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2495 Effects of Splenomegaly in Children with Sickle Cell Anemia Treated with Hydroxyurea: Secondary Analysis of the Sphere Trial

Program: Oral and Poster Abstracts
Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Sickle Cell Disease, Clinical Research, Hemoglobinopathies, Diseases, Adverse Events
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Emmanuela Eusebio Ambrose, MD1,2, George A. Tomlinson, PhD3*, Patrick S. Ngoya, MD2*, Susan E. Stuber, MA4,5*, Teresa S. Latham, MA4*, Abel Nkono Makubi, PhD, MD, MSc6*, Russell E. Ware4,5,7 and Luke R. Smart, MD4,5,7,8

1Bungando Medical Centre, Mwanza, Tanzania, United Republic of
2Catholic University of Health and Allied Sciences, Mwanza, Tanzania, United Republic of
3University Health Network, Toronto, ON, CAN
4Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
5Global Health Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
6Department of Hematology, Benjamin Mkapa Hospital, Dodoma, Tanzania, United Republic of
7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
8Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

Introduction: Sickle cell anemia (SCA) typically causes splenic dysfunction and atrophy early in life, but in sub-Saharan Africa, many children have persistent splenomegaly that can lead to splenic sequestration and hypersplenism with recurrent cytopenias. We performed a secondary analysis of the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE, NCT03948867) trial to elucidate the associations among splenomegaly, clinical complications, hydroxyurea dose, and dose-limiting toxicities (DLTs).

Methods: SPHERE was a prospective, phase 2 trial of open-label hydroxyurea to decrease stroke risk in Tanzanian children, 2-16 years old, with SCA. Participants underwent transcranial Doppler (TCD) ultrasound screening, and those with elevated (≥170 cm/s) TCD velocities were eligible for treatment. Hydroxyurea was initiated at 20 mg/kg/day and escalated to maximum tolerated dose (MTD) based on peripheral blood counts. Palpable splenomegaly was assessed at each visit and categorized as nonpalpable, 1-4.9 cm, or ≥5 cm. Splenic volume was calculated using ultrasound measurements at baseline and annually. Longitudinally, splenomegaly was categorized based on the cumulative frequency of palpable splenomegaly: not present (<5% of visits), intermittent (5-50% of visits), or persistent (>50% of visits). Incidence of adverse events (AE), transfusions, and DLTs were compared between categories of splenomegaly persistence using incidence rate ratios (IRRs).

Results: A total of 196 children with SCA, mean age 6.8 years, were enrolled. Palpable splenomegaly was identified at baseline in 48/196 children (24%): 16 (8%) 1-4.9 cm and 32 (16%) ≥5 cm. Palpable splenomegaly at enrollment was associated with prior splenic sequestration, previous transfusions and lower baseline hemoglobin (7.0±1.3 g/dL in ≥5 cm, 7.8±0.7 g/dL in 1-4.9 cm, and 7.8±1.1 g/dL in the nonpalpable category), but not G6PD deficiency or alpha thalassemia status. Ultrasonography at enrollment identified enlarged spleen volumes in 78 children (40%) using published age- and height-matched norms. Splenic volumes correlated with splenic palpation categories: 227±232 mL in ≥5 cm, 119±79 mL in 1-4.9 cm, and 7.8±1.1 mL in the nonpalpable category.

Over 4.2 years of hydroxyurea treatment in 53 children, palpable splenomegaly was persistent in 10/53 (19%), intermittent in 11/53 (21%), and nonpalpable in 32/53 (60%). After 12 months of treatment, the mean hydroxyurea dose was lower in those with persistent (21.9±4.8 mg/kg/day) than intermittent (27.4±6.1 mg/kg/day) or nonpalpable (27.6±5.1 mg/kg/day, p=0.019) splenomegaly. Baseline hemoglobin was similar between groups (6.8±1.4 g/dL in persistent, 7.5±0.8 g/dL in intermittent, 7.3±1.0 g/dL in nonpalpable, p=0.278). After 12 months of treatment mean hemoglobin had improved in all groups (8.8±1.1 g/dL in persistent, 9.7±0.7 g/dL in intermittent, 9.2±1.0 g/dL in not present, p=0.289), as had mean hemoglobin F (25.5% in persistent, 28.2% in intermittent, and 23.8% in nonpalpable, p=0.390). The TCD velocity decreased in all three categories of splenomegaly (-33±17.0 cm/s in persistent, -50.0±11.3 cm/s in intermittent, and -29.4±26.0 cm/s in nonpalpable, p=0.072).

Total incident AEs were higher in those with intermittent splenomegaly (IRR 1.7, 95% CI 1.3-2.1, p<0.0001), and persistent splenomegaly (IRR 1.5, 95% CI 1.1-2.0, p=0.0069), as were incident grade 3 AEs (intermittent IRR 2.4, 95% CI 1.3-4.2, p=0.0017; persistent IRR 2.7, 95% CI 1.5-4.8, p=0.0010). Transfusions occurred more frequently only in those with persistent splenomegaly (IRR 4.1, 95% CI 2.1-7.8, p<0.0001). DLTs were more frequent in those with intermittent splenomegaly (IRR 3.2, 95% CI 1.8-5.6, p=0.0001) and persistent splenomegaly (IRR 2.1, 95% CI 1.0-4.1, p=0.0492). Malaria incidence was similar among the three groups.

Conclusions: Splenomegaly is common in children with SCA living in sub-Saharan Africa. Children with large and persistent splenomegaly achieved a lower hydroxyurea dose, but had similar incremental benefits in hemoglobin, hemoglobin F, and TCD velocity. Persistent splenomegaly should not deter treatment with hydroxyurea but may require more frequent monitoring for adverse events. Future studies are needed to determine the optimal hydroxyurea monitoring and dose adjustment in children with splenomegaly as well as the role of splenectomy.

Disclosures: Tomlinson: Editas Inc: Consultancy; Spectral Inc: Consultancy. Ware: Merck Pharmaceuticals: Other: Medical Advisory Board; Novo Nordisk: Other: Health Equity Advisory Board; Theravia: Other: Medical Advisory Board; Nova Laboratories: Other: Medical Advisory Board.

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