Lower neutrophil counts after hematopoietic stem cell transplant for sickle cell disease patients using donors with duffy-null phenotype

Abstract Background: Individuals with the Duffy null phenotype (red blood cells that lack the Fya and Fyb antigens) have fewer circulating neutrophils but no increased risk of infection. The Duffy null phenotype is very common in certain populations with 65-70% of African Americans having it. Studies have shown mixed findings regarding the impact of Duffy null status on absolute neutrophil count (ANC) and hydroxyurea therapy in patients with sickle cell disease (SCD). Duffy null status has never been studied in the context of hematopoietic stem cell transplantation (HSCT). With reduced toxicity conditioning and improved outcomes using alternative donors, HSCT is increasingly being utilized to cure SCD. Objective: To determine if HSCT donor Duffy null status impacts HSCT recipient ANC after HSCT for SCD. Methods: We conducted a retrospective study of patients with SCD who underwent HLA-identical sibling donor HSCT at our pediatric hospital. HSCT recipients and donors had red blood cell molecular phenotyping as part of their clinical care. Median ANC at various times was compared for the Duffy null vs. Duffy non-null groups using the Mann-Whitney test. Results: A total of 74 patients with SCD underwent HLA-identical sibling donor HSCT with myeloablative (n=35), reduced intensity (n=10), or nonmyeloablative (n=29) conditioning. Duffy null status was concordant for 70/74 (94.6%) donor-recipient pairs with 60 both being Duffy null and 10 both being Duffy non-null. Three donors were Duffy non-null with Duffy null recipients, and one donor was Duffy null with a Duffy non-null recipient. Pre-HSCT, Duffy null patients with SCD did not have significantly different ANC compared to Duffy non-null patients: median 3.51 x 103/µL (IQR 2.30-5.57) vs. 3.24 x 103/µL (1.49-5.08), p=0.66. Baseline donor ANC was significantly lower for Duffy null donors compared to Duffy non-null donors: median 2.38 x 103/µL (IQR1.58-3.09) vs. 3.84 x 103/µL (IQR3.54-4.85), p<0.0001). Early post-HSCT ANC values were not significantly different between patients who received HSCT from Duffy null donors compared to Duffy non-null donors: Day +30 Duffy null median 3.14 x 103/µL (IQR 2.11-3.81) vs. Duffy non-null median 2.33 x 103/µL (IQR 1.37-3.32), p=0.074; Day +100 Duffy null median 2.43 x 103/µL (IQR 1.74-3.34) vs. Duffy non-null median 3.07 x 103/µL (IQR 1.79-5.19), p=0.29. Further post-HSCT, ANC values were significantly lower in patients who received HSCT from Duffy null donors compared to Duffy non-null donors: Day +365 Duffy null median 1.76 x 103/µL (IQR 1.49- 2.95) vs Duffy non-null median 3.41 x 103/µL (IQR 2.26-6.14), p=0.0098); last follow-up Duffy null median 1.90 x 103/µL (IQR 1.51-2.64) vs Duffy non-null median 3.73 x 103/µL (IQR 2.39-4.12), p=0.0042. During the first year post-HSCT, 5 patients had major clinical events: 1 patient had secondary graft failure, 2 patients underwent second transplant for decreasing myeloid donor chimerism, and 2 patients died. Excluding these 5 patients did not change the significant findings regarding ANC differences between the Duffy null and Duffy non-null donor groups. Most patients received potentially myelosuppressive sulfamethoxazole-trimethoprim prophylaxis continuously post-HSCT: 46/61 (75.4%) patients with Duffy null donors vs. 12/13 (92.3%) patients with Duffy non-null donors, p=0.27. Conclusion: Among pediatric patients who underwent HLA-identical sibling HSCT for SCD, after day +100 post-HSCT patients with Duffy null donors had significantly lower ANC values compared to patients with Duffy non-null donors. HSCT donor Duffy null status should be considered when evaluating ANC after HSCT and may have clinical implications.