Pharmacokinetics of high‐dose methotrexate in infants treated for acute lymphoblastic leukemia

Lönnerholm, Gudmar; Valsecchi, Maria Grazia; Lorenzo, Paola De; Schrappe, Martin; Hovi, Liisa; Campbell, Myriam; Mann, Georg; Janka‐Schaub, Gritta; Li, Chi Kong; Starý, Jan; Hann, Ian; Pieters, Rob

doi:10.1002/pbc.21925

Cited by 23 publications

(10 citation statements)

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“…In the clinic, plasma concentration of MTX and release of calcium folinate are monitored dynamically to reduce the occurrence of chemotherapy-induced adverse effects. A previous study demonstrated the existence of individual differences in the pharmacokinetics, effectiveness, and toxicity of MTX, suggesting there might be some potential gene targets affecting the pharmacokinetics and pharmacodynamics of MTX [12]. FPGS is an important enzyme in MTX metabolism, and catalyzed poly glutamic acid is the core of folate antagonists-associated cytotoxic therapy [13,14].…”

Section: Discussionmentioning

confidence: 99%

Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia

Huang

Tong

et al. 2016

Med Sci Monit

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BackgroundThe aim of this study was to investigate the association of the polymorphism of folylpolyglutamate synthetase (FPGS) with the dynamic plasma concentration of methotrexate (MTX) in pediatric patients with acute lymphocytic leukemia (ALL), as well as the prognosis.Material/Methods57 ALL patients and 31 age and sex-matched children (control) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism was performed for the analysis of the genotype of FPGS rs1544105 and high-performance liquid chromatography for measurement of MTX plasma concentration after 24-h and 44-h treatment. Overall survival was analyzed by Kaplan-Meier method.ResultsNo differences were observed between patients and controls regarding the distribution frequency of genotype and alleles of rs1544105. Patients carrying AA genotype had a significantly higher plasma concentration of MTX after 24 h than those carrying GG or GA (P<0.05) and no differences were found after 44 h. Kaplan-Meier survival analysis showed a longer median survival time in patients with AA than other genotypes with significant difference in overall survival.ConclusionsPolymorphism of FPGS rs1544105 might be used as an effective approach for prediction of the treatment outcome of MTX.

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Section: Discussionmentioning

confidence: 99%

Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia

Huang

Tong

et al. 2016

Med Sci Monit

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“…Only 1 population pharmacokinetic study including infants <6 months has been published, but it was in patients with acute lymphoblastic leukaemia, had a small patient population of infants only ( n = 17), and had limited covariates (weight, age, body surface area and sex) . Other pharmacokinetic studies in infants have been published but often with contradictory pharmacokinetic results . These limited evaluations have been inadequate, suffering from small numbers of infants, and heterogeneous enrolment criteria and treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

“…11 Other pharmacokinetic studies in infants have been published but often with contradictory pharmacokinetic results. 12,13 These limited evaluations have been inadequate, suffering from small numbers of infants, and heterogeneous enrolment criteria and treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Panetta

Roberts

Huang

et al. 2020

Brit J Clinical Pharma

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Aims No population pharmacokinetic studies of high‐dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing. Methods Patients received 4 monthly courses of HDMTX (5 g/m2 or 2.5 g/m2 for infants aged ≤31 days) as a 24‐h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities. Results The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02–4.7 years) in 648 courses. The population clearance and volume were 90 mL/min/m2 and 14.4 L/m2, respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co‐treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants ≤31 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage. Conclusions By aggressively following institutional clinical guidelines, HDMTX‐related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.

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“…PK analysis of highdose MTX (5 g/m 2 /dose) in the Interfant-99, applying the aforementioned dose reduction rule, indicated a slightly lower MTX clearance in younger infants, but the toxicity profile was similar to that for older infants. 37 …”

Section: Chemotherapymentioning

confidence: 99%

Recent progress in the treatment of infant acute lymphoblastic leukemia

Tomizawa

2015

Pediatrics International

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Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL) rearrangement (MLL-r), which account for approximately 80% of cases, is still a major challenge for pediatric hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North America, and Japan have rescued approximately half of the MLL-r ALL patients with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation. Recent progress has clarified the unique mechanism of MLL-r ALL: the aberrant methylation and histone modifications via DOT1L and other related molecules by MLL fusion proteins lead to leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the study groups in Europe (Interfant), North America (Children's Oncology Group), and Japan (Japanese Pediatric Leukemia/Lymphoma Study Group) is under way.Key words acute lymphoblastic leukemia, epigenetics, hematopoietic stem cell transplantation, infant, mixed lineage leukemia.Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, is the most common type of malignant neoplasms in children and adolescents, with approximately 444-532 cases diagnosed annually in Japan. 1 Optimal use of "old drugs", developed between the 1950s and 1970s under successive collaborative clinical trials, has improved the outcome of childhood ALL to achieve an event-free survival (EFS) rate of 80.4-87.2% and an overall survival (OS) rate of 91.8-93.5% in recently completed clinical trials. [2][3][4][5] The progress in the treatment of infant ALL (diagnosed at age <12 months), however, is lagging behind compared with the treatment of children ≥1 year: EFS and OS remain at 41.7-50.9% and 44.8-60.5%, respectively (Table 1). 9,[11][12][13] In this review, advances in the pathobiology and clinical management of ALL in infants is described. Epidemiology and characteristicsInfant ALL accounts for <5% of childhood ALL, with 20-25 new cases diagnosed annually in Japan. In children ≥1 year, ALL comprises 75-80% of all childhood leukemia because of the high peak incidence of B-lineage ALL between the age of 2 and 5 years, with a predominance in boys. In contrast, the incidence of ALL in infants is the same as that of acute myeloid leukemia (AML), with a slight predominance in girls. 1,11 Biologically and clinically, infant ALL consists of two distinct subtypes: one involves rearrangements of mixed lineage leukemia (MLL also called KMT2A), which accounts for approximately 80% of infant ALL; and the other with germline MLL. Infant ALL with rearranged MLL (MLL-r) is a highly aggressive leukemia with high white blood cell (WBC) count and frequent involvement of extramedullary sites including the central nervous system (CNS) at diagnosis. 9,11 In addition, MLL-r ALL has a very immature CD10-ne...

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Pharmacokinetics of high‐dose methotrexate in infants treated for acute lymphoblastic leukemia

Abstract: Our data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose.

Cited by 23 publications

References 14 publications

Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia

Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Recent progress in the treatment of infant acute lymphoblastic leukemia

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