What is known and objective To perform a meta‐analysis exploring the optimal single‐dose regimen for managing tumour lysis syndrome (TLS) in children and adults with haematological malignancies. Methods We systematically searched PubMed, MEDLINE, Web of Science, the Cochrane Library and the ClinicalTrials.gov website for studies regarding single‐dose rasburicase in paediatric and adult patients with TLS. Data were analysed using Open MetaAnalyst statistical software. Results Fifteen adult studies (fourteen retrospective studies and one randomized controlled trial) and four observational studies using children were extracted, with a total of 906 and 92 subjects, respectively. Single doses of 1·5, 3, 4·5, 6, 7·5 mg and weight‐based single doses of 0·05 and 0·15 mg/kg were compared. The response rate for 6, 7·5 mg and 0·15 mg/kg single doses was 90% (95% CI: 0·825–0·974), 98·6% (95% CI: 0·957–1·015) and 93·6% (95% CI: 0·864–1·007), respectively, and higher than other dosing regimens tested. The single doses of 6 mg and 0·15 mg/kg rasburicase decreased uric acid levels more than the other regimens, and the mean uric acid reduction was 8·45 mg/dL (95% CI, 7·51–9·38) and 10 mg/dL (95% CI, 8·58–11·42), respectively. What is new and conclusion Our meta‐analysis revealed that, for adult patients, a single 6 mg rasburicase dose is sufficient to normalize and sustain lower uric acid and creatinine levels in adults with TLS. This dose, therefore, balances cost and efficacy of treatment. The 3‐ and 4·5‐mg single dose can be considered if the baseline uric acid level <12 mg/dL, with close monitoring of clinical and biochemical parameters, and repeat dosing if required. The 1·5 mg and 0·15 mg/kg single dose were sufficient to manage TLS in children.

Background: Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial.Methods: Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library andClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 μM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events.Results: Thirteen studies involving 548 pediatric patients (aged 0.3–18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 μM × min, the mean AUC value of < 900 μM × min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 μM × min (RR = 0.370, 95% CI: 0.205–0.666) and < 1500 μM × min (RR = 0.409, 95% CI: 0182–0.920).Conclusions: In children, Bu mean AUC above the cut-off value of 900 μM × min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 μM × min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

Background: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP. Methods: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice. Results: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity. Conclusion: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and risk of hemorrhage. Treatment with eltrombopag increases and maintains hemostatic platelet counts; however, to date, long-term data are lacking on the outcome of children with ITP who are treated with eltrombopag. This prospective, observational, longitudinal cohort study evaluated the efficacy and safety of eltrombopag in pediatric patients with persistent or chronic ITP. For the 116 pediatric patients enrolled, duration of eltrombopag treatment was at least 3 months. Median effective dose was 25 mg/day, 50 mg/day, and 50 mg/day, respectively, for children age 5 years or younger, 6 to 11 years, or 12 years or older. In all, 89 patients (76.7%) achieved overall response, 53 (45.7%) achieved complete response, and 36 (31.0%) achieved response. Median platelet counts increased by week 1 and were sustained throughout the treatment period. During treatment with eltrombopag, the proportion of patients with grade 1 to 4 bleeding symptoms decreased from 83.61% at baseline to 9.88% at 6 months when only grade 1 was reported. Forty-three patients (37.1%) reported using concomitant medications at study entry, which was reduced to 1 patient (2.5%) who needed concomitant medications at 12 months. All adverse events were grade 1 or 2 according to Common Terminology Criteria for Adverse Events. No serious adverse events, cataracts, malignancies, or thromboses were reported during the study. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts and reducing bleeding in most pediatric patients with persistent or chronic ITP. Combined with future studies, these findings will help establish how eltrombopag should best be used in the management of pediatric patients with East Asian ancestry.

Background: Nanomedicines have significant advantages in enhancing the oral bioavailability of drugs, but a deeper understanding of the underlying mechanisms remains to be interpreted. Hence, the present study aims to explain the uptake and trafficking mechanism for 6-MP nanomedicines we previously constructed. Methods: 6-MP loaded poly(lactide-co-glycolide) (PLGA) nanomedicines (6-MPNs) were prepared by the multiple emulsion method. The transcytosis mechanism of 6-MPNs was investigated in Caco-2 cells, Caco-2 monolayers, follicle associated epithelium (FAE) monolayers and rats, including transmembrane pathway, intracellular trafficking, paracellular transport and the involvement of transporter. Results: Pharmacokinetics in rats showed that the area under the curve (AUC) of 6-MP in the 6-MPNs group (147.3 ± 42.89 μg/L·h) was significantly higher than that in the 6-MP suspensions (6-MPCs) group (70.31 ± 18.24 μg/L·h). The uptake of 6-MPNs in Caco-2 cells was time-, concentration- and energy-dependent. The endocytosis of intact 6-MPNs was mediated mainly through caveolae/lipid raft, caveolin and micropinocytosis. The intracellular trafficking of 6-MPNs was affected by endoplasmic reticulum (ER)-Golgi complexes, late endosome-lysosome and microtubules. The multidrug resistance associated protein 4 (MRP4) transporter-mediated transport of free 6-MP played a vital role on the transmembrane of 6-MPNs. The trafficking of 6-MPNs from the apical (AP) side to the basolateral (BL) side in Caco-2 monolayers was obviously improved. Besides, 6-MPNs affected the distribution and expression of zona occludens-1 (ZO-1). The transport of 6-MPNs in FAE monolayers was concentration- and energy-dependent, while reaching saturation over time. 6-MPNs improved the absorption of the intestinal Peyer’s patches (PPs) in rats. Conclusion: 6-MPNs improve the oral bioavailability through multiple pathways, including active transport, paracellular transport, lymphatic delivery and MRP4 transporter. The findings of current study may shed light on the cellular uptake and transcellular trafficking mechanism of oral nanomedicines.