Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia.

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. METHODS: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. RESULTS: The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1-390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35-28.7; p <0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded.  No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity. CONCLUSION: Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.

Time to Start Delivering Iron Chelation Therapy in Newly Diagnosed Severe ß-Thalassemia.

BACKGROUND: Iron overload is still a major complication of severe ß-thalassemia. Indication to start iron chelation therapy is based on serum ferritin (SF) or transferrin saturation (TS) level or the amount of transfusion. The goal of this study is to analyse the pattern of iron status, the amount of transfusion regarding the time to start iron chelator, and serum hepcidin levels in newly diagnosed severe ß-thalassemia. METHODS: A prospective cohort study was performed at Hasan Sadikin General Hospital on newly diagnosed severe ß-thalassemia patients. Subjects had not received any blood transfusion with normal liver function test, CRP, and IL-6 levels who consumed normal diet according to age. The SF and TS levels indicate iron status, while hepcidin level indicates iron regulator status. Main indicator to start iron chelation therapy when SF level ≥1.000 ng/mL, TS level ≥70%, or after receiving transfusion at least 10 times. Statistical analysis used Mann-Whitney and Spearman. RESULTS: Forty-two newly severe ß-thalassemia, 30 (71.4%), were diagnosed before 1 year old, mean 9.9 ± 6.4 months, range 2-24 months. Range amount of transfusion until SF level reached ≥1,000 ng/mL were 4-12 times, mean 7 ± 2 times. Mean SF and TS level at diagnosis were 365.6 ± 194.9 ng/mL and 67.3 ± 22.5%, while hepcidin level was normal, mean 242.6 ± 58 ng/mL. 36/42 patients have reached SF >1000 ng/mL with amount of transfusion less than 10 times. There was no significant difference of SF, TS, and hepcidin levels when SF >1000 ng/mL in the group with amount of transfusion 7-12 and less than 7 (p = 0.454, p = 0.084, p = 0.765), respectively. A significant positive correlation between SF and amount of transfusion was observed (p < 0.001; r = 0.781). CONCLUSION: Iron overload in severe ß-thalassemia patients might occur earlier even before they received 10 times transfusion. Hepcidin serum level tends to increase when iron overload just started.