Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35–350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was < 4.5 × 10^?6 M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

大剂量甲氨蝶呤目标浓度个体化调整研究

目的 探讨大剂量甲氨蝶呤(MTX)24 h输注治疗儿童急性淋巴细胞白血病目标浓度个体化调整的方法.方法 本研究涉及24例患儿105个疗程,检测MTX开始输注后第1和第6小时的血药浓度,根据已建立的大剂量MTX群体药物动力学模型,推算出该疗程稳态血药浓度(CSS)的预测值.根据CSS预测值,于MTX开始输注后第8小时调整MTX输注速度和剂量.MTX输注后第23小时再检测血药浓度(CSS实测值).结果 为达目标浓度,17例(71%)患儿进行了剂量调整.45个疗程(43%)调整了剂量,42个疗程增加了剂量,3个疗程减少了剂量.早期阶段(诱导缓解和巩固治疗方案后的大剂量MTX的疗程)29个疗程中有16个疗程增加了剂量,1个疗程减少了剂量;维持阶段76个疗程中有26个疗程增加了剂量,2个疗程减少了剂量.最终有95个(90%)疗程的CSS实测值达目标范围,8个疗程小于目标范围,2个疗程大于目标范围.如果不调整剂量,仅有74个(70%)疗程的CSS(不调整)在目标范围.调整MTX剂量,与不调整相比,可以明显增加CSS实测值达目标范围的疗程数(χ2=13.366,P=0.000).在剂量不调整的60个疗程中,CSS实测值和CSS预测值有较好的直线相关性(r=0.487,P=0.000);CSS实测值与MTX输注后第6小时的血药浓度也有一定的直线相关性(r=0.389,P=0.002).105个疗程MTX的总清除率(CL)实测值是(7.01±2.06)L/(m2·h).在所有疗程间CL相差最大达4.4倍,同一患儿不同疗程间CL相差最大达2.9倍.CL与患儿的年龄、体重和总胆红素呈直线负相关,与血磷呈直线正相关;化疗早期阶段疗程的CL有高于维持阶段疗程的倾向(P均＜0.05).结论 105个疗程大剂量MTX化疗,疗程间CL差异最大达4.4倍,需要目标浓度个体化调整.通过检测MTX输注后第1和第6小时的血药浓度,调整MTX输注速度和剂量,最终90%疗程的CSS实测值达目标范围.早期阶段大剂量MTX化疗更需要目标浓度个体化调整.     

New aspects of the determination of blood methotrexate levels in leukemic children

Serum and CSF concentrations after medium dosage of methotrexate (MTX; 500 mg/m2 - 1,000 mg/m2) have been determined by an enzymatic assay during 142 infusions in children with ALL. If the dose of MTX was 500 mg/m2 MTX concentrations in CSF were under 10(-6) M/l in 40% of the treatments but only in 22%, when the dose was increased to 1,000 mg/m2. The systemic clearance of MTX was found to be increased significantly by the 2nd MTX treatment in children who relapsed thereafter. Such a phenomenon was not observed in children who continued in remission. The relapse free survival of children, whose MTX-clearance remained constant by the 2nd MTX treatment was significantly longer. No serious MTX toxicity has been observed in our patients.     

Cerebrospinal Fluid and Plasma Methotrexate Levels Following High-Dose Regimen Given as a 3-Hour Intravenous Infusion in Children with Nonhodgkin's Lymphoma

In the French non Hodgkin's lymphoma protocols, central nervous system prophylaxis is provided by high-dose methotrexate (HD-MTX), given as a 3-hour IV infusion of 3 g/m² MTX along with intrathecal MTX injection. The incidence of CNS relapse is less than 3%. We designed a study to evaluate the MTX transfer across the blood brain barrier in terms of cytotoxic concentrations, during these short-term infusions. Cerebrospinal fluid and plasma MTX levels were measured during 61 courses in 29 children with non Hodgkin's lymphoma; none of them had central nervous system disease. Samples were obtained either 4, 12, 18, or 24 hours after the start of HD-MTX IV infusion. A potentially cytotoxic MTX level (10^-6 M) was reached in all courses at 4 hours (median: 2.3 × 10^-6 M) and remained available in 8/16 courses at 12 hours (median: 1.0 × 10^-6 M) and in only 2/17 courses at 18 hours (median: 0.29 × 10^-6 M). Twenty-four hours after the start of HD-MTX IV infusion, CSF MTX level was always less than 10^-6 M. The plasma MTX levels were 260, 1.3, 1.0, and 1.7 × 10^-6 M at 4, 12, 18, and 24 hours, respectively. There was no correlation between plasma and CSF MTX levels. These data show that potentially cytotoxic MTX concentrations can be reached in CSF after a 3-hour IV infusion of 3 g/m² in every patient and remain available for at least 8 hours in half of them.     

Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue

Three adolescents and one child with osteosarcoma were studied during multiple courses of high-dose methotrexate, citrovorum factor rescue (HDMTX-CFR), with one adolescent treated intermittently over a period of 6 years. Plasma phenylalanine (Phe) and tyrosine (Tyr) were measured immediately before the infusion of MTX and then daily until serum MTX fell below 10(-7) M. At 24 hours, all showed marked increases in Phe and in the Phe/Tyr ratio. This suggests inhibition of dihydropteridine reductase (DHPR) which, in association with hepatic Phe hydroxylase, controls plasma concentrations of Phe. Inhibition of this enzyme system is not relieved by CFR. In the adolescent patients, although MTX levels in plasma declined steadily, Phe concentrations, which fell between 24 and 48 hours, rose to a new peak at 4-7 days. Possible reasons for this secondary increase are discussed. The patient with the longest exposure to HDMTX showed an increase in pretreatment Phe/Tyr ratios with time, suggesting damage to liver parenchymal cells not indicated by standard tests of liver function. Evaluation of plasma Phe during the course of HDMTX-CFR may permit assessment of intracellular concentrations of MTX or its metabolites in the liver without interference by CFR.     

METHOTREXATE IN THE PLASMA AND CEREBROSPINAL FLUID OF CHILDREN TREATED WITH INTERMEDIATE DOSE METHOTREXATE

ABSTRACT. Rechnitzer, C, Scheibel, E. and Hendel, J. (University Clinic of Paediatrics, Rigshospitalet and Department of Clinical Chemistry, Finsen Institute, Copenhagen, Denmark). Methotrexate in the plasma and cerebrospinal fluid of children treated with intermediate dose methotrexate. Acta Paediatr Scand, 70:615,.–Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m²) the mean concentrations achieved 1 to 4¹/₂ hours after the start of infusion were 1.3×10^-7 mol/l in cerebrospinal fluid and 1.7×10^-5 mol/1 in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1×10^-7 mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1×10^-7 mol/l.     

Oral mucositis and salivary methotrexate concentration in intermediate-dose methotrexate therapy for children with acute lymphoblastic leukemia

The relationship between salivary methotrexate (MTX) concentration and severity of oral mucositis after administration of MTX was investigated in six children with acute lymphoblastic leukemia. They received two administrations of MTX at 500 mg/m2 with one third given bolusly and the remainder by 24-hour continuous infusion. No significant difference among patients or administration session was observed in serum MTX concentration. Detectable concentrations of salivary MTX (greater than 0.01 microM) were observed during nine of the ten infusions. A concentration of 0.1 microM or more, apparently lasting at least 12 hours, was observed during one infusion and followed by severe mucositis. During two of the ten infusions for different patients, concentrations of 0.04 to 0.07 microM and 0.02 to 0.04 microM, apparently lasting at least 12 and 18 hours, respectively, were observed, followed by moderate mucositis. During the other seven infusions, either much shorter or no increase in salivary MTX concentration was observed, with only mild or no subsequent mucositis. Analysis by Kendall's rank method showed a statistical correlation between concentration at 6 hours of infusion and severity of oral mucositis. The findings suggest that the early secretion of MTX into saliva has a significant role in the development of oral mucositis in leukemic children.     

Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children's Oncology Group

Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia enrolled in the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate-dose MTX (1 g/m) given as a 24 hours infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The 5 year continuous complete remission was 76±1.4% versus 85±3.0% for those patients with steady state MTX levels less than or equal to and greater than 14 μM, respectively (P=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 μM, compared with non-Hispanic children, 9.95 μM (P=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX:folate ratio identified children at increased risk of failure.     

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

BACKGROUND: The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. PROCEDURE: Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. RESULTS: Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. CONCLUSIONS: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.     

胸苷酸合成酶基因多态性对甲氨喋呤治疗急性淋巴细胞白血病患儿不良反应的影响

目的探讨不同胸苷酸合成酶(TS)基因型对急性淋巴细胞白血病(ALL)患儿经大剂量甲氨蝶呤(HD-MTX)治疗后不良反应的影响。方法选取2011年3月至2013年3月确诊的ALL患儿73例,提取其基因组DNA,PCR扩增后测序鉴定TS基因型。观察并记录所有ALL患儿经HD-MTX化疗后的不良反应,并监测化疗后42~48 h MTX血药浓度。结果 73例ALL患儿接受HD-MTX治疗后,其不良反应主要包括中性粒细胞减少、血红蛋白降低、血小板减少、肝脏毒性、黏膜损害和胃肠道反应,不同TS基因型患儿化疗后不良反应发生率比较差异均无统计学意义,各基因型与ALL患儿化疗后42~48 h MTX血药浓度的变化无关联。结论 TS基因多态性对ALL患儿HD-MTX化疗后不良反应的发生无影响。     

The effect of methotrexate pharmacokinetics and of leucovorin rescue on the prognosis of osteosarcoma

A total of 129 high-dosage methotrexate therapies performed in 19 patients with osteosarcoma were retrospectively analyzed. Serum methotrexate peak concentrations were found to vary widely, both inter-individually as well as in the same patient. The measured MTX peak concentrations correlated closely with pharmacokinetic data such as area under the curve and total body clearance. No correlations were found between the serum MTX correlations and different times after methotrexate administration. Increase in leucovorin rescue or low MTX peak concentrations were associated with poor prognosis. High-dosage methotrexate therapies with leucovorin rescue need to be further optimized in accordance with biochemical knowledge of the mode of action and the individual pharmacokinetic data of methotrexate. Such optimization may be expected to improve the prognosis for osteosarcoma. Serum methotrexate concentrations should be determined not only 24, 48, and 72 hours after methotrexate administration, in order to avoid elevated toxicity of the therapy, but also at the start of methotrexate infusion, in order to influence MTX peak concentrations at an early stage if necessary. Measurement of L-leucovorin in serum will be necessary, to enable a restrictive leucovorin rescue to be performed safely.     

Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate

A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n - 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m²) and daily 6-mer-captopurine (40-111 mg/m²). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine. © 1994 Wiley-Liss, Inc.     

Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.     

Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5-33.6 g/m2 to children with acute lymphoblastic leukemia

Concentrations of 7-hydroxy-methotrexate (7-OH-MTX) were determined in serum samples obtained after 266 infusions of methotrexate administered to 58 children with acute lymphoblastic leukemia. The dose of methotrexate (MTX) was in the range of 0.5-33.6 g/m2. Pharmacokinetic parameters (metabolic index, drug/metabolite ratio, half-life) of 7-OH-MTX and their relationship to the kinetics of methotrexate were analyzed. A great variability was observed in the extent and time-course of the metabolite formation. The concentration of the metabolite was higher than that of the parent compound at any examined time after the end of the 24 hours' infusion. The increase of 7-OH-MTX levels at the end of the methotrexate infusion was found to be proportionate to the increase of the dose of MTX. Males had significantly higher metabolite levels than did females (P less than 0.01) in the dose range of 0.5-8.0 g/m2. The age of the patients also significantly influenced the rate of the metabolite formation. The serial number of the treatment courses did not have effect on the metabolism of MTX. Dose dependency of the elimination half-life of the metabolite was found. Although a tendency was observed that patients in continuous complete remission had higher metabolite levels than those who relapsed, the difference was not significant. Further studies are needed to determine the clinical importance of 7-OH-MT.     

Methotrexate levels and outcome in osteosarcoma

BACKGROUND: Peak serum concentrations of methotrexate (MTX) have been reported to correlate with outcome in osteosarcoma (OS). Modification of the MTX dose to achieve peak levels between 700 and 1,000 micromol/L has been recommended. The goal of the study was to assess whether there is a correlation between histologic necrosis of the tumor and/or prognosis with peak MTX serum concentration. PROCEDURE: Treatment included multi-agent adjuvant chemotherapy, including high-dose MTX (12 g/m2). Peak MTX levels were drawn following a 4-hr infusion. Histologic evaluation for percent necrosis was done at the time of definitive resection. RESULTS: The median peak MTX level (n = 52 patients) was 1,060 micromol/L (range: 410-4,700 micromol/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 micromol/L or higher. Response to pre-operative chemotherapy was: 18% Grade I necrosis, 35% Grade II, 31% Grade III, and 16% Grade IV. No significant association was found between the mean peak MTX levels and necrosis (P = 0.44). Event-free survival (EFS) for the 48 patients with non-metastatic disease at diagnosis was 76% at 4 years of follow-up, with no association between the mean peak MTX level and EFS (P = 0.24). CONCLUSIONS: The absence of a demonstrable correlation between peak MTX levels and histologic necrosis or EFS may suggest that most patients achieve therapeutic levels when MTX is given at a dose of 12 g/m(2). The significant degree of intra-patient variability in peak levels poses a dilemma for pharmacokinetic adjustment. Continued use of HD-MTX in all patients, rather than dose adapted therapy, may be justified.     

Pharmacokinetics, dose adjustments, and 6-mercaptopurine/ methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold above the population median, but without unacceptable bone-marrow toxicity. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia followed high-dose MTX infusions. Due to the risk of fatal myelo-suppression we recommend up-front determination of TPMT activity in patients treated with 6MP or azathioprine.     

The course of biological parameters and 6-mercaptopurine pharmacokinetics during maintenance treatment of children with acute lymphoblastic leukaemia

Twenty patients on maintenance therapy (MT) for acute lymphoblastic leukaemia (ALL) with oral 6-mercaptopurine (6-MP) and methotrexate (MTX) were studied. White cell and red cell indices and platelets counts were monitored every second week as were drug levels. Mean values for 6-MP and MTX doses, and blood component parameters were calculated for each 6-month period for the whole patient group. 6-MP plasma concentrations and liver-function tests were determined once every six months and mean values calculated. 6-MP and MTX mean doses did not change significantly during MT. The mean area under the concentration versus time curve (AUC) 0-4 hours varied slightly from the start to the end of the MT (257 and 296 ng/ml.h, respectively). The mean plasma peak concentration increased from 98 ng/ml to 195 ng/ml (p less than 0.01) during the same period. There were significant decreases between the initial white blood cell counts (WBC) and red blood cell counts (RBC) as compared to levels at the end of therapy (p less than 0.01 and 0.02, respectively). A linear correlation was found between 6-MP peak concentrations and both WBC (r = 0.96) and RBC (r = 0.87). At the end of MT liver function tests became normal in all except 6 patients. In conclusion, MT have moderate effects on bone marrow and liver and monitoring 6-MP plasma concentration might be of value for determination of the optimal WBC levels during MT.     

The Course of Biological Parameters and 6-Mercaptopurine Pharmacokinetics during Maintenance Treatment of Children with Acute Lymphoblastic Leukaemia

ABSTRACT. Twenty patients on maintenance therapy (MT) for acute lymphoblastic leukaemia (ALL) with oral 6-mercaptopurine (6-MP) and methotrexate (MTX) were studied. White cell and red cell indices and platelets counts were monitored every second week as were drug levels. Mean values for 6-MP and MTX doses, and blood component parameters were calculated for each 6-month period for the whole patient group. 6-MP plasma concentrations and liver-function tests were determined once every six months and mean values calculated. 6-MP and MTX mean doses did not change significantly during MT. The mean area under the concentration versus time curve (AUC) 0-4 hours varied slightly from the start to the end of the MT (257 and 296 ng/ml-h, respectively). The mean plasma peak concentration increased from 98 ng/ml to 195 ng/ml ( p <0.01) during the same period. There were significant decreases betwen the initial white blood cell counts (WBC) and red blood cell counts (RBC) as compared to levels at the end of therapy ( p <0.01 and 0.02, respectively). A linear correlation was found between 6-MP peak concentrations and both WBC ( r =0.96) and RBC ( r =0.87). At the end of MT liver function tests became normal in all except 6 patients. In conclusion, MT have moderate effects on bone marrow and liver and monitoring 6-MP plasma concentration might be of value for determination of the optimal WBC levels during MT.     

Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

维族、汉族急性淋巴细胞白血病患儿甲氨蝶呤不良反应探讨

目的：通过对维吾尔族及汉族急性淋巴细胞白血病（ALL）患儿甲氨蝶呤（MTX）血药浓度监测结果的分析,为MTX不良反应的发生提供判断依据。方法：根据24 h MTX血药浓度监测结果,将28例（汉族 15 例,维吾尔族 13 例）接受大剂量MTX化疗的ALL患儿分为>10 μmol/L与≤10 μmol/L组;根据48 h MTX血药浓度监测结果分为>1.0 μmol/L与≤1.0 μmol/L组。采用酶放大免疫测定法对行MTX治疗的所有患儿给药后24 h及48 h血药浓度进行检测并观察不良反应发生情况。结果：不良反应发生率在不同24 h MTX血药浓度组间差异无统计学意义(P>0.05);48 h MTX血药浓度>1.0 μmol/L组的消化道反应及黏膜损害发生率高于血药浓度≤1.0 μmol/L组 (P0.05);汉族患儿24 h及48 h MTX血药浓度均高于维吾尔族(P<0.05);除消化道反应外,汉族患儿肝功能异常、黏膜损害及骨髓抑制的发生率高于维吾尔族患儿 (P<0.05)。结论：24 h MTX血药浓度不能预测不良反应的发生,48 h MTX血药浓度对不良反应的发生有一定预测价值;24 h、48 h MTX血药浓度及不良反应发生率在维吾尔族及汉族间存在差异;MTX血药浓度监测结果可能对及时调整MTX用量,从而达到MTX个体化治疗具有重要意义。