Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Poster II
Hematology Disease Topics & Pathways:
sickle cell disease, Diseases, Non-Biological, Therapies, Hemoglobinopathies, Clinically relevant, pharmacology
Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single‐center prospective study that demonstrated individualized, pharmacokinetic (PK)‐guided hydroxyurea dosing in young patients (mean age 12.1 months at initiation) results in robust and sustained HbF levels >30-40% for most adherent patients. The longitudinal follow-up phase of TREAT aims to comprehensively evaluate hematologic parameters and organ function to demonstrate the long-term benefits of this treatment strategy. During clinic visits (every 3-6 months), TREAT participants had complete blood counts (CBCs) with the ADVIA® 2120i system. This automated analyzer quantifies hyperchromic RBCs within seconds by directly measuring cell hemoglobin concentration, where DRBCs are known to correspond to RBCs with a measured MCHC >41 g/dL. Data were analyzed at baseline and after at least 6 months of hydroxyurea therapy (M≥6). α- and β-globin genotypes were determined for all patients.
Results: Thirty-three TREAT participants had ADVIA data available for analysis (Table). All had homozygous SCA except one with sickle-β0-thalasemia; 17 (51.5%) were male. The median age at hydroxyurea initiation was 10.3 months (mean 26.1 months; range 6 months - 17 years). The median duration of hydroxyurea therapy was 27.7 months (mean 31.5). At baseline, median %DRBCs was 2.1%. Baseline %DRBCs were directly correlated with age at initiation of hydroxyurea (p=0.022) and inversely correlated with baseline HbF (p=0.001). After initiation of hydroxyurea (M≥6), there was a 47.6% reduction in %DRBCs (p=0.001). Median %DRBCs at M≥6 was directly correlated with absolute reticulocyte (ARC) (p=0.002), absolute neutrophil (ANC) (p=0.003) and platelet counts (p<0.001) and inversely correlated with Hb (p=0.013) and hematocrit (Hct) (p=0.019), consistent with the laboratory benefits of hydroxyurea. In bivariate analysis, the change in %DRBCs from baseline was directly correlated with baseline %DRBCs (p<0.001) and inversely correlated with baseline HbF (p=0.005). In multivariate analysis, baseline %DRBCs was the only biologic parameter that independently predicted %DRBC change (β=-0.86, p<0.001, model r2=0.91; Figure). Even when baseline %DRBCs were only mildly increased (as low as 1.5%), participants had a marked decline in %DRBC with hydroxyurea. When baseline %DRBCs were very low at baseline (<1.5%), they remained low after treatment. Of note, there was no correlation between %DRBC change and α-thalassemia status.
Conclusions: DRBCs can be rapidly quantified without the tedium of classical density-gradient fractionation methods using the automated ADVIA 2120i hematology analyzer, which directly measures hyperchromic RBCs. These data from TREAT demonstrate the feasibility of serial %DRBC measurements in clinical trials and clinical practice. TREAT participants had low baseline DRBCs compared to untreated adult SCA patients (reported mean ≈12%), reflecting the young age of these patients. Nevertheless, there was a significant decline in %DRBCs with treatment that correlated strongly with the known laboratory benefits of hydroxyurea. In conclusion, automated DRBC measurements are a robust biomarker that can be incorporated in a panel of laboratory measurements of response to hydroxyurea (and severity of SCA). A larger, multicenter study of PK-guided hydroxyurea therapy (HOPS, NCT03789591) is currently underway in 11 US sickle cell centers and will provide generalizable data on DRBC responses with optimal hydroxyurea therapy.
Disclosures: Malik: Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. Kalfa: Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding.
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