Original Article
Conventional Compared with Individualized Chemotherapy for Childhood Acute Lymphoblastic Leukemia
N Engl J Med 1998; 338:499-505February 19, 1998
- Abstract
Background
The rate of clearance of antileukemic agents differs by a factor of 3 to 10 among children with acute lymphoblastic leukemia. We hypothesized that the outcome of treatment would be improved if doses were individualized to prevent low systemic exposure to the drugs in patients with fast drug clearance.
Methods
We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine. The doses of these drugs were based on body-surface area (in the conventional-therapy group) or the rates of clearance of the three medications in each patient (in the individualized-treatment group). In the individualized-treatment group, doses were increased in patients with rapid clearance and decreased in patients with very slow clearance.
Results
Patients who received individualized doses had significantly fewer courses of treatment with systemic exposures below the target range than did patients who received conventional doses (P<0.001 for each medication). Among the patients with B-lineage leukemia, those who received individualized therapy had a significantly better outcome than those given conventional therapy (P = 0.02); the mean (±SE) rates of continuous complete remission at five years were 76±6 percent and 66±7 percent, respectively. There was no significant difference between treatments for patients with T-lineage leukemia (P = 0.54). In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia.
Conclusions
Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.
Media in This Article
Figure 4
Kaplan–Meier Estimates of Continuous Complete Remission in Patients with B-Lineage Acute Lymphoblastic Leukemia.Figure 2
Percentage of Treatment Courses during Which Systemic Exposures Were below, within, or above the Target Range in the 91 Patients Receiving Individualized Doses of Methotrexate, Teniposide, and Cytarabine and the 91 Receiving Conventional Doses.Article Activity
- Article
Childhood acute lymphoblastic leukemia is curable in approximately 70 percent of children.1,2 Many of the children who are not cured have presenting features that are indistinguishable from those in children who are cured. We reasoned that because systemic clearance of anticancer drugs differs by a factor of 3 to 10 among patients,3 those with rapid drug clearance may benefit less than those with slower clearance if the dose is determined only according to body-surface area. This hypothesis was based in part on our finding that the outcome was significantly worse among children with acute lymphoblastic leukemia who had low plasma concentrations of methotrexate due to rapid clearance than among those with slower clearance.4 On the basis of these data and similar pharmacodynamic data for teniposide5 and cytarabine,6 we performed a prospective study in which patients with acute lymphoblastic leukemia were randomly assigned to receive doses of these drugs that were based on body-surface area or the clearance of the drugs in each patient.
Methods
Patients and Treatment
Between October 1988 and November 1991, we registered 188 consecutive patients with newly diagnosed acute lymphoblastic leukemia (age range, 4.3 months to 18.8 years) in Total Therapy Study XII at St. Jude Children's Research Hospital in Memphis, Tennessee. Figure 1Figure 1
Study Protocol for Patients with Childhood Acute Lymphoblastic Leukemia Treated with Conventional or Individualized Chemotherapy. shows the protocol for randomization and treatment. The study was approved by the institutional review board, and informed consent was obtained from the patients' parents or guardians. The diagnostic studies, immunophenotyping, and cytogenetic analyses were performed as described previously.7,8 Remission-induction therapy for all patients consisted of prednisone, vincristine, asparaginase, daunorubicin, teniposide, and cytarabine, given over a four-week period as described previously.9 All patients received low-dose trimethoprim–sulfamethoxazole as prophylaxis against Pneumocystis carinii pneumonia. All patients received intrathecal treatment with methotrexate, hydrocortisone, and cytarabine in age-adjusted doses on days 2 and 22 of induction therapy and every six weeks through week 59. Only high-risk patients and those with central nervous system leukemia at diagnosis underwent cranial irradiation (18 and 24 Gy, respectively, during weeks 59 to 61).
Patients with complete remissions were stratified according to race (nonwhite vs. white). White patients were further stratified according to the DNA index (ratio of DNA content in leukemic G0/G1 cells to that in normal G0/G1 cells, <1.16 vs. >1.16), and white patients with a DNA index of <1.16 were stratified according to age (2 to 10 years vs. other ages) and leukocyte count per cubic millimeter (<25,000 vs. >25,000). After stratification, the patients were randomly assigned to receive conventional or individualized treatment.
Patients with complete remissions received continuation therapy for 120 weeks. The regimen consisted of daily oral mercaptopurine (75 mg per square meter of body-surface area) and weekly parenteral methotrexate (40 mg per square meter), interrupted every six weeks during the first year for treatment with either intravenous high-dose methotrexate with leucovorin10 (given during weeks 1, 13, 25, 37, and 49) or the combination of teniposide and cytarabine (given as simultaneous intravenous infusions during weeks 7, 19, 31, 43, and 55). For patients randomly assigned to receive conventional therapy, fixed doses were given on the basis of the patient's body-surface area (methotrexate, 1500 mg per square meter; teniposide, 200 mg per square meter; and cytarabine, 300 mg per square meter). Plasma samples were obtained from all patients for measurements of methotrexate, teniposide, and cytarabine concentrations. Methotrexate was measured by a fluorescence polarization immunoassay (TDx, Abbott Laboratories, North Chicago, Ill.) in plasma samples obtained before and 1, 6, 23, and 42 hours after the start of the 24-hour intravenous infusion.10 After the start of simultaneous, 4-hour infusions of teniposide and cytarabine, teniposide was measured in plasma obtained at 1.5, 3.5, 8, and 24 hours, and cytarabine in samples obtained at 1.5 and 3.5 hours, with the use of assays previously reported.11,12
Dose Adjustments
In the individualized-treatment group, the doses of methotrexate, teniposide, and cytarabine were adjusted according to systemic drug clearance in each patient.13 The target range of systemic exposure was defined a priori as the area under the plasma concentration–time curve corresponding to the 50th to 90th percentile for children treated with conventional doses of these medications. This range was based on prior pharmacokinetic studies in children.3 The target range was 580 to 950 μM· hour for methotrexate, 360 to 525 μM·hour for teniposide, and 22.5 to 60 μM· hour for cytarabine. Methotrexate clearance was estimated on the basis of the plasma concentrations at one and six hours, with the use of a two-compartment model and a Bayesian algorithm.10 If the clearance of methotrexate indicated that systemic exposure was outside the target range, the dose rate was adjusted eight hours after the start of the infusion to achieve an exposure within the target range (i.e., 800 μM·hour), but the dose was not decreased to an infusion rate that would produce a steady-state plasma concentration of <20 μM during the infusion. The minimum of 20 μM was selected because it is 25 percent above the value (16 μM) that was associated with an increased risk of relapse in our previous study,4 providing a margin of error for dose adjustments. Cytarabine and teniposide clearances were estimated with the use of a one-compartment pharmacokinetic model (for cytarabine) or a two-compartment model (for teniposide) and a Bayesian algorithm.13,14 If the clearance of either medication indicated that systemic exposure was outside the target range, the next dose given was calculated to achieve an exposure within the target range (i.e., 450 μM· hour for teniposide and 42 μM · hour for cytarabine).
The process described above was repeated for each course with all three medications. As a precaution, the maximal increase in the dose of teniposide or cytarabine was limited to 50 percent of the previous dose, with the escalation in doses continuing from one course to the next, as necessary, until systemic exposure was within the target range. For both treatment groups, if two successive courses of either teniposide plus cytarabine or high-dose methotrexate resulted in a delay of seven or more days before the resumption of treatment (because of an absolute neutrophil count of less than 300 per cubic millimeter, a platelet count of less than 50,000 per cubic millimeter, mucositis of grade 4 according to the National Cancer Institute's classification, grade 4 hepatotoxicity, or grade 3 or 4 infection), subsequent doses were decreased by 25 percent.
Assessment of Outcome and Statistical Analysis
Continuous complete remission was defined as spanning the interval from the date of complete remission to the date of the first treatment failure or the last contact with the patient. Fisher's exact test was used to evaluate correlations between subgroups of patients and base-line clinical characteristics. Distributions of event-free survival and continuous complete remission were estimated according to the method of Kaplan and Meier and compared with the stratified Mantel–Haenszel test. Correlations between continuous complete remission and time-dependent covariates were evaluated with the Cox proportional-hazards model and the Wald test. Longitudinal binary measures, such as the percentage of courses with toxic effects, were analyzed with the SAS version 6.12 macro Glimmix, which uses the Proc Mixed program in the SAS/STAT software. All reported P values are for two-sided tests.
Results
Of the 188 patients enrolled in the study, 182 (97 percent) had complete remissions. Half these patients (91) were randomly assigned to conventional treatment, and the other half to individualized treatment. There were no significant differences in base-line demographic or clinical characteristics between the two groups (Table 1Table 1
Demographic and Clinical Characteristics of the Patients.). Likewise, there were no significant differences in the frequency of central nervous system involvement at diagnosis (P = 0.48) or in the prevalence of lymphoblasts with rearranged TEL or MLL genes (P = 0.34 and P = 1.0, respectively) or t(1;19) or t(9;22) chromosomal translocations (P = 0.39 and P = 0.68, respectively).For all patients, the mean rate of clearance was 103 ml per minute per square meter (coefficient of variation, 26.0 percent) for methotrexate, 14.6 ml per minute per square meter (coefficient of variation, 39.6 percent) for teniposide, and 969 ml per minute per square meter (coefficient of variation, 62.3 percent) for cytarabine. The mean rate of clearance did not differ significantly between the group assigned to conventional treatment and the group assigned to individualized treatment: methotrexate, 102 ml per minute per square meter (coefficient of variation, 27 percent) and 104 ml per minute per square meter (coefficient of variation, 26 percent); teniposide, 14.2 ml per minute per square meter (coefficient of variation, 33 percent) and 15.0 ml per minute per square meter (coefficient of variation, 44 percent); and cytarabine, 1010 ml per minute per square meter (coefficient of variation, 68 percent) and 931 ml per minute per square meter (coefficient of variation, 55 percent), respectively. For all the drugs, the median coefficient of variation in clearance was lower in individual patients than between patients: 17 percent versus 26 percent for methotrexate, 17 percent versus 40 percent for teniposide, and 43 percent versus 62 percent for cytarabine.
Systemic Exposure
The proportion of courses of treatment in which systemic exposures were below the target range was significantly lower in the individualized-treatment group than in the conventional-treatment group (P<0.001 for each medication) (Figure 2Figure 2
Percentage of Treatment Courses during Which Systemic Exposures Were below, within, or above the Target Range in the 91 Patients Receiving Individualized Doses of Methotrexate, Teniposide, and Cytarabine and the 91 Receiving Conventional Doses.). In the individualized-treatment group, systemic exposure was below the target range in 7.7 percent of courses of methotrexate, 14.6 percent of courses of teniposide, and 20.7 percent of courses of cytarabine, in part because the first course of teniposide and cytarabine was not adjusted, and because the maximal increase in the dose of each drug was limited to 50 percent of the previous dose. The respective median doses in the conventional-treatment group and the individualized-treatment group were 1502 mg per square meter (5th to 95th percentile, 1418 to 1580) and 1992 mg per square meter (5th to 95th percentile, 1301 to 3088) for methotrexate, 200 mg per square meter (5th to 95th percentile, 194 to 207) and 245 mg per square meter (5th to 95th percentile, 158 to 424) for teniposide, and 300 mg per square meter (5th to 95th percentile, 290 to 306) and 375 mg per square meter (5th to 95th percentile, 221 to 752) for cytarabine. The five courses of each medication were given over a median period of 55 weeks in both treatment groups.Toxicity
There were no differences in the number of severe toxic effects after courses of either high-dose methotrexate or teniposide plus cytarabine in the two treatment groups, with the exception that there were more grade 3 or 4 infections after courses of teniposide plus cytarabine in the individualized-treatment group (7.3 percent, vs. 3.4 percent; P = 0.02) (Table 2Table 2
Toxic Effects of Chemotherapy in the Two Treatment Groups.). There were no deaths from infections related to therapy in either group. The proportions of patients in whom the dose of teniposide plus cytarabine was reduced by 25 percent because of excessive toxicity were identical in the two treatment groups (7.7 percent).Outcome
Kaplan–Meier estimates of overall and event-free survival at five years for all 188 patients, regardless of randomization, were 83±3 percent and 67±4 percent, respectively (Figure 3AFigure 3
Kaplan–Meier Estimates of Overall and Event-free Survival among All 188 Patients Enrolled in the Study (Panel A), and Kaplan–Meier Estimates of Continuous Complete Remission among the 182 Patients Randomly Assigned to Individualized or Conventional Treatment (Panel B).). The Kaplan–Meier estimate of continuous complete remission at five years was 72±6 percent in the individualized-treatment group and 66±6 percent in the conventional-treatment group (Figure 3B). Because there was a significant statistical interaction between treatment and leukemia-cell lineage (P = 0.05), the comparison of outcomes in the two groups was performed separately for patients with B-lineage leukemia (84 percent of the patients) and those with T-lineage leukemia (16 percent of the patients). In the group with B-lineage leukemia, there were 8 hematologic and 2 central nervous system relapses among the 69 patients assigned to individualized treatment, and there were 15 hematologic, 9 central nervous system, and 2 testicular relapses among the 74 patients assigned to conventional treatment. In the group with T-lineage leukemia, three hematologic and three central nervous system relapses occurred among the 13 patients who received individualized treatment, and one hematologic and four central nervous system relapses occurred among the 14 patients who received conventional treatment.Among the patients with B-lineage leukemia, the individualized-treatment group had a significantly better outcome than the conventional-treatment group (P = 0.02); the rates of continuous complete remission at five years were 76±6 percent and 66±7 percent, respectively (Figure 4Figure 4
Kaplan–Meier Estimates of Continuous Complete Remission in Patients with B-Lineage Acute Lymphoblastic Leukemia.). The relative risk of a relapse in the conventional-treatment group, as compared with the individualized-treatment group, was 2.0 (95 percent confidence interval, 1.08 to 3.72). In contrast, among the patients with T-lineage leukemia, there was no significant difference in outcome between the patients receiving individualized treatment and those receiving conventional treatment (rates of continuous complete remission at five years, 64±14 percent and 46±14 percent, respectively; P = 0.54), although because of the relatively small number of patients with T-lineage leukemia, the study had limited power to detect differences.Relation of Systemic Exposure to Clinical Outcome
Cox proportional-hazards regression was used to assess the relation between systemic exposure (i.e., the time-dependent average systemic exposure for all courses and the proportion of courses with systemic exposures above the lower limit of the target range) and the duration of continuous complete remission. The probability of failure was assessed for the period during which individualized or conventional therapy was given (i.e., the first 462 days). In patients with B-lineage leukemia, the risk of a relapse during this period was significantly related to both the average systemic exposure to methotrexate (P = 0.02) and the proportion of courses with systemic exposures above the target threshold (580 μM·hour, P = 0.02). With each decrease of 100 μM· hour in the average systemic exposure to methotrexate, the relative risk increased by a factor of 1.79. In the group of patients with B-lineage leukemia, the risk of an early relapse among patients with no courses involving systemic exposures above the target threshold was 6.5 times the risk among patients with all courses involving exposures above the target threshold. The risk of an early relapse was not related to the average systemic exposure to teniposide or cytarabine (P = 0.26 and P = 0.27, respectively) or the proportion of courses with systemic exposures above the target threshold (P = 0.08 and P = 0.40, respectively). In the group with T-lineage leukemia, the risk of an early relapse tended to be associated with the average systemic exposure to cytarabine (P = 0.07) but not with systemic exposure to methotrexate (P = 0.92) or teniposide (P = 0.26).
Discussion
This study demonstrates that in the treatment of childhood B-lineage acute lymphoblastic leukemia, increasing the dose of methotrexate in patients with rapid clearance of the drug significantly improves the outcome without increasing the toxicity. Several previous studies also found a relation between systemic exposure to chemotherapy and anticancer effects,15 but none of them were prospective, randomized trials designed to determine whether therapeutic interventions based on these relations could result in a better clinical outcome.
Our study indicates that conventional chemotherapy sometimes fails because patients receive inadequate doses of drugs, not because their leukemia is drug-resistant. This finding extends the results of earlier studies documenting inferior results when the intensity of chemotherapy was reduced by giving lower doses of medication.16,17 Our results show that lower systemic exposure due to rapid drug clearance can adversely affect the outcome in children with acute lymphoblastic leukemia. The recommended (i.e., conventional) doses of chemotherapeutic drugs are typically within the limits that essentially all patients can tolerate, regardless of the rate at which the medication is metabolized or eliminated in individual patients. For this reason, it is not surprising that such doses may be suboptimal in some patients. That the intensity of early treatment with methotrexate can significantly influence the risk of a relapse in acute lymphoblastic leukemia is consistent with a previous demonstration of a superior outcome in children treated with a single high dose of methotrexate at the time of diagnosis.18
Why did individualized therapy benefit only the children with B-lineage leukemia? It is possible that the target range of systemic exposure to methotrexate was inadequate in the patients with T-lineage leukemia. Recent studies of methotrexate accumulation in leukemic lymphoblasts have shown that T-lineage blasts accumulate active metabolites (methotrexate polyglutamates) less avidly than do B-lineage blasts but that higher doses can result in greater accumulations.19-22 Improvements in treating T-lineage leukemia have been attributed in part to the use of higher doses of methotrexate (5 g per square meter),23 which produced concentrations above the target range in our study.
Our findings that individual differences in drug clearance can result in differences in efficacy and that these differences can be overcome in part by individualized therapy are not unprecedented. Other drugs with relatively narrow therapeutic indexes, such as aminoglycoside antibiotics, cyclosporine, and anticonvulsant agents, are commonly administered in individualized doses.
Our findings raise the question whether it is necessary to individualize the doses of antileukemic agents in all children with B-lineage acute lymphoblastic leukemia. We found that individualizing the dose of methotrexate was beneficial, but this approach may not apply to all antileukemic agents; there was no evidence of a benefit in individualizing the doses of teniposide and cytarabine. These results suggest that methotrexate may be the critical drug for dose adjustments in treatment regimens similar to ours. An alternative to individualizing the dose of methotrexate is to select a dose that produces adequate concentrations even in patients with rapid drug clearance (e.g., 2.5 g per square meter in patients with B-lineage leukemia), although the potential for greater neurotoxicity may limit this strategy. In view of the low variation in drug clearance in individual patients, as compared with the variation between patients, it might be possible to use a single clearance estimate (after the first dose) to adjust the doses for all subsequent treatment courses.
It is possible that with more aggressive treatment of leukemia, optimizing the dose will be less important. However, less intensive protocols are now being evaluated for the treatment of patients who have leukemia with favorable genetic and clinical features, to prevent serious toxic effects.24,25 Unfortunately, even with the most sophisticated methods of risk assignment, some of these presumably lower-risk patients have relapses when treated with less intensive regimens.
It remains to be determined whether easily monitored biologic end points (e.g., the leukocyte count) can be used to identify patients who are receiving inadequate doses of antileukemic agents. Nevertheless, in patients receiving combination chemotherapy with agents that have overlapping toxic effects, measurement of drug concentrations in plasma may be the best method for determining whether appropriate doses are being used in individual patients.
Supported in part by grants from the National Institutes of Health (CA20180, R37 CA36401, CA51001, and CA21765), the State of Tennessee, and the American Lebanese Syrian Associated Charities.
We are indebted to all the persons involved in the treatment of the patients and the individualization of doses, including Drs. D.K. Baker, F. Behm, M. Christensen, W.M. Crist, E. Gregory, D.A. Kalwinsky, H.H. Mahmoud, J. Mirro, S. Raimondi, W.M. Roberts, R. Riberio, G.K. Rivera, M.H. Sanders, J.T. Sandlund, V. Santana, J.V. Simone, C.F. Stewart, and L. Stricklin; to N. Kornegay for her expertise in data-base management and quality control; to our dedicated postdoctoral fellows, Drs. W.P. Petros, T.S. Madden, M. Sunderland, H.L. McLeod, D.J. Murry, R. Evans, T.W. Synold, D.S. Sonnichsen, S. Baker, M. Tonda, C. Kearns, and A. Galpin; to medical technologists C.R. Stewart, E.T. Melton, M. Needham, B. Alexander, M. Chung, and L. McNinch and research nurses S. Ring, L. Walters, T. Kuehner, and M. Edwards; to Y. Yanshevski for his biomedical-modeling expertise; to P.L. Harrison for her contributions to the statistical analyses; and most important, to the patients and parents who volunteered to participate in the study.
Source Information
From the Departments of Pharmaceutical Sciences (W.E.E., M.V.R., J.H.R., W.R.C.), Biostatistics and Epidemiology (J.M.B.), and Hematology–Oncology (C.-H.P.), St. Jude Children's Research Hospital; and the Colleges of Pharmacy (W.E.E., M.V.R., J.H.R., W.R.C.) and Medicine (W.E.E., C.-H.P.), University of Tennessee — both in Memphis.
Address reprint requests to Dr. Evans at St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105.
- References
References
1
Pui C-H . Childhood leukemias. N Engl J Med 1995;332:1618-1630
Full Text | Web of Science | Medline2
Simone JV . Childhood leukemia as a model for cancer research. Cancer Res 1979;39:4301-4307
Web of Science | Medline3
Rodman JH ,Relling MV ,Stewart CF , et al. Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children. Semin Oncol 1993;20:18-29
Web of Science | Medline4
Evans WE ,Crom WR ,Abromowitch M , et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia: identification of a relation between concentration and effect. N Engl J Med 1986;314:471-477
Full Text | Web of Science | Medline5
Rodman JH ,Abromowitch M ,Sinkule JA ,Hayes FA ,Rivera GK ,Evans WE . Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J Clin Oncol 1987;5:1007-1014
Web of Science | Medline6
Plunkett W ,Liliemark JO ,Adams TM , et al. Saturation of 1-β-D-arabinofuranosylcytosine 5'-triphosphate accumulation in leukemia cells during high-dose 1-β-D-arabinofuranosylcytosine therapy. Cancer Res 1987;47:3005-3011
Web of Science | Medline7
Behm FG ,Raimondi SC ,Schell MJ ,Look AT ,Rivera GK ,Pui C-H . Lack of CD45 antigen on blast cells in childhood acute lymphoblastic leukemia is associated with chromosomal hyperdiploidy and other favorable prognostic features. Blood 1992;79:1011-1016
Web of Science | Medline8
Williams DL ,Harris A ,Williams KJ ,Brosius MJ ,Lemonds W . A direct bone marrow chromosome technique for acute lymphoblastic leukemia. Cancer Genet Cytogenet 1984;13:239-257
CrossRef | Web of Science | Medline9
Rivera GK ,Raimondi SC ,Hancock ML , et al. Improved outcome in childhood acute lymphoblastic leukemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991;337:61-66
CrossRef | Web of Science | Medline10
Relling MV ,Fairclough D ,Ayers D , et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 1994;12:1667-1672
Web of Science | Medline11
Evans WE ,Rodman JH ,Relling MV , et al. Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia. J Pharmacol Exp Ther 1992;260:71-77
Web of Science | Medline12
Sinkule JA ,Evans WE . High-performance liquid chromatographic assay for cytosine arabinoside, uracil arabinoside and some related nucleosides. J Chromatogr 1983;274:87-93
CrossRef | Web of Science | Medline13
Evans WE ,Rodman JH ,Relling MV , et al. Individualized dosages of chemotherapy as a strategy to improve response for acute lymphocytic leukemia. Semin Hematol 1991;28:Suppl 4:15-21
Web of Science | Medline14
Rodman JH ,Furman WL ,Sunderland M ,Rivera G ,Evans WE . Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients. J Clin Oncol 1993;11:287-293
Web of Science | Medline15
Pinkel D ,Hernandez K ,Borella L , et al. Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer 1971;27:247-256
CrossRef | Web of Science | Medline16
Devita VT . Dose-response is alive and well. J Clin Oncol 1986;4:1157-1159
Web of Science | Medline17
Evans WE ,Relling MV . Clinical pharmacokinetics-pharmacodynamics of anticancer drugs. Clin Pharmacokinet 1989;16:327-336
CrossRef | Web of Science | Medline18
Niemeyer CM ,Gelbar RD ,Tarbell NJ , et al. Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update). Blood 1991;78:2514-2519
Web of Science | Medline19
Synold TW ,Relling MV ,Boyett JM , et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 1994;94:1996-2001
CrossRef | Web of Science | Medline20
Masson E ,Relling MV ,Synold TW , et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo: a rationale for high-dose methotrexate. J Clin Invest 1996;97:73-80
CrossRef | Web of Science | Medline21
Galpin AJ ,Schuetz JD ,Masson E , et al. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity. Mol Pharmacol 1997;52:155-163
Web of Science | Medline22
Barredo JC ,Synold TW ,Laver J , et al. Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 1994;84:564-569
Web of Science | Medline23
Reiter A ,Schrappe M ,Ludwig W-D , et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994;84:3122-3133
Web of Science | Medline24
Mahoney DH Jr ,Camitta BM ,Leventhal BG , et al. Repetitive low dose oral methotrexate and intravenous mercaptopurine treatment for patients with lower risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group pilot study. Cancer 1995;75:2623-2631
CrossRef | Web of Science | Medline25
Veerman AJP ,Hahlen K ,Kamps WA , et al. High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 1996;14:911-918
Web of Science | Medline
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R A Wilke, H Xu, J C Denny, D M Roden, R M Krauss, C A McCarty, R L Davis, T Skaar, J Lamba, G Savova. (2011) The Emerging Role of Electronic Medical Records in Pharmacogenomics. Clinical Pharmacology & Therapeutics 89:3, 379-386
CrossRef11
Jacob Nersting, Louise Borst, Kjeld Schmiegelow. (2011) Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia. Clinical Proteomics 8:1, 8
CrossRef12
Abha A. Gupta, James R. Anderson, Alberto S. Pappo, Sheri L. Spunt, Roshni Dasgupta, Daniel J. Indelicato, Douglas S. Hawkins. (2011) Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma. Cancern/a-n/a
CrossRef13
Frances A. Tylavsky, Karen Smith, Harriet Surprise, Sarah Garland, Xiaowei Yan, Elizabeth McCammon, Melissa M. Hudson, Ching-Hon Pui, Sue C. Kaste. (2010) Nutritional intake of long-term survivors of childhood acute lymphoblastic leukemia: Evidence for bone health interventional opportunities. Pediatric Blood & Cancer 55:7, 1362-1369
CrossRef14
Steven W Paugh, Gabriele Stocco, William E Evans. (2010) Pharmacogenomics in pediatric leukemia. Current Opinion in Pediatrics 22:6, 703-710
CrossRef15
Sarah L. Noble, Eric Sherer, Robert E. Hannemann, Doraiswami Ramkrishna, Terry Vik, Ann E. Rundell. (2010) Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia. Journal of Theoretical Biology 264:3, 990-1002
CrossRef16
Dylan M Bach, Joely A Straseski, William Clarke. (2010) Therapeutic drug monitoring in cancer chemotherapy. Bioanalysis 2:5, 863-879
CrossRef17
Barbara Faganel Kotnik, Vita Dolžan, Iztok Grabnar, Janez Jazbec. (2010) Relationship of the reduced folate carrier gene polymorphism G80A to methotrexate plasma concentration, toxicity, and disease outcome in childhood acute lymphoblastic leukemia. Leukemia & Lymphoma 51:4, 724-726
CrossRef18
K Schmiegelow, E Forestier, M Hellebostad, M Heyman, J Kristinsson, S Söderhäll, M Taskinen. (2010) Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia 24:2, 345-354
CrossRef19
C H Pui, D Pei, J T Sandlund, R C Ribeiro, J E Rubnitz, S C Raimondi, M Onciu, D Campana, L E Kun, S Jeha, C Cheng, S C Howard, M L Metzger, D Bhojwani, J R Downing, W E Evans, M V Relling. (2010) Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24:2, 371-382
CrossRef20
Judith Meza-Junco, Michael B Sawyer. (2009) Drug exposure: still an excellent biomarker. Biomarkers in Medicine 3:6, 723-731
CrossRef21
Sima Jeha, Ching-Hon Pui. (2009) Risk-adapted Treatment of Pediatric Acute Lymphoblastic Leukemia. Hematology/Oncology Clinics of North America 23:5, 973-990
CrossRef22
Kjeld Schmiegelow. (2009) Advances in individual prediction of methotrexate toxicity: a review. British Journal of Haematology 146:5, 489-503
CrossRef23
Kenneth K. Khamly, Vicky J. Thursfield, Michael Fay, Jayesh Desai, Guy C. Toner, Peter F.M. Choong, Samuel Y.K. Ngan, Gerard J. Powell, David M. Thomas. (2009) Gender-specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood. International Journal of Cancer 125:2, 426-431
CrossRef24
Pui, Ching-Hon, Campana, Dario, Pei, Deqing, Bowman, W. Paul, Sandlund, John T., Kaste, Sue C., Ribeiro, Raul C., Rubnitz, Jeffrey E., Raimondi, Susana C., Onciu, Mihaela, Coustan-Smith, Elaine, Kun, Larry E., Jeha, Sima, Cheng, Cheng, Howard, Scott C., Simmons, Vickey, Bayles, Amy, Metzger, Monika L., Boyett, James M., Leung, Wing, Handgretinger, Rupert, Downing, James R., Evans, William E., Relling, Mary V., . (2009) Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation. New England Journal of Medicine 360:26, 2730-2741
Full Text25
H. Hayashi, C. Fujimaki, T. Daimon, S. Tsuboi, T. Matsuyama, K. Itoh. (2009) Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. Journal of Clinical Pharmacy and Therapeutics 34:3, 355-361
CrossRef26
Gudmar Lönnerholm, Maria Grazia Valsecchi, Paola De Lorenzo, Martin Schrappe, Liisa Hovi, Myriam Campbell, Georg Mann, Gritta Janka-Schaub, Chi-Kong Li, Jan Stary, Ian Hann, Rob Pieters, . (2009) Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. Pediatric Blood & Cancer 52:5, 596-601
CrossRef27
E Hénin, B You, E VanCutsem, PM Hoff, J Cassidy, C Twelves, KP Zuideveld, F Sirzen, C Dartois, G Freyer, M Tod, P Girard. (2009) A Dynamic Model of Hand-and-Foot Syndrome in Patients Receiving Capecitabine. Clinical Pharmacology & Therapeutics 85:4, 418-425
CrossRef28
Meyling H. Cheok, William E. Evans, Leo Kager. (2009) High-dose Methotrexate: The Rationale…. Journal of Pediatric Hematology/Oncology 31:3, 224-225
CrossRef29
G Stocco, MH Cheok, KR Crews, T Dervieux, D French, D Pei, W Yang, C Cheng, C-H Pui, MV Relling, WE Evans. (2009) Genetic Polymorphism of Inosine Triphosphate Pyrophosphatase Is a Determinant of Mercaptopurine Metabolism and Toxicity During Treatment for Acute Lymphoblastic Leukemia. Clinical Pharmacology & Therapeutics 85:2, 164-172
CrossRef30
Meyling H. Cheok, Nicolas Pottier, Leo Kager, William E. Evans. (2009) Pharmacogenetics in Acute Lymphoblastic Leukemia. Seminars in Hematology 46:1, 39-51
CrossRef31
Kristine R. Crews, Yinmei Zhou, Jennifer L. Pauley, Scott C. Howard, Sima Jeha, Mary V. Relling, Ching-Hon Pui. (2009) Effect of allopurinol versus urate oxidase on methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia. CancerNA-NA
CrossRef32
J Yang, A Bogni, C Cheng, WK Bleibel, X Cai, Y Fan, W Yang, JCC Rocha, D Pei, W Liu, ME Dolan, C-H Pui, MV Relling. (2008) Etoposide Sensitivity Does Not Predict MLL Rearrangements or Risk of Therapy-Related Acute Myeloid Leukemia. Clinical Pharmacology & Therapeutics 84:6, 691-697
CrossRef33
Marie Louise Davidsen, Kim Dalhoff, Kjeld Schmiegelow. (2008) Pharmacogenetics Influence Treatment Efficacy in Childhood Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology 30:11, 831-849
CrossRef34
Bo Gao, Heinz-Josef Klumpen, Howard Gurney. (2008) Dose calculation of anticancer drugs. Expert Opinion on Drug Metabolism & Toxicology 4:10, 1307-1319
CrossRef35
Xavier Thomas, Quoc-Hung Le. (2008) Central nervous system involvement in adult acute lymphoblastic leukemia. Hematology 13:5, 293-302
CrossRef36
Shesh N. Rai, Melissa M. Hudson, Elizabeth McCammon, Laura Carbone, Francis Tylavsky, Karen Smith, Harriet Surprise, John Shelso, Chin-Hon Pui, Sue Kaste. (2008) Implementing an intervention to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia: BONEII, a prospective placebo-controlled double-blind randomized interventional longitudinal study design. Contemporary Clinical Trials 29:5, 711-719
CrossRef37
Gudmar Lönnerholm, Britt-Marie Frost, Jonas Abrahamsson, Mikael Behrendtz, Anders Castor, Erik Forestier, Mats Heyman, Donald R. A. Uges, Siebold S. N. de Graaf. (2008) Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia. British Journal of Haematology 142:4, 616-621
CrossRef38
Pierre Durieux, Ludovic Trinquart, Isabelle Colombet, Julie Niès, RT Walton, Anand Rajeswaran, Myriam Rège-Walther, Emma Harvey, Bernard Burnand, Pierre Durieux. 2008. Computerized advice on drug dosage to improve prescribing practice. .
CrossRef39
MA Barras, SB Duffull, JJ Atherton, B Green. (2008) Individualized Compared With Conventional Dosing of Enoxaparin. Clinical Pharmacology & Therapeutics 83:6, 882-888
CrossRef40
Nobuko Hijiya, Clinton F. Stewart, Yinmei Zhou, Dario Campana, Elaine Coustan-Smith, Gaston K. Rivera, Mary V. Relling, Ching-Hon Pui, Amar Gajjar. (2008) Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse. Cancer 112:9, 1983-1991
CrossRef41
Nicolas Pottier, Meyling Cheok, Leo Kager. (2008) Antileukemic drug effects in childhood acute lymphoblastic leukemia. Expert Review of Clinical Pharmacology 1:3, 401-413
CrossRef42
Alan Kambiz Fotoohi, Freidoun Albertioni. (2008) Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leukemia & Lymphoma 49:3, 410-426
CrossRef43
Hideki Hayashi, Chihiro Fujimaki, Seiji Tsuboi, Taiji Matsuyama, Takashi Daimon, Kunihiko Itoh. (2008) Application of Fluorescence Polarization Immunoassay for Determination of Methotrexate-Polyglutamates in Rheumatoid Arthritis Patients. The Tohoku Journal of Experimental Medicine 215:1, 95-101
CrossRef44
Ganping Zhou, Zuofu Cai, Shedian Zhou, Zhichun Feng, Feng Xu. (2008) A Simplistic Individualization Method for 6-Mercaptopurine in Acute Lymphoblastic Leukemia Children. International Journal of Pharmacology 4:1, 64-66
CrossRef45
Anthe S Zandvliet, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema. (2008) Population Pharmacokinetics and Pharmacodynamics for Treatment Optimization??in Clinical Oncology. Clinical Pharmacokinetics 47:8, 487-513
CrossRef46
Tugba Boyunegmez Tumer, Gulen Ulusoy, Orhan Adali, Gurses Sahin, Sevgi Gozdasoglu, Emel Arinç. (2007) The low frequency of defectiveTPMT alleles in Turkish population: A study on pediatric patients with acute lymphoblastic leukemia. American Journal of Hematology 82:10, 906-910
CrossRef47
Jerzy P. Szaflarski, Jason M. Meckler, Magdalena Szaflarski, Lori A. Shutter, Michael D. Privitera, Stephen L. Yates. (2007) Levetiracetam use in critically ill patients. Neurocritical Care 7:2, 140-147
CrossRef48
J Shamash, T Powles, W Ansell, J Stebbing, K Mutsvangwa, P Wilson, S Asterling, S Liu, P Wyatt, S P Joel, R T D Oliver. (2007) GAMEC – a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours. British Journal of Cancer 97:3, 308-314
CrossRef49
Christine Piard, Françoise Bressolle, May Fakhoury, Daolun Zhang, Karina Yacouben, André Rieutord, Evelyne Jacqz-Aigrain. (2007) A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemotherapy and Pharmacology 60:4, 609-620
CrossRef50
Paul S. Gaynon. (2007) Treatment of pediatric acute lymphoblastic leukemia: Progress achieved and challenges remaining. Current Hematologic Malignancy Reports 2:3, 193-201
CrossRef51
Céline Dartois, Annabelle Lemenuel-Diot, Christian Laveille, Brigitte Tranchand, Michel Tod, Pascal Girard. (2007) Evaluation of Uncertainty Parameters Estimated by Different Population PK Software and Methods. Journal of Pharmacokinetics and Pharmacodynamics 34:3, 289-311
CrossRef52
S.A. Kaestner, G.J. Sewell. (2007) Chemotherapy Dosing Part II: Alternative Approaches and Future Prospects. Clinical Oncology 19:2, 99-107
CrossRef53
(2007) The Research Agenda of the American College of Clinical Pharmacy. Pharmacotherapy 27:2, 312-324
CrossRef54
R. Jasmine ., P. Daisy ., B.N.Selvakumar .. (2007) Evaluating the Antibacterial Activity of Elephantopus scaber Extracts on Clinical Isolates of ß-lactamase Producing Methicillin Resistant Staphylococcus aureus from UTI Patients. International Journal of Pharmacology 3:2, 165-169
CrossRef55
S.A. Kaestner, G.J. Sewell. (2007) Chemotherapy Dosing Part I: Scientific Basis for Current Practice and Use of Body Surface Area. Clinical Oncology 19:1, 23-37
CrossRef56
Hideki Hayashi, Chihiro Fujimaki, Kazuyuki Inoue, Toshio Suzuki, Kunihiko Itoh. (2007) Genetic Polymorphism of C452T (T127I) in Human γ-Glutamyl Hydrolase in a Japanese Population. Biological & Pharmaceutical Bulletin 30:4, 839-841
CrossRef57
T V Ch Skärby, H Anderson, J Heldrup, J A Kanerva, H Seidel, K Schmiegelow. (2006) High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 20:11, 1955-1962
CrossRef58
Josefine Palle, Frost Britt-Marie, Gustafsson G??ran, Hellebostad Marit, Kanerva Jukka, Liliemark Eva, Schmiegelow Kjeld, L??nnerholm Gudmar. (2006) Etoposide pharmacokinetics in children treated for acute myeloid leukemia. Anti-Cancer Drugs 17:9, 1087-1094
CrossRef59
M. Sandström, H. Lindman, P. Nygren, M. Johansson, J. Bergh, M.O. Karlsson. (2006) Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients. Cancer Chemotherapy and Pharmacology 58:2, 143-156
CrossRef60
John O. Glass, Wilburn E. Reddick, Chin-Shang Li, Fred H. Laningham, Kathleen J. Helton, Ching-Hon Pui. (2006) Computer-aided detection of therapy-induced leukoencephalopathy in pediatric acute lymphoblastic leukemia patients treated with intravenous high-dose methotrexate. Magnetic Resonance Imaging 24:6, 785-791
CrossRef61
Alan V. Boddy. (2006) Recent developments in the clinical pharmacology of classical cytotoxic chemotherapy. British Journal of Clinical Pharmacology 62:1, 27-34
CrossRef62
Michael Cole, Alan V. Boddy, Pamela Kearns, Kok H. Teh, Lisa Price, Annie Parry, Andrew D.J. Pearson, Gareth J. Veal, . (2006) Potential clinical impact of taking multiple blood samples for research studies in paediatric oncology: How much do we really know?. Pediatric Blood & Cancer 46:7, 723-727
CrossRef63
Stuart S. Winter, Mark T. Holdsworth, Meenakshi Devidas, Dennis W. Raisch, Allen Chauvenet, Yaddanapudi Ravindranath, Jonathan M. Ducore, Michael D. Amylon. (2006) Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: A report of POG study 9296. Pediatric Blood & Cancer 46:2, 179-186
CrossRef64
Pui, Ching-Hon, Evans, William E., . (2006) Treatment of Acute Lymphoblastic Leukemia. New England Journal of Medicine 354:2, 166-178
Full Text65
Dolores Aumente, Dolores Santos Buelga, John C Lukas, Pedro Gomez, Antonio Torres, Maria Jos?? Garc??a. (2006) Population Pharmacokinetics of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukaemia. Clinical Pharmacokinetics 45:12, 1227-1238
CrossRef66
Edske ter Bals, Gertjan JL Kaspers. (2005) Treatment of childhood acute myeloid leukemia. Expert Review of Anticancer Therapy 5:5, 917-929
CrossRef67
Xavier Thomas. (2005) Emerging drugs for adult acute lymphoblastic leukaemia. Expert Opinion on Emerging Drugs 10:3, 591-617
CrossRef68
N Hijiya, W Liu, J T Sandlund, S Jeha, B I Razzouk, R C Ribeiro, J E Rubnitz, S C Howard, E P Kyzer, D S Redd, C Cheng, G K Rivera, M M Hudson, M V Relling, C-H Pui. (2005) Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19:8, 1399-1403
CrossRef69
Bernd Meibohm, Stephanie Läer, John C. Panetta, Jeffrey S. Barrett. (2005) Population pharmacokinetic studies in pediatrics: Issues in design and analysis. The AAPS Journal 7:2, E475-E487
CrossRef70
B. Boesler. (2005) Clinical course of haemodialysis patients with malignancies and dose-adjusted chemotherapy. Nephrology Dialysis Transplantation 20:6, 1187-1191
CrossRef71
Gaston K. Rivera, Yinmei Zhou, Michael L. Hancock, Amar Gajjar, Jeffrey Rubnitz, Raul C. Ribeiro, John T. Sandlund, Melissa Hudson, Mary Relling, William E. Evans, Ching-Hon Pui. (2005) Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 103:2, 368-376
CrossRef72
Milly E de Jonge, Alwin D R Huitema, Jan H M Schellens, Sjoerd Rodenhuis, Jos H Beijnen. (2005) Individualised Cancer Chemotherapy: Strategies and Performance of Prospective Studies on Therapeutic Drug Monitoring with Dose Adaptation. Clinical Pharmacokinetics 44:2, 147-173
CrossRef73
E. Groninger, J.H. Proost, S.S.N. de Graaf. (2004) Pharmacokinetic studies in children with cancer. Critical Reviews in Oncology/Hematology 52:3, 173-197
CrossRef74
John O. Glass, Wilburn E. Reddick, Cara Reeves, Ching-Hon Pui. (2004) Improving the segmentation of therapy-induced leukoencephalopathy in children with acute lymphoblastic leukemia using a priori information and a gradient magnitude threshold. Magnetic Resonance in Medicine 52:6, 1336-1341
CrossRef75
Dalibor Valik, Martin Radina, Jaroslav Sterba, Borivoj Vojtesek. (2004) Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics 5:8, 1151-1162
CrossRef76
Maja Krajinovic, Albert Moghrabi. (2004) Pharmacogenetics of methotrexate. Pharmacogenomics 5:7, 819-834
CrossRef77
Jeffrey E. Rubnitz, Shelly Lensing, Yinmei Zhou, John T. Sandlund, Bassem I. Razzouk, Raul C. Ribeiro, Ching-Hon Pui. (2004) Death during induction therapy and first remission of acute leukemia in childhood. Cancer 101:7, 1677-1684
CrossRef78
Qing Cheng, Bainan Wu, Leo Kager, J Carl Panetta, Jie Zheng, Ching-Hon Pui, Mary V Relling, William E Evans. (2004) A substrate specific functional polymorphism of human ??-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 14:8, 557-567
CrossRef79
Renato Bassan, Gemma Gatta, Carlo Tondini, Roel Willemze. (2004) Adult acute lymphoblastic leukaemia. Critical Reviews in Oncology/Hematology 50:3, 223-261
CrossRef80
Irene Aquerreta, Azucena Aldaz, Joaqu
n Gir
CrossRef81
Pui, Ching-Hon, Cheng, Cheng, Leung, Wing, Rai, Shesh N., Rivera, Gaston K., Sandlund, John T., Ribeiro, Raul C., Relling, Mary V., Kun, Larry E., Evans, William E., Hudson, Melissa M., . (2003) Extended Follow-up of Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. New England Journal of Medicine 349:7, 640-649
Full Text82
Susanne Bredenberg, Dag Nyholm, Sten-Magnus Aquilonius, Christer Nyström. (2003) An automatic dose dispenser for microtablets—a new concept for individual dosage of drugs in tablet form. International Journal of Pharmaceutics 261:1-2, 137-146
CrossRef83
E.J Estlin, G.J Veal. (2003) Clinical and cellular pharmacology in relation to solid tumours of childhood. Cancer Treatment Reviews 29:4, 253-273
CrossRef84
Lewis B. Silverman, Stephen E. Sallan. (2003) Newly diagnosed childhood acute lymphoblastic leukemia: update on prognostic factors and treatment. Current Opinion in Hematology 10:4, 290-296
CrossRef85
Jean-Pierre Boissel, François Gueyffier, Michel Cucherat, Giampiero Bricca. (2003) Pharmacogenetics and Responders to a Therapy: Theoretical Background and Practical Problems. Clinical Chemistry and Laboratory Medicine 41:4, 564-572
CrossRef86
Ching-Hon Pui, Mary V Relling, William E Evans. (2002) Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia. Best Practice & Research Clinical Haematology 15:4, 741-756
CrossRef87
Evelyn D. Lobo, Joseph P. Balthasar. (2002) Pharmacodynamic modeling of chemotherapeutic effects: Application of a transit compartment model to characterize methotrexate effects in vitro. AAPS PharmSci 4:4, 212-222
CrossRef88
Javier G Blanco, Mathew J Edick, Michael L Hancock, Naomi J Winick, Thierry Dervieux, Michael D Amylon, Robert O Bash, Frederick G Behm, Bruce M Camitta, Ching-Hon Pui, Susana C Raimondi, Mary V Relling. (2002) Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies. Pharmacogenetics 12:8, 605-611
CrossRef89
Lisa E. Davis. 2002. Oncology Specialty Pharmacy Practice. , 611-626.
CrossRef90
Ingo K Mellinghoff, Charles L Sawyers. (2002) The emergence of resistance to targeted cancer therapeutics. Pharmacogenomics 3:5, 603-623
CrossRef91
Annick Rousseau, Pierre Marquet. (2002) Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundamental and Clinical Pharmacology 16:4, 253-262
CrossRef92
Matthias Schwab, Elke Schaffeler, Claudia Marx, Christine Fischer, Thomas Lang, Christoph Behrens, Michael Gregor, Michel Eichelbaum, Ulrich Zanger, Bernd Kaskas. (2002) Pharmacogenetics 12:6, 429-436
CrossRef93
Ching-Hon Pui, Mary V. Relling, Dario Campana, William E. Evans. (2002) Childhood acute lymphoblastic leukemia. Reviews in Clinical and Experimental Hematology 6:2, 161-180
CrossRef94
Wilburn E. Reddick, John O. Glass, James W. Langston, Kathleen J. Helton. (2002) Quantitative MRI assessment of leukoencephalopathy. Magnetic Resonance in Medicine 47:5, 912-920
CrossRef95
D R Newell. (2002) Getting the right dose in cancer chemotherapy – time to stop using surface area?. British Journal of Cancer 86:8, 1207-1208
CrossRef96
Dario Campana, Elaine Coustan-Smith. (2002) Advances in the immunological monitoring of childhood acute lymphoblastic leukaemia. Best Practice & Research Clinical Haematology 15:1, 1-19
CrossRef97
Courtney V. Fletcher, Peter L. Anderson, Thomas N. Kakuda, Timothy W. Schacker, Keith Henry, Cynthia R. Gross, Richard C. Brundage. (2002) Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS 16:4, 551-560
CrossRef98
Elisabet Lidbrink, Jonas Bergh. (2002) Chemotherapy of Breast Cancer. American Journal of Cancer 1:3, 165-171
CrossRef99
Annick Rousseau, Christophe Sabot, Nicole Delepine, Gerard Delepine, Jean Debord, Gerard Lach??tre, Pierre Marquet. (2002) Bayesian Estimation of Methotrexate Pharmacokinetic Parameters and Area Under the Curve in Children and Young Adults with Localised Osteosarcoma. Clinical Pharmacokinetics 41:13, 1095-1104
CrossRef100
E.J Estlin. (2001) Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine. Cancer Treatment Reviews 27:6, 351-363
CrossRef101
E.J. Estlin, S.M. Yule, S.P. Lowis. (2001) Consolidation therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of cytosine arabinoside, epipodophyllotoxins and cyclophosphamide. Cancer Treatment Reviews 27:6, 339-350
CrossRef102
Giuseppe Toffoli, Giuseppe Corona, Roberto Sorio, Isabelle Robieux, Barbara Basso, Anna Maria Colussi, Mauro Boiocchi. (2001) Population pharmacokinetics and pharmacodynamics of oral etoposide. British Journal of Clinical Pharmacology 52:5, 511-519
CrossRef103
Ching-Hon Pui. (2001) Risk Assessment in Acute Lymphoblastic Leukemia: Beyond Leukemia Cell Characteristics. Journal of Pediatric Hematology/Oncology 23:7, 405-408
CrossRef104
Ching-Hon Pui, Dario Campana, William E Evans. (2001) Childhood acute lymphoblastic leukaemia – current status and future perspectives. The Lancet Oncology 2:10, 597-607
CrossRef105
Fernando Marco, Encarna Bureo, Arancha Bermúdez, Elena Fernández-Fontecha, Alberto Zubizarreta. (2001) Treatment of acute leukemia in children: recent advances and future challenges. Expert Review of Anticancer Therapy 1:3, 479-486
CrossRef106
Junichi Hara, Yong-Dong Park, Akira Yoshioka, Keiko Yumura-Yagi, Urara Koudera, Gaku Hosoi, Masahiro Sako, Yoshiyuki Kosaka, Kimihiko Sano, Hideo Misu, Osamu Mabuchi, Noriyuki Aoyagi, Masuji Yamamoto, Akio Tawa, Hiroshi Miyata, Haruki Tanaka, Makiko Kikkawa, Mutsuro Shimodera, Keisei Kawa-Ha. (2001) Intensification of Chemotherapy Using Block Therapies as Consolidation and Reinduction Therapies for Acute Lymphoblastic Leukemia During Childhood. International Journal of Hematology 74:2, 165-172
CrossRef107
Mark L. Bernstein, Gregory H. Reaman, Steven Hirschfeld. (2001) DEVELOPMENTAL THERAPEUTICS IN CHILDHOOD CANCER. Hematology/Oncology Clinics of North America 15:4, 631-655
CrossRef108
Laura L. Jung, William C. Zamboni. (2001) Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it?. Drug Resistance Updates 4:4, 273-288
CrossRef109
Eiichi Ishii, Haruhiko Eguchi, Akinobu Matsuzaki, Hiroyuki Koga, Fumio Yanai, Hiroshi Kuroda, Kiyoshi Kawakami, Hiroshi Ayukawa, Kensuke Akiyoshi, Junji Kamizono, Yuji Tamai, Naoko Kinukawa, Jun Okamura. (2001) Outcome of acute lymphoblastic leukemia in children with AL90 regimen: Impact of response to treatment and sex difference on prognostic factors. Medical and Pediatric Oncology 37:1, 10-19
CrossRef110
Akinobu Matsuzaki, Eiichi Ishii, Yoshihisa Nagatoshi, Haruhiko Eguchi, Hiroyuki Koga, Fumio Yanai, Hiroko Inada, Keiko Nibu, Yuji Tamai, Kensuke Akiyoshi, Hideki Nakayama, Toshiro Hara, Hiromichi Take, Sumio Miyazaki, Jun Okamura. (2001) Long-Term Outcome of Treatment With Protocols AL841, AL851, and ALHR88 in Children With Acute Lymphoblastic Leukemia: Results Obtained by the Kyushu-Yamaguchi Children’s Cancer Study Group. International Journal of Hematology 73:3, 369-377
CrossRef111
Anders Grahn??n, Mats O. Karlsson. (2001) Concentration-Controlled or Effect-Controlled Trials. Clinical Pharmacokinetics 40:5, 317-325
CrossRef112
H.J.G. Desir??e van den Bongard, Ron A. Math??t, Jos H. Beijnen, Jan H.M. Schellens. (2000) Pharmacokinetically Guided Administration of Chemotherapeutic Agents. Clinical Pharmacokinetics 39:5, 345-367
CrossRef113
Jonas Bergh, Tom Wiklund, Björn Erikstein, Elisabet Lidbrink, Henrik Lindman, Per Malmström, Pirkko Kellokumpu-Lehtinen, Nils-Olof Bengtsson, Gustaf Söderlund, Gun Anker, Erik Wist, Susanne Ottosson, Eeva Salminen, Per Ljungman, Harald Holte, Jonas Nilsson, Carl Blomqvist, Nils Wilking. (2000) Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. The Lancet 356:9239, 1384-1391
CrossRef114
Joaquim F. Bonal. (2000) Clinical Pharmacy in Inpatient Care. Pharmacotherapy 20:10 Part 2, 264S-272S
CrossRef115
M. G. Rots, R. Pieters, G. J. L. Kaspers, A. J. P. Veerman, G. J. Peters, G. Jansen. (2000) Classification Of Ex Vivo Methotrexate Resistance In Acute Lymphoblastic and Myeloid Leukaemia. British Journal of Haematology 110:4, 791-800
CrossRef116
E. J. Estlin, M. Ronghe, G. A. A. Burke, S. M. Yule. (2000) The Clinical and Cellular Pharmacology Of Vincristine, Corticosteroids, l-Asparaginase, Anthracyclines and Cyclophosphamide In Relation To Childhood Acute Lymphoblastic Leukaemia. British Journal of Haematology 110:4, 780-790
CrossRef117
E. J. Estlin, S. P. Lowis, A. G. Hall. (2000) Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia. British Journal of Haematology 110:1, 29-40
CrossRef118
Annick Rousseau, Pierre Marquet, Jean Debord, Christophe Sabot, G??rard Lach??tre. (2000) Adaptive Control Methods for the Dose Individualisation of Anticancer Agents. Clinical Pharmacokinetics 38:4, 315-353
CrossRef119
Holger Seidel, Anders Andersen, Jan Terje Kvaløy, Randi Nygaard, Peter J Moe, Geir Jacobsen, Bo Lindqvist, Lars Slørdal. (2000) Variability in methotrexate serum and cerebrospinal fluid pharmacokinetics in children with acute lymphocytic leukemia: relation to assay methodology and physiological variables. Leukemia Research 24:3, 193-199
CrossRef120
Chessells. (2000) THE MANAGEMENT OF HIGH-RISK LYMPHOBLASTIC LEUKAEMIA IN CHILDREN. British Journal of Haematology 108:2, 204-216
CrossRef121
Batia Stark, Rivka Sharon, Gideon Rechavi, Dina Attias, Ami Ballin, Gabriel Cividalli, Yoav Burstein, Dalia Sthoeger, Ayala Abramov, Rina Zaizov. (2000) Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia. Cancer 88:1, 205-216
CrossRef122
Ching-Hon Pui. (2000) Acute lymphoblastic leukemia in children. Current Opinion in Oncology 12:1, 3-12
CrossRef123
M. V. Relling, M. L. Hancock, G. K. Rivera, J. T. Sandlund, R. C. Ribeiro, E. Y. Krynetski, C.-H. Pui, W. E. Evans. (1999) Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S-Methyltransferase Gene Locus. JNCI Journal of the National Cancer Institute 91:23, 2001-2008
CrossRef124
Franck Odoul, Chantal Le Guellec, Jean-Pierre Lamagnère, Dominique Breilh, Marie-Claude Saux, Gilles Paintaud, Elisabeth Autret-Leca. (1999) Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach. Fundamental & Clinical Pharmacology 13:5, 595-604
CrossRef125
Mary V Relling, Jeffrey E Rubnitz, Gaston K Rivera, James M Boyett, Michael L Hancock, Carolyn A Felix, Larry E Kun, Andrew W Walter, William E Evans, Ching-Hon Pui. (1999) High incidence of secondary brain tumours after radiotherapy and antimetabolites. The Lancet 354:9172, 34-39
CrossRef126
Nicholas H. G. Holford. (1999) Target concentration intervention: beyond Y2K. British Journal of Clinical Pharmacology 48:1, 9-13
CrossRef127
Howard L. McLeod, Sally Coulthard, Angela E. Thomas, Stuart C. Pritchard, Derek J. King, Susan M. Richards, O. B. Eden, Andrew G. Hall, Brenda E. S. Gibson. (1999) Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. British Journal of Haematology 105:3, 696-700
CrossRef128
Federico Sackmann-Muriel, Marı́a Sara Felice, Pedro Alberto Zubizarreta, Elizabeth Alfaro, Marta Gallego, Jorge Rossi, Ana Marı́a Cygler. (1999) Treatment results in childhood acute lymphoblastic leukemia with a modified ALL-BFM’90 protocol: lack of improvement in high-risk group. Leukemia Research 23:4, 331-340
CrossRef129
Lennard. (1999) Therapeutic drug monitoring of antimetabolic cytotoxic drugs. British Journal of Clinical Pharmacology 47:2, 131-143
CrossRef130
Charles R. Yates, Ching-Hon Pui, William E. Evans. (1998) Pharmacodynamic Monitoring of Cancer Chemotherapy: Childhood Acute Lymphoblastic Leukemia as a Model. Therapeutic Drug Monitoring 20:5, 453-458
CrossRef131
Wood, Alastair J.J., , Pui, Ching-Hon, Evans, William E., . (1998) Acute Lymphoblastic Leukemia. New England Journal of Medicine 339:9, 605-615
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