Effects of Splenomegaly in Children with Sickle Cell Anemia Treated with Hydroxyurea: Secondary Analysis of the Sphere Trial
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.004 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".