Objectives: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. Methods: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesis available evidence. A multicenter cross-sectional study was conducted by questionnaires to evaluate patients’ perception and willingness on individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. Results: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to medication (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), management of toxicities. Of them, 12 are strong recommendations. Conclusions: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX medication to health care providers.

Background: Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy (19CAR-T) has achieved impressive clinical achievements in both adult and pediatric relapsed/refractory (r/r) B-lineage acute lymphoblastic leukemia (B-ALL). However, the application and effect of CAR-T therapy in B-ALL patients with extramedullary relapse are rarely issued even disqualified in some clinical trials. Here, we examined the efficacy of 19CAR-T in patients with both bone marrow and extramedullary involvement. Methods: CAR-T cells were generated by a lentiviral vector transfection into primary human T lymphocytes to express anti-CD19 and anti-CD22 single chain antibody fragments (scFvs) with the cytoplasmic domains of 4-1BB and CD3ζ. Patients diagnosed as r/r B-ALL with extramedullary origination were infused with anti-CD19 CAR-T cells. The clinical responses were evaluated by bone marrow aspiration, imaging, and flow cytometry examination. Results: A total of 8 patients received 19CAR-T infusion and all of them acquired complete remission (CR), in which only 1 patient was bridged to hematopoietic stem cell transplantation (HSCT). Even though there were 3 patients relapsed after infusion, they received 19/22CAR-T infusion sequentially and acquired the second remission. To date, 5 patients are continuous CR, and all patients are still alive. The mean follow-up time was 21.9 months while the 24-month estimated event-free survival (EFS) is 51.4%. Conclusions: Anti-CD19 CAR-T therapy can lead to clinical remission for extramedullary relapsed pediatric B-ALL patients. However, the problem of CD19+ relapses after CAR-T remained to be solved. For patients relapsing after CAR-T, the second CAR-T therapy suggests creating another opportunity of remission for subsequent HSCT.

Objective This study aimed to assess the development and current state of management and outcome for neuroblastoma (NB) in Shanghai China. Methods The clinical characteristics and survival rates of a large cohort of 717 NB cases in the recent 10 years from two children’s medical institutions in Shanghai China were retrospectively analyzed. Results The 8y-EFS and OS of the whole cohort in the 10 years were 67.6±2.2% and 81.2±2.1%. Our risk stratification system was updated twice during the 10 years, forming three periods. The percentage of very low risk (VLR) cohort who accepting only surgery without chemotherapy was increased in 2016-2018 period than the 2010-2015 period and 2008-2009 period. While the 3y-EFS of the three periods were similar (P=0.961). The outcome in VLR and low risk (LR) patients were excellent with 8y-EFS around 92% (VLR=93.0±2.8%, LR= 92.1±1.8%). The outcome in high risk (HR) patients was significantly poorer with 8y-EFS only as 16.6±4.1% even than intermediate risk (IR) patients with 8y-EFS as 69.6±4.4% (P<0.001). Conclusions The revision of our risk stratification system was effective, making an increasing percentage of patients without chemotherapy while with similar EFS rates. The VLR and LR cohort had excellent outcomes, however the HR cohort with most of the mortality remains one of the greatest challenges. Enriching the transplant resources, importing melphalan to make ASCT more available and effective, and importing advanced novel therapies like anti-GD2 antibody and 131I-mIBG are our objectives to improve the survival of the HR patients.