Legacy data show that approximately 40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level of <0.01% on day 19 of induction therapy had excellent outcomes with low-intensity treatment. We investigated the impact of MRD levels between 0.001% and <0.01% early in remission induction on the outcome of VLR ALL treated with a low-intensity regimen. Between October 2011 and September 2015, 200 consecutive patients with B-precursor ALL with favorable clinicopathologic features and MRD levels of <0.01%, as assessed by flow cytometry in the bone marrow on day 19 and at the end of induction therapy, received reduced-intensity therapy. The 5-year event-free survival was 89.5% (± 2.2% SE), and the overall survival was 95.5% (± 1.5% SE). The 5-year cumulative incidence of relapse (CIR) was 7% (95% CI, 4% to 11%). MRD levels between 0.001% and <0.01% on day 19 were detectable in 29 patients. These patients had a 5-year CIR significantly higher than that of patients with undetectable residual leukemia (17.2% ± 7.2% vs 5.3% ± 1.7%, respectively; P = .02). Our study shows that children with VLR ALL can be treated successfully with decreased-intensity therapy, and it suggests that the classification criteria for VLR can be further refined by using a more sensitive MRD assay.

Hypertension (HTN) is one of the most common chronic diseases, with a prevalence of 45.6% among US adults aged 20 years and older. 1 It is a primary risk factor for multiple adverse cardiovascular outcomes, including angina, myocardial infarction, heart failure, and stroke. 2 Use of antihypertensive drugs to control high blood pressure (BP), particularly high systolic BP (SBP), has been proven to reduce cardiovascular risks and prevent target organ damage. 3,4 However, recent data demonstrate that among hypertensives taking antihypertensive medications, approximately half of European Americans (EAs) and almost two-thirds of African Americans (AAs) have poorly controlled BP. 1,5,6 In addition to increased cardiovascular risk, poorly controlled BP often results in prescribing additional antihypertensive drugs, which may lead to poor adherence, increased risk for adverse events, and additional treatment costs. 7 Inter-patient

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.

Patients with higher genetic West African ancestry (GWAA) have hypertension (HTN) that is more difficult to treat and have higher rates of cardiovascular diseases (CVD) and differential responses to antihypertensive drugs than those with lower GWAA. The mechanisms underlying these disparities are poorly understood. Using data from 84 ancestry-informative markers in US participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, the GWAA proportion was estimated. Using multivariable linear regression, the baseline levels of 886 metabolites were compared between PEAR participants with GWAA < 45% and those with GWAA ≥ 45% to identify differential metabolites and metabolic clusters. Metabolites with a false discovery rate (FDR) < 0.2 were used to create metabolic clusters, and a cluster analysis was conducted. Differential clusters were then tested for replication in PEAR-2 participants. We identified 353 differential metabolites (FDR < 0.2) between PEAR participants with GWAA < 45% (n = 383) and those with GWAA ≥ 45% (n = 250), which were used to create 24 metabolic clusters. Of those, 13 were significantly different between groups (Bonferroni p < 0.002). Four clusters, plasmalogen and lysoplasmalogen, sphingolipid metabolism and ceramide, cofactors and vitamins, and the urea cycle, were replicated in PEAR-2 (Bonferroni p < 0.0038) and have been previously linked to HTN and CVD. Our findings may give insights into the mechanisms underlying HTN racial disparities.

Despite the availability of many antihypertensive drug classes, half of hypertensives have uncontrolled blood pressure (BP). We sought to assess the effect of age on BP response in European-American (EA) and African-American (AA) hypertensives. Clinic BP from the Pharmacogenomics Evaluation of Antihypertensive Responses-2 study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100mg twice-daily and chlorthalidone 25mg daily for 8~9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 EAs and 119 AAs by age with adjustment for baseline BP and gender. EA<50 years responded better to metoprolol than chlorthalidone (DBP:−9.6±8.0 vs.−5.9±6.8 mmHg, adjusted-P=0.003), whereas those≥50 years responded better to chlorthalidone than metoprolol (SBP:−18.7±13.8 vs.−13.6±14.8 mmHg, adjusted-P=0.008). AA<50 years responded similarly to both drugs, whereas those≥50 years responded better to chlorthalidone than metoprolol (−17.0±13.2/−9.6±7.5 vs.−7.0±18.6/−6.7±9.3 mmHg, adjusted-P<0.0001/0.008). Therefore, age should be considered when selecting antihypertensive therapy.