Safety of delayed leucovorin "rescue" following high-dose methotrexate in children.

High-dose methotrexate (HDMTX) with leucovorin (CF) "rescue" is being investigated for treatment of many malignant tumors. CF is usually begun 2 hours after ending the HDMTX infusion. However, since CF and methotrexate compete for the same cellular transport system, at high extracellular methotrexate concentrations it may be impossible to "rescue" cells with CF. A regimen of HDMTX with delayed leucovorin "rescue" was therefore designed. In this program, a 6-hour infusion of methotrexate (7.5 gm/m2) was followed 24 hours later by leucovorin "rescue." Nine patients with osteogenic sarcoma received 115 courses of this treatment. Toxicity was minimal. Plasma methotrexate values were identical to those following early CF 'rescue" regimens. HDMTX with delayed "rescue" is well tolerated. Although theoretically sound, further studies are needed to determine its efficacy in comparison to standard early "rescue" regimens.     

Plasma phenylalanine: Tyrosine ratios during high-dose methotrexate-citrovorum “rescue”

We have measured phenylalanine and tyrosine in the plasma of patients with osteogenic sarcoma undergoing chemotherapy with high-dose methotrexate (HDMTX) citrovorum factor rescue (CFR). During 14 treatments in six different patients, the phenylalanine to tyrosine ratio (PHE/TYR) at 21 to 38 hours was elevated over pretreatment levels. The observed increase in plasma phenylalanine is attributed to inhibition by MTX of the phenylalanine hydroxylase system of the liver, which is not folate-dependent and thus is not corrected by administration of CF. A post-infusion increase in PHE/TYR of 571% after 22 hours in one patient and of 410% after 30 hours in another were associated with marked MTX toxicity. The greatest increase in PHE/TYR seen in a patient who did not experience toxicity was was 249% in 21 hours. Thus, in this group of patients, there appears to be a correlation between evidence of clinical MTX toxicity and the magnitude of the percentage increase in PHE/TYR in the plasma, which indicates inhibition of a liver enzyme and thus reflects the intracellular concentration of MTX.     

Treatment of advanced malignant melanoma with high dose methotrexate and folinic acid rescue

Twenty-eight patients with advanced malignant melanoma were treated with high dose methotrexate (HDMTX) and folinic acid (FA) rescue. Nineteen patients were treated with 6-hour infusions and 10 patients with 24-hour infusions. One patient in the 6-hour infusion group showed a partial response. In the 24-hour infusion group there were no responses but there was a significant increase in renal toxicity. It is concluded that HDMTX and FA rescue are not useful agents in the treatment of advanced malignant melanoma.     

Safety and Efficacy of I-Leucovorin Rescue Following High-Dose Methotrexate for Osteosarcoma

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patient, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate. © 1995 Wi1ey-Liss, Inc.     

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.     

Sequential chemotherapy of advanced colorectal cancer with standard or high-dose methotrexate followed by 5-fluorouracil

Thirty patients with advanced measurable colorectal cancer were randomized to receive either methotrexate (MTX) 200 mg/m² or 40 mg/m², followed in four hours by 5-fluorouracil (5-FU) 600 mg/m². Patients receiving the higher dose MTX were given leucovorin rescue 24 hours later. Eight of 13 patients treated with 200 mg/m² MTX + 5-FU developed severe hematologic toxicity, leading to two toxic deaths. In addition, 9/13 developed mild azotemia, and three patients had severe gastrointestinal toxicity. No patients with prior chemotherapy responded to either regimen. Among those without prior chemotherapy, there were two of six and three of eight partial responses, respectively, in the 200 mg/m² and 40 mg/m² MTX regimens. Sequential 200 mg/m² MTX followed by 5-FU after four hours has unacceptable toxicity. Sequential treatment with standard dose MTX + 5-FU is tolerable and merits further study.     

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.     

Retrospective study on elimination delay of methotrexate in high-dose therapy of childhood acute lymphoblastic leukemia in China

OBJECTIVES: The aim of this study was to observe the morbidity of elimination delay in Chinese children with acute lymphoblastic leukemia during high-dose methotrexate (HDMTX) therapy and the toxicities. PATIENTS AND METHODS: A total of 121 children with acute lymphoblastic leukemia on HDMTX therapy were enrolled into this study. Patients were divided into groups on the basis of either dosage (3 g/m vs. 5 g/m) or infusion duration (7 h vs. 24 h). CF/MTX index was used to determine the calcium folinate (CF) rescuing intensity and toxicity was evaluated according to World Health Organization criteria. RESULTS: The overall morbidity of elimination delay was 12.1% in a total of 497 infusions. Patients with elimination delay had lower platelet count (P<0.01) and greater cumulative CF rescuing intensity (P<0.001). In 3-g group, children with elimination delay experienced severer oral mucous membrane damage (P<0.05) than those without elimination delay, and postponement of following chemotherapy (P=0.001). No significant difference was found in morbidity of elimination delay between 3 and 5-g groups (P>0.05) or 7 and 24-hour infusion groups (P>0.05). The only raised adverse effect in 5-g group was gastrointestinal (P=0.003) as compared with 3-g group. The CF rescuing intensity of 5-g group without elimination delay was lower than that of the 3-g group (P<0.01). CONCLUSIONS: (1) HDMTX with 5 g/m is as safe as 3 g/m under adequate hydration and alkalization. Twenty-four-hour infusion is optimal. (2) Individualized dosing is necessary.     

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.     

Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib

We aimed to determine whether patients receiving dasatinib or imatinib concurrently with high‐dose methotrexate (HDMTX) had slower methotrexate clearance than patients not receiving a tyrosine kinase inhibitor (TKI) during the HDMTX infusion. Patients concurrently receiving dasatinib and HDMTX (N = 7) had significantly slower MTX clearance (P = 0.008) than patients not receiving a TKI (N = 111). Two patients receiving a TKI during a HDMTX infusion required glucarpidase. In vitro studies showed that dasatinib significantly inhibited methotrexate uptake by SLCO1B1‐expressing cells (P = 0.009). There may be an interaction between dasatinib and HDMTX, mediated by the transporter SLCO1B1, that causes a delay in MTX clearance.     

大剂量氨甲喋呤两种用药方式的肝脏毒性比较

为探讨大剂量氨甲喋呤对肝脏的毒副作用与给药方式的关系，本文作者将41例已确诊为急性淋巴细胞白血病的患儿随机地分为两组，分别利用两种不同的投药方式应用HDMTX。方法一为HDMJX总量的1／3在30分钟内静脉注射，余量在10～12，小时内静脉滴注，滴注MTX后24小时用CF解救。方法二为HDMTX总量的1／10在30分钟内静脉注射，余量在6小时内静脉滴注，HDMTX静脉注射用药后36小时用CF解救。通过对用药前后患儿的血sGPT的对比来判断MTX对肝脏的毒性。对比结果（P＜0．05）提示方法一所至肝脏毒性大于方法二。     

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective

Background

We describe the safety, feasibility, and provide a cost‐estimate of outpatient high‐dose methotrexate administration (HDMTX) among an urban, underserved population.

Procedure

A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m²) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level ≤0.1 µmol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations.

Results

Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of <10 µmol/L at 24 hr post‐HDMTX. No patients were found to have a MTX level of >50 µmol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle.

Conclusion

Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost‐effective. Pediatr Blood Cancer. 2010;55:1296–1299. © 2010 Wiley‐Liss, Inc.     

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.     

急性淋巴细胞白血病并中枢神经系统白血病的诊断与治疗

目的：探讨急性淋巴细胞白血病（ALL）并中枢神经系统白血病（CNSL）的诊断与治疗及影响发病和预后的因素。方法：对1990－1999年收治117例临床资料进行回顾分析。结果：CNSL发生距确诊ALL的中位数时间为8个月,高危型组发生率（54．85）明显高于标危型组（23．7％）。31例CNSL中以脑脊液（CSF）异常作出诊断远比临床症状多。CNSL治疗效果显示,大剂量氨甲喋呤＋三联鞘注＋四组（CR＋IT）相当。结论：为避免诊断假阳性造成的过度治疗,CSF仅有幼稚细胞而白细胞计数政党者诊断CNSL应慎重,HDMTX＋IT＋FC是治疗CNSL的有效措施。     

How long can folinic acid rescue be delayed after high‐dose methotrexate without toxicity?

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42–48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m²) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30–36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m²) be started no later than 36 hours from the start of MTX (5–6 g/m²). Pediatr Blood Cancer 2014;61:7–10. © 2013 Wiley Periodicals, Inc.     

High-Dose Methotrexate and Continuous Infusion Ara-C in Children's Non-Hodgkin's Lymphoma: Phase II Studies and Their Use in Further Protocols

Twenty-three children with refractory or relapsed non-Hodgkin's lymphoma (NHL) received high-dose methotrexate (HD-MTX), and 9 received Ara-C by continuous intravenous infusion, as phase II studies. They all had previously received a protocol including vincristine, adriamycin, cyclophosphamide, IV push Ara-C, asparaginase, intrathecal MTX, and cranial irradiation, and had failed to respond or had relapsed. HD-MTX was given at the dose of 6 g/m² or more with leucovorin rescue, Ara-C at the dose of 100 mg/m² /day by continuous infusion over 10 days. Among the 22 evaluable patients receiving HD-MTX, 10 responses (7 CR; 3 PR) were observed. Among the 9 patients receiving Ara-C, 4 responded (1 CR; 3 PR). Toxicity in those previously heavily treated patients was acceptable. These two drugs are now successfully included in childhood NHL treatment protocols.     

四氢叶酸钙对大剂量甲氨蝶呤化疗大鼠肠黏膜保护作用的研究

目的探讨不同剂量和时间四氢叶酸钙(calcium5-formyltetrahydrofolate,CF)对大剂量甲氨蝶呤(high-dose methotrexate,HDMTX)化疗大鼠肠黏膜的保护作用。方法实验分两部分,均分5组,设正常对照组(A组,腹腔注射生理盐水),和空白对照组(B组,腹腔注射MTX,不予CF解救)。第一部分:不同剂量CF对HDMTX化疗大鼠肠黏膜的保护作用。C组:1%CF解救组;D组:2%CF解救组;E组:8%CF解救组(百分数为CF总量占MTX的百分比)。C、D、E组腹腔注射MTX,于注射后12h肌注CF,A、B组肌注生理盐水,6小时一次,共7次。第二部分:不同时间CF对HDMTX化疗入鼠肠黏膜的保护作用,C组:12h解救组;D组:24h解救组;E组:30h解救组。C、D、E组腹腔注射MTX。C、D、E组分别于腹腔注射HDMTX后12、24、30h予肌注CF,CF总剂量为MTX的5%;A、B组于腹腔注射后24h分别肌注生理盐水,各组均6小时一次,共7次。于腹腔注射后78h处死存活大鼠,取空肠标本观察形态,测定绒毛长度和隐窝深度。结果两部分均A组肠壁厚弹性好,绒毛密集、排列整齐,B、C、D、E组肠壁充血水肿变薄,和A组比较,小肠绒毛变短,隐窝深度变浅,差异有统计学意义(P<0.05);第一部分B、C组改变较D、E组更明显(P<0.05);C组与B组比较差异无统计学意义(P>0.05);D组与E组比较差异无统计学意义(P>0.05)。第二部分B、E组改变较C、D组更显著(P<0.05);B组与E组比较差异无统计学意义(P>0.05);C组与D组比较差异无统计学意义(P>0.05)。结论CF对HDMTX所致大鼠肠黏膜损害有保护作用;其保护作用存在剂量和时间依赖性。     

Clinical pharmacology of methotrexate

Methotrexate (MTX), a potent folate antagonist by virtue of its ability to inhibit the enzyme dihydrofolate reductase [1], continues to be a useful cancer chemotherapeutic agent [2]. Information not only on its mechanism of action, but also its pharmacology has led to improved dosage schedules of this drug alone and in combination. The use of high (gm) doses of MTX followed by leucovorin “rescue” has required close attention to the blood levels of this drug and has stimulated further studies of its clinical pharmacology, especially of high-dose regimens. This review summarizes the present status of the clinical pharmacology of MTX.     

Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma

A 15-year-old girl with homozygous sickle cell anemia (HbSS) and osteosarcoma is described. Delayed clearance of methotrexate (MTX) after the second course of high-dose MTX (HDMTX) led to the development of renal and hepatic toxicities. Rescue was accomplished with high-dose leucovorin, intravenous carboxypeptidase G2, and thymidine. Although the renal and hepatic abnormalities resolved, focal tonic-clonic seizures developed, accompanied by abnormal brain imaging. Four weeks after this episode, all clinical and biochemical abnormalities resolved. Preexistent end-organ damage associated with HbSS may compromise the ability to deliver high-dose chemotherapy with curative intent in patients with malignant disease.     

Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate

Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.