Introduction. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is a prospective multicenter open-label trial that has already demonstrated hydroxyurea treatment at maximum tolerated dose (MTD) is safe, feasible, and offers major benefits for children with sickle cell anemia living in sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). One unexpected benefit was a significant reduction in the number of malaria infections, including those with Grade 3 severity or above, across four trial sites in varied epidemiological settings. The overall rate of symptomatic malaria infections decreased from 46.9 events per 100 patient-years during screening to 22.9 events per 100 patient-years on treatment, an incidence rate ratio of 0.49 (95% confidence intervals [CI] = 0.37-0.66). This decreased rate of malaria was observed during the first 12 months of treatment, but declined further between Months 12-36, after the children had dose escalation to achieve hydroxyurea MTD at 22.5 mg/kg/day. Potential mechanisms of malaria protection remain unknown at this time, but could relate to both patient characteristics as well as treatment-related laboratory changes in hemoglobin (Hb), mean corpuscular volume (MCV), absolute neutrophil count (ANC), or fetal hemoglobin (HbF).
Methods. Malaria infections were recorded in the REACH REDCap electronic database. Using several methods for recurrent events, with time-varying predictors as well as landmark analysis, associations with infections recorded during study treatment were assessed for multiple variables including trial site, high or low malaria season, age, gender, spleen status, hydroxyurea dose, MTD status, latest laboratory values (Hb, MCV, ANC, and HbF, all measured at least 15 days prior to the onset of the infection), as well as genetic modifiers alpha-thalassemia and G6PD deficiency. Univariate relationships were assessed using the Anderson-Gill model, followed by multiple regression to estimate Hazard Ratios (HR) with 95% CI's. Additional analyses were performed using a gap-time model that resets the clock after each infection, as well as using only the first infection in each participant; the subset of 200 acute blood-smear proven malaria infections was also analyzed separately.
Results. A total of 635 children were enrolled in REACH and eligible for analysis, of whom 606 started hydroxyurea treatment. There were 333 malaria infections recorded during 1580 patient-years of observation, including 50 during screening and 283 on treatment, of which 200 had documented positive blood smears at the clinical site. Significant associations for malaria risk were identified with higher ANC (HR = 1.06 per 1 x 109 neutrophils/L, CI = 1.02-1.10, P=0.005), higher MCV (HR = 1.01 per fL, CI = 1.00-1.02), and palpable splenomegaly (HR 1-4cm = 1.73, CI = 1.22-2.45, P= 0.002, HR ≥5cm = 1.52, CI = 1.04-2.21, P=0.03). In multiple regression, the latest ANC and MCV, as well as splenomegaly remained significant but higher HbF was also associated with more malaria (HR = 1.02 per %HbF, CI = 1.00-1.03, P=0.03). These trends were consistent when using the landmark, gap-time and first infection analytical approaches. Analysis of only documented blood-smear positive malaria infections again identified higher ANC, MCV, and splenomegaly as risk factors, but found no association with HbF. Achieving MTD was found to confer significant protection against documented malaria infections (HR = 0.62, CI=0.39-1.00, P=0.048).
Conclusion. Hydroxyurea treatment in children with sickle cell anemia living in sub-Saharan Africa is associated with a decreased risk of malaria infections, particularly after achieving MTD. The mechanisms by which hydroxyurea protects against malaria are likely multi-factorial, but do not appear to be related to HbF induction, as higher HbF values were not protective and in some analyses were a risk factor. However, a higher ANC was significantly associated with malaria risk in all models and analyses; since hydroxyurea treatment lowers the ANC, dose escalation to MTD may confer protection against malaria infection by reducing inflammation. Spleen status is also crucial and the role of splenomegaly as a risk factor for malaria requires further investigation.
Ware:Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation; Bristol Myers Squibb: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.