Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group.

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

The comparison of plasma arsenic concentration and urinary arsenic excretion during treatment with Realgar-Indigo naturalis formula and arsenic trioxide in children with acute promyelocytic leukemia.

Realgar-Indigo naturalis formula (RIF) is a traditional Chinese medicine containing As4S4 and effective in treating acute promyelocytic leukemia (APL). The dose of RIF remains to be determined in pediatric patients. Comparison of plasma arsenic concentrations and toxicity between RIF and arsenic trioxide (ATO) treatment in APL may help to establish an appropriate therapeutic dose of RIF for children. From October 2018 to March 2020, 19 pediatric patients with APL treated with SCCLG-APL protocol were included, 9 in RIF group at 135 mg/kg/day orally three times daily, and 10 in ATO group at 0.16 mg/kg/day intravenously over 12 h daily. Peak and trough plasma arsenic concentrations were assayed at D1, 2, 7 and 14 of induction treatment. Urine arsenic excretions were assessed with spot urine samples and the measurements were adjusted using creatinine. Toxicities were compared between two groups. The plasma arsenic concentration reached steady state at D7 either in the RIF or ATO group, and the mean peak and trough concentrations were similar between two groups (P > 0.05), which were 0.54 µmol/L and 0.48 µmol/L in RIF group, and 0.63 µmol/L and 0.51 µmol/L in ATO group, respectively. Urine arsenic excretion rate was positively correlated with the concentration of plasma arsenic. The rates of treatment-related adverse events were similar in two groups. In conclusion, the dose of RIF at 135 mg/kg/day may be an appropriate therapeutic dose in children with APL. Urine arsenic level can be used as an indicator to estimate plasma arsenic concentration. Trial registration www.clinicaltrials.gov NCT02200978.

Whole transcriptome sequencing and integrated network analysis elucidates the effects of 3,8-Di-O-methylellagic acid 2-O-glucoside derived from Sanguisorba offcinalis L., a novel differentiation inducer on erythroleukemia cells.

Acute erythroid leukemia (AEL) is a rare and aggressive hematologic malignancy with no specific treatment. Sanguisorba officinalis L. (S. officinalis), a well-known traditional Chinese medicine, possesses potent anticancer activity. However, the active components of S. officinalis against AEL and the associated molecular mechanisms remain unknown. In this study, we predicted the anti-AML effect of S. officinalis based on network pharmacology. Through the identification of active components of S. officinalis, we found that 3,8-Di-O-methylellagic acid 2-O-glucoside (DMAG) not only significantly inhibited the proliferation of erythroleukemic cell line HEL, but also induced their differentiation to megakaryocytes. Furthermore, we demonstrated that DMAG could prolong the survival of AEL mice model. Whole-transcriptome sequencing was performed to elucidate the underlying molecular mechanisms associated with anti-AEL effect of DMAG. The results showed that the total of 68 miRNAs, 595 lncRNAs, 4030 mRNAs and 35 circRNAs were significantly differentially expressed during DMAG induced proliferation inhibition and differentiation of HEL cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed miRNAs, lncRNAs, mRNAs and circRNAs were mainly involved in metabolic, HIF-1, MAPK, Notch pathway and apoptosis. The co-expression networks showed that miR-23a-5p, miR-92a-1-5p, miR-146b and miR-760 regulatory networks were crucial for megakaryocyte differentiation induced by DMAG. In conclusion, our results suggest that DMAG, derived from S. officinalis might be a potent differentiation inducer of AEL cells and provide important information on the underlying mechanisms associated with its anti-AEL activity.

Plasma 25-Hydroxyvitamin D Concentrations Are Inversely Associated with All-Cause Mortality among a Prospective Cohort of Chinese Adults Aged ≥80 Years.

BACKGROUND: High concentrations of plasma 25-hydroxyvitamin D [25(OH)D], a marker of circulating vitamin D, have been associated with a lower risk of mortality in epidemiologic studies of multiple populations, but the association for Chinese adults aged ≥80 y (oldest old) remains unclear. OBJECTIVE: We investigated the association between plasma [25(OH)D] concentration and all-cause mortality among Chinese adults aged ≥80 y. DESIGN: The present study is a prospective cohort study of 2185 Chinese older adults (median age: 93 y). Prospective all-cause mortality data were analyzed for survival in relation to plasma 25(OH)D using Cox proportional hazards regression models, with adjustments for potential sociodemographic and lifestyle confounders and biomarkers. The associations were measured with HR and 95% CIs. RESULTS: The median plasma 25(OH)D concentration was 34.4 nmol/L at baseline. Over the 5466 person-year follow-up period, 1100 deaths were identified. Men and women were analyzed together as no effect modification by sex was found. After adjusting for multiple potential confounders, the risk of all-cause mortality decreased as the plasma 25(OH)D concentration increased (P-trend <0.01). Compared with the lowest age-specific quartile of plasma 25(OH)D, the adjusted HRs for mortality for the second, third, and fourth age-specific quartiles were 0.72 (95% CI: 0.57, 0.90), 0.73 (95% CI: 0.58, 0.93), and 0.61 (95% CI: 0.47, 0.81), respectively. The observed associations were broadly consistent across age and other subgroups. Sensitivity analyses generated similar results after excluding participants who died within 2 y of follow-up or after further adjustment for ethnicity and chronic diseases. CONCLUSIONS: A higher plasma 25-hydroxyvitamin D concentration was associated with a reduced risk of all-cause mortality among Chinese adults aged ≥80 y. This observed inverse association warrants further investigation in randomized controlled trials testing vitamin D supplementation in this age group.

Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study.

Intravenous arsenic trioxide (ATO) has been adopted as the first-line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As4 S4 , has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML-RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all-trans-retinoic acid and low intensity chemotherapy. End points included event-free survival (EFS), adverse events and hospital days. After a median 3-year follow-up, the estimated 5-year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.