2020 CSCO Guidelines for The Diagnosis and Treatment of Lymphoma in Children and Adolescents. Clinical application of high doses of methotrexate.

On June 21, 2020, "China Society of Clinical Oncology (CSCO) guidelines for diagnosis and treatment of childhood and adolescent lymphoma" was successfully held in the form of online live broadcast.experts and scholars in hematological oncology and pediatrics gathered online to exchange and share research results, and pay close attention to the release of the first edition of guidelines for diagnosis and treatment of lymphoma in children and adolescents.during the meeting, Professor Yang Lihua of Zhujiang Hospital of Southern Medical University gave a detailed interpretation of the clinical application of high-dose methotrexate (HDMTX) in children and adolescents. Yimaitong is organized as follows. Br / >, which is involved in the intracellular synthesis of tetrahydrofolate.however, MTX competes with folic acid for folate lipid carrier (RFC) - mediated cell uptake and enters cells to form poly (glutamic methotrexate) (mtxpg), which has a longer residence time in cells, higher affinity with DHFR and thymidylate synthase (TS), and stronger cytotoxicity.through high affinity binding with DHFR, MTX can prevent FH2 from reducing to fh4, thus affecting DNA synthesis.in addition, high-dose folic acid supplementation did not affect the cytotoxicity of MTX.therefore, rescue programs are needed to alleviate the toxic effects.with the deepening research on the mechanism of action of MTX, the treatment of MTX is gradually becoming personalized.however, ABCC2, slc19a1 (also known as RFC), MTHFR (methyl tetraacyl acid reductase) and TYMS involved in the transformation process of MTX to mtxpg all lead to the close relationship between MTX toxicity and its concentration. However, there is still no relevant experimental evidence, so there is no reliable clinical advice on drug dose adjustment.definition of HDMTX calcium folinate rescue (CFR) HDMTX the conventional dose of MTX should be 10-20mg / m2, while HDMTX should be more than 100 times of the conventional dose (20mg / kg or 1.0g/m2).due to the saturation of mtxpg and considering the toxic reaction (ADR), it is not the higher the HDMTX dose, the better.the concentration of CSF for effective prevention of CNSL needs to be > 1um, and the ratio of CNS / blood is usually 3%.therefore, the blood drug concentration should be > 30um, if not, it should be strengthened.significance: the blood concentration of the drug is significantly increased, which can pass through BBB and reach the solid tumor with poor blood supply.the premise of HDMTX application is that CFR (calcium formyltetrahydrofolate rescue) 5-methyltetrahydrofolate (5-MTHF) is the main active component of folate in human body, accounting for 98% of folic acid content in plasma.the antidote formyltetrahydrofolate (LCV) is unstable in the human body. Under the action of MTHFR, it changes into 5-MTHF, and crosses the blocking site of MTX, which makes normal cells continue to synthesize DNA and protein, and plays a rescue role.the ability of normal cells to utilize exogenous LCV is much higher than that of tumor cells, and the recovery ability of DNA synthesis of normal cells after rescue is faster than that of tumor cells. Theoretically, the PK / PD of 3hdmtx will not "rescue the tumor or over rescue" in theory For 24h infusion, the loading dose should be set according to different patients, so as to ensure that the plasma concentration of MTX can quickly reach a stable state during the follow-up infusion.the loading dose is usually 1 / 10 of the plasma MTX concentration after half an hour MTX infusion.previous pharmacokinetic data show that it usually takes more than 9 hours for patients to reach steady state after receiving MTX infusion.in order to obtain a certain curative effect, in addition to paying attention to the peak dose concentration, a certain amount of total exposure should be ensured. Therefore, it is necessary to extend the infusion time. Currently, 24h infusion is commonly used internationally.MTX will enter the excretion phase soon after the infusion is stopped.80% MTX and its metabolites 7-OHMTX (main) and dampa were excreted by kidney.the excretion of MTX is promoted by hydration to increase high urine flow and alkalization of urine to increase the solubility of MTX and its metabolites.because LCV competes with MTX for RFC mediated cell uptake, LCV rescue is ineffective when MTX plasma concentration is high.➤ most of the adverse reactions occurred in the elimination phase, with decreased filtration and secretion, and increased reabsorption.➤ compared with the exposure time, the cytotoxic effect caused by exposure time was greater ➤ kidney injury led to accumulation of MTX toxicity, resulting in ADR such as mucositis, hepatitis and dermatitis.➤ the main mechanism of nephrotoxicity induced by MTX: crystalline nephropathy: deposition of MTX and its metabolites in renal tubules.direct tubular toxicity: MTX induced oxygen free radicals damage tubular cells.PK parameters related to efficacy ➤ all: CPSS and total exposure (AUC) (a certain concentration of cumulative exposure for a certain period of time) as leukemia is a mobile tumor, it is exposed to the blood circulation, so the peak concentration of drugs does not need to be too high. The main factor related to the efficacy is the steady-state concentration of drugs.➤ solid tumors: Cmax (significantly higher than all) is different from leukemia. In the treatment of solid tumors, it is necessary to ensure that the drug concentration reaches a certain level in order to make the drug penetrate the tumor cell membrane and tumor microenvironment, and realize the killing of tumor cells.PK parameters related to ADR ➤ MTX concentration and duration of elimination phase ➤ If MTX concentration is less than 0.1um, folic acid metabolism is restored to HDMTX clinical application. The dose regimen of 2hdmtx should be prepared before the treatment of 1 HDMTX. The short-range infusion of HDMTX does not need the loading dose. The higher the peak concentration is, the better the better. However, the long-range infusion needs to set the loading dose to avoid serious toxic effects.the dose of 3hdmtx regulates the prevention and treatment of toxicity reaction (ADR) of 4hdmtx. High dose folic acid competes with low concentration MTX in excretion phase, competes with RFC pathway and binds with DHFR, which promotes the dissociation of MTX binding to DHFR. calcium folinate (CF) is metabolized into 5-mtf after being treated by liver and intestinal mucosa, and the duration of action is 3-6h. 80% - 90% of the metabolites are excreted through the kidney, and 5% - 8% are excreted in the feces. CF had no effect on MTX neurotoxicity. CF has no antitumor effect. CF oral dosage > 25mg / D, it is better to use intramuscular injection or intravenous injection (oral absorption saturation volume is 25mg / D). when CF was used 12-18 hours after the end of HDMTX: CFR was not very effective when the blood concentration of MTX was very high. glucanase (carboxypeptidase G2) is a recombinant bacterial carboxypeptidase. glucanase can be used to reduce MTX plasma levels in patients with MTX induced AKI and delayed MTX clearance. intravenous infusion of glucanase can decompose MTX into two inactive metabolites which are mainly eliminated by liver rather than kidney. glucanase has no effect on intracellular MTX, and LCV rescue therapy is still necessary until MTX is completely removed. glucanase should be used within 48-60 hours after the start of HDMTX infusion. Beyond this time point, glucanase will not prevent the occurrence of fatal toxicity. LCV was not used for 2 hours before or after glucanase administration because LCV is also the metabolic substrate of glucanase. when MTX has cerebral toxicity, calcium folinate is ineffective. MTX can interfere with the metabolism of SAH in vivo, so the synthesis of S-adenosylmethionine is greatly reduced, which leads to the occurrence of cerebrovascular and white matter lesions. adenosine can be supplemented by aminophylline in clinic, so as to help the normal operation of cerebral vascular function. aminophylline dose: 2.5mg/kg, PI 45-60min or 0.5mg/kg/h, pi-12h. based on the mechanism of MTX, Professor Yang Lihua introduced in detail the detection items before and after the treatment of HDMTX, the dose adjustment of MTX in the treatment, and the treatment details for children patients. Professor Yang Lihua showed a large number of research data and results during the speech, which provided detailed and accurate guidance and suggestions for the clinical application of HDMTX in children and adolescents. subsequently, Professor Hu Shaoyan of children's Hospital Affiliated to Suzhou University, Professor Chang Jian of Bethune First Hospital of Jilin University, and Professor Han Binghong of Harbin Institute of Hematology and oncology, discussed what rescue plan should be adopted for the brain disease caused by MTX, and how to adjust the drug dosage reasonably according to different patients. please scan the QR code below: Stamp "read the original", and we will make progress together