Splenomegaly patterns and clinical impact in African children with sickle cell anemia on hydroxyurea treatment Free

Introduction. Splenomegaly is a challenging complication for children with sickle cell anemia (SCA) in sub-Saharan Africa, with little experience gained from high-income countries where splenic infarction and involution occur early in life. The etiology, persistence, and consequences of splenomegaly are poorly understood, especially regarding the effects of hydroxyurea treatment. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731 and NCT06171217) is an ongoing Phase 1/2 trial of open-label hydroxyurea with dose optimization to maximum tolerated dose (MTD) for children with SCA in four African countries. With over 5,000 participant-years of treatment exposure, we address the characteristics and consequences of splenomegaly in this clinical setting.

Methods. Children aged 1-10 years with SCA were enrolled at 4 clinical sites in Angola, Democratic Republic of Congo, Kenya, and Uganda. After a 3-month screening phase, hydroxyurea was prescribed at fixed dose for 6 months, escalated to MTD by Month 24, and subsequently optimized with mild myelosuppression. Spleen size below the costal margin was recorded at each scheduled and unscheduled visit. Cross-sectional analysis compared age, sex, clinical site, growth parameters, alpha thalassemia (1-gene or 2-gene deletion), and G6PD deficiency across four baseline spleen categories: non-palpable, moderate (1-4 cm), large (≥ 5 cm), or splenectomy with correlations. Longitudinal analysis categorized the frequency of palpable splenomegaly over repeated assessments as never (splenectomy), rare (<5%), intermittent (5-50%), or persistent (>50%). Mean laboratory values and current optimized daily doses were calculated in these categories, plus rates per 100 patient-years (pt-yr) for dose-limiting toxicities (DLT), transfusions, malaria infections, and deaths. Rate ratios (RR) and 95% confidence intervals were calculated for persistent vs. non-persistent splenomegaly.

Results: A total of 606 children started hydroxyurea. At enrollment, 10/606 (1.7%) had splenectomy, 49/606 (8.1%) had moderate splenomegaly, and 50/606 (8.3%) had large splenomegaly. Compared to no palpable spleen, any splenomegaly at baseline was associated with a lower hemoglobin (6.9±1.3 vs 7.3±1.0 g/dL, p<0.001) and lower platelet count (287±117 vs 432±168 x 10⁹/L, p<0.001). Children with alpha thalassemia had a greater prevalence of baseline splenomegaly (20.0% vs 12.4%, p=0.0019), but G6PD deficiency had no effect. Excluding 10 children with splenectomy at enrollment, palpable splenomegaly was recorded at least once during treatment in 346/596 (58.1%) children, usually in the first 2 years. Children with 2-gene deletion alpha thalassemia also had a higher risk of developing splenomegaly (~70% vs. ~50%, p=0.004). Over 8.5±2.4 years of follow-up and a median of 54 assessments per child, palpable splenomegaly was rare in 384/596 (64.4%), intermittent in 148/596 (24.8%), and persistent in 64/596 (10.7%). The average optimized hydroxyurea doses for these 3 categories were 28.6±5.3 mg/kg/day, 27.1±6.1 mg/kg/day, and 23.1±6.4 mg/kg/day, p<0.001. Lab consequences of persistent splenomegaly, compared to rare or intermittent splenomegaly, included a lower hemoglobin (6.9±1.4 vs 8.2±1.3 g/dL, p<0.001), lower MCV (90±12 vs 97± 14 fL, p<0.001), and lower platelet count (201±83 vs 383±171 x 10⁹/L, p<0.001), but a slighter higher absolute neutrophil count (4.3±2.1 vs 3.9±1.8 x 10⁹/L, p=0.122). Additional consequences of persistent splenomegaly included a high rate of DLT (67.0/100 pt-yr; RR=3.72 [2.62-5.37]; p<0.001), particularly for anemia and thrombocytopenia. Transfusions (31.0/100 pt-yr; RR=4.54 [3.08-6.78]; p<0.001) and all-cause death (2.3/100 pt-yr, RR=2.38 [1.15-4.55]; p=0.028) were also more common. Malaria was highest in children with intermittent splenomegaly (31.6/100 pt-yr; RR=1.58 [1.27-1.96]; p<0.001).

Conclusions. Splenomegaly is common among children with SCA living in sub-Saharan Africa and complicates their clinical care despite sustained hydroxyurea at MTD. Persistent splenomegaly is especially problematic and associated with lower baseline lab values, lower hydroxyurea doses, more DLT, and greater clinical morbidity including more transfusions and more deaths. The importance of alpha thalassemia and recurrent malaria in the development of splenomegaly remains poorly understood. New recommendations for wider malaria chemoprophylaxis may help reduce splenomegaly in children with SCA.