Persistent Splenomegaly is associated with Morbidity in Tanzanian Children with Sickle Cell Anemia: Secondary Analysis of the SPHERE Trial

Introduction: African children with sickle cell anemia (SCA) often have splenomegaly with recurrent cytopenias that complicate management, rather than the splenic atrophy typically observed in SCA. Methods: We analyzed the presence, persistence, and impact of splenomegaly in the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial (NCT03948867), an open-label trial of dose-escalated hydroxyurea to prevent stroke in Tanzanian children with SCA. Palpable splenomegaly was recorded at each visit. Annual ultrasound measurements were compared to age- and height-related references. Longitudinally, palpable splenomegaly was categorized as infrequent (present in <5% visits), intermittent (10-50% visits), or persistent (>50% visits). Adverse events (AE) and hydroxyurea dose-limiting toxicities (DLT) were compared using incidence rate ratios (IRR) among the three categories. Results: At enrollment, splenomegaly was identified in 48/196 (25%) by palpation and 78 (40%) by ultrasound. Across 221 patient-years of treatment in 53 children, splenomegaly was intermittent in 19% and persistent in 21%. At 12 months, children with persistent splenomegaly were compared to those with infrequent splenomegaly and had achieved similar hydroxyurea dose (23.1 vs 27.6 mg/kg/day, p=0.136), hemoglobin (9.0 vs 9.1g/dL, p=0.877) and HbF (23.8 vs 24.3%, p=0.481), but experienced more vaso-occlusive AE (IRR=3.8, p-value 0.122), transfusions (IRR=7.1, p-value 0.014), and DLTs (IRR=3.2, p-value 0.073). Conclusion: Splenomegaly is common in Tanzanian children with SCA, often persistent, worsens clinical outcomes and complicates hydroxyurea. Its cause remains unclear and further investigation is urgently needed to clarify its etiology, improve its management, and ensure optimal hydroxyurea treatment.