sβ⁰ and Sβ⁺) on MTD of HU therapy at a tertiary pediatric hospital. The study population included children between ages 0-19 years with documented Duffy genotyping who received care at our institution between 01/01/2022 to 12/31/2024. Laboratory data including complete blood counts (CBC), bilirubin, hemoglobin electrophoresis and lactate dehydrogenase (LDH) were collected from patients' routine hematology clinic appointments. Clinical outcomes evaluated include MTD of HU (mg/kg/day), frequency of hospitalizations for SCD related sequalae, abnormal transcranial doppler findings, incidence of stroke, and frequency of red blood cell (RBC) transfusions. We compared demographic characteristics, lab values and outcomes between Duffy-null and Duffy non-null patients using two-sample T test, Wilcoxon Rank sum test, Chi Square and Fischer's exact test where appropriate.

Results: We collected data from 85 eligible study participants, 61 (71.8%) of which were Duffy-null and 24 (28.2%) of which were Duffy non-null. There were 31 females (50.82%) in Duffy-null group and 13 females (54.17%) in Duffy non-null group. There were 7 Duffy-null patients and 4 Duffy non-null patients on chronic transfusion therapy. Laboratory values including white blood cell (WBC), hemoglobin (Hgb), hematocrit (HCT), mean corpuscular volume (MCV), absolute reticulocyte count, ANC, bilirubin, and LDH were not statistically different between Duffy-null and Duffy non-null SCD patients on HU therapy. HU dosing was not significantly different between Duffy-null (mean 24.77 ± 5.75 mg/kg/day) and Duffy non-null patients (mean 23.79 ± 8.26 mg/kg/day, p=0.60). There was also no significant difference between the number of RBC transfusion events between Duffy-null (mean 4.24 ± 9.95 events) and Duffy non-null (mean 4.91 ± 8.63 events, p=0.38) patients on HU therapy. The number of hospitalizations within the 2-year period from 01/01/2022 to 12/31/2024 showed no difference between Duffy-null and Duffy non-null participants (mean 2.49 ± 3.70 vs mean 2.42 ± 2.90, p=1.00). There was a similar distribution of abnormal (Duffy-null 5.45% vs Duffy non-null 9.52%), normal (Duffy-null 78.18% vs Duffy non-null 80.95%), and conditional (Duffy-null 16.36% vs Duffy non-null 9.52%) middle cerebral artery (MCA) velocity in transcranial doppler ultrasound (TCD) between Duffy-null and Duffy non-null (p=0.63). There were no significant differences in the incidence of stroke between Duffy-null and Duffy non-null groups (14.85% vs 12.50%, p=1.00).

Conclusion: Among pediatric patients with SCD on HU therapy, there were no significant differences in laboratory values including ANC between Duffy-null and Duffy non-null patients. There were also no significant differences in clinical outcomes including MTD of HU, number of RBC transfusions, incidences of abnormal TCDs and stroke or hospitalizations for SCD related sequalae. These findings suggest Duffy-null status may not impact MTD of HU and clinical outcomes in children with SCD.