Original Article
Systemic Exposure to Mercaptopurine as a Prognostic Factor in Acute Lymphocytic Leukemia in Children
N Engl J Med 1990; 323:17-21July 5, 1990
- Abstract
- Abstract
Background.
Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse.
Methods.
To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted.
Results.
There was a significant difference in the mean (±SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636±197 nmol per liter X minutes in those who relapsed, as compared with 2424±177 nmol per liter X minutes in those who did not (P<0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043±12,812 nmol per liter X minutes) than in those who did not (168,862±18,830 nmol per liter X minutes) (P<0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan–Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter X minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P<0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter X minutes had a significantly better prognosis than those with a lower exposure (P<0.005).
Conclusions.
Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure. (N Engl J Med 1990; 323: 17–21.)
Media in This Article
Figure 1
Relapse-free Survival in Children at Low or Standard Risk of Relapse, According to the Area under the Curve.Figure 2
Relapse-free Survival in Children at Low or Standard Risk of Relapse, According to Area under the Curve.Article Activity
- Article
During the past two decades there has been a substantial improvement in prognosis for patients with acute lymphocytic leukemia in childhood. However, despite a success rate of more than 90 percent in inducing remission, 30 to 40 percent of children relapse while receiving maintenance therapy. Such patients are much more likely to die of their disease.1
Patients with acute lymphocytic leukemia can be classified according to their prognosis as being at low, standard, or high risk of relapse (Table 1Table 1
Risk Classification of Patients with Acute Lymphocytic Leukemia.*). In many centers, maintenance therapy for children at low or standard risk (Table 1) consists of a daily oral dose of mercaptopurine (75 mg per square meter of body-surface area), and a weekly oral dose of methotrexate (20 mg per square meter). In addition, the children receive monthly pulsed doses of vincristine and prednisone.Wide variation in the bioavailability of oral mercaptopurine has recently been documented,4 suggesting that children who receive apparently similar doses of the drug per unit of body size may be exposed systemically to substantially different amounts. In a study of intravenous methotrexate, Evans and his colleagues have recently shown that children with acute lymphocytic leukemia who are exposed to relatively low concentrations of the drug because of relatively fast clearance rates are more likely to relapse during maintenance therapy.5
Further evidence for the potential importance of pharmacokinetic variability during maintenance therapy comes from studies showing that children who relapse receive significantly lower cumulative doses of chemotherapy.6
In this prospective study we assessed the correlation between systemic exposure to mercaptopurine, as expressed in terms of the area under the concentration-time curve, and the relapse rate in children with acute lymphocytic leukemia who were at low or standard risk of relapse.
Methods
Patients
After obtaining Institutional approval and written parental consent, we prospectively followed 30 children given a diagnosis of acute lymphocytic leukemia between 1980 and 1986 and at low or standard risk according to the accepted criteria (Table 1), on the basis of age, white-cell count at diagnosis, presence of lymphoma syndrome, and bone marrow features, according to the FAB (French-American-British) classification.2 The risk category dictated the protocols of therapy, with the treatments for those at low risk and those at standard risk differing only in the use of cranial irradiation and an earlier consolidation phase for those at standard risk.
Pharmacokinetic Studies
The pharmacokinetics of mercaptopurine during maintenance therapy was studied in the patients after an overnight fast, with oral doses of the drug of 50 to 75 mg per square meter. One-milliliter blood samples were drawn through an indwelling antecubital catheter just before the dose was given and 30, 60, 90, 120, 180, 240, 300, and 360 minutes later. Samples were immediately centrifuged, and the serum was frozen until it was analyzed, within one week.
Mercaptopurine concentrations were measured by high-performance liquid chromatography.7 The analytical procedure was essentially that of Whalen et al.,7 with minor modifications. Briefly, the methanol in the mobile phase was replaced by acetonitrile, and the mobile phase was renewed every two days. Patient samples were centrifuged promptly, and the plasma was kept on ice in the dark until extraction; a delay of one to two hours did not result in a marked loss of mercaptopurine. Extraction was carried out as previously described until the 600 μl of organic extract was transferred to a second tube. This extract may be stored at -20°C; stability for more than six months has been confirmed.
On the day of assay, the extract was briefly warmed to room temperature and back-extracted into 100 μl of 0.1 M hydrochloric acid; 70 μl was promptly injected onto the column. The instruments were those described, except for a variable-wavelength spectrophotometer with a deuterium lamp, set at 313 nm and 0.005 absorbance unit full scale (481 Lambda Max, Waters Scientific, Mississauga, Ont., Canada). The limit of sensitivity (three times base-line noise) was 2 μg per liter.
The coefficient of variation of this test is less than 5 percent within the range measured in the present study. The measurements were performed once during maintenance therapy in 14 patients, twice in 8, and three times in 8. When more than one measurement was performed, the mean area under the curve was used for subsequent calculations.
The area under the concentration-time curve was calculated with use of the Niazi program on an HP91 calculator (Hewlett-Packard, Portland, Oreg.); extrapolation to infinity was performed with use of the elimination half-life in each patient, as generated by the ADAPT program.8
The standard area under the curve was defined as that produced by 1 mg of the drug per square meter, in order to correct for the slightly different doses per square meter received by the children.
For each child, the mean maintenance doses of mercaptopurine and methotrexate were calculated by adding all doses per square meter taken during maintenance therapy and dividing the cumulative dose by the length of the maintenance period (in days). In calculating mean doses we look into account changes in body weight and height that occurred during the years of maintenance therapy. Systemic exposure to mercaptopurine was then calculated as the standard area under the curve times the mean daily maintenance dose.
The total number of days of interrupted mercaptopurine and methotrexate therapy, as well as the number of interruptions, was calculated from the medical record for each child. Similarly, mean white-cell and neutrophil counts for the maintenance period were calculated for each child on the basis of the values measured during the monthly clinic visits.
Statistical Analysis
Differences in laboratory and pharmacokinetic values between children who relapsed and those who did not were compared with use of the two-tailed Student t-test for unpaired results. The survival of children stratified according to small and large standard areas under the curve of mercaptopurine or systemic exposure to the drug was analyzed with the Kaplan–Meier method, and differences were Studied with the MantelHaenszel method. All data are presented as means ±SEM.
Measurement of Xanthine Oxidase Activity
The low oral bioavailability of mercaptopurine is attributed to first-pass metabolism of the drug by intestinal and hepatic xanthine oxidase.9 The inhibition of this enzyme by allopurinol has been shown to result in absolute bioavailability (that is, an area under the curve similar to that achieved with the same dose given intravenously).
To examine whether variability in xanthine oxidase activity contributes to the observed variability in the systemic exposure to mercaptopurine, we measured xanthine oxidase activity using caffeine as a source of substrate. Caffeine is metabolized by different enzymes, one of which is xanthine oxidase. The urinary ratio of l-methyluric acid to l-methylxanthine after the administration of caffeine (250 ml of Coca-Cola) has been shown to reflect xanthine oxidase activity and to correlate with the endogenous rate of production of uric acid by the enzyme.10
For the correlation between mercaptopurine kinetics and xanthine oxidase activity, 10 additional patients with acute lymphocytic leukemia in remission were studied during maintenance therapy for 5 to 48 months (median, 12.5). There were seven girls and three boys, and their ages varied from 3.6 to 16 years (median, 12.5). Nine of them received oral mercaptopurine daily and intravenous methotrexate every second week; one received oral methotrexate. Other drugs included vincristine and prednisone given as monthly pulsed doses and trimethoprim–sulfamethoxazole given daily. Only three patients received their full dose of mercaptopurine; in the remaining seven the dose was reduced because of clinically important myelotoxicity. The dose was reduced by 20 to 30 percent in two patients, by 40 percent in one patient, and by 50 percent or more in four patients. Full doses of methotrexate were given to seven patients, and reduced doses to three. One patient received 85 percent of the dose, and two received between 70 and 80 percent of the dose. All the patients received a full dose of vincristine and prednisone. A second group of 36 children with acute lymphocytic leukemia was studied to establish the relation between the peak concentration of mercaptopurine and the area under the concentration-time curve.
All the children with acute lymphocytic leukemia were studied after they had fasted overnight. Mercaptopurine, trimethoprim–sulfamethoxazole, and other drugs were withheld for 24 to 36 hours before the study was conducted. The last dose of methotrexate was given at least 15 days before the study. All the patients had either an angiographic or a butterfly catheter inserted in an antecubital vein. Oral mercaptopurine was given in a dose of 75 mg per square meter. Blood samples to determine mercaptopurine concentrations were drawn just before the test dose was given and 30, 60, 90, and 120 minutes after. Blood samples were processed and mercaptopurine measured as described above. After the 60-minute sample, the children were served breakfast. The study, with the same test dose, was repeated in each child within two months.
The second group consisted of 36 children with acute lymphocytic leukemia who received from 20 to 75 mg of mercaptopurine per square meter after an overnight fast. Blood samples were drawn just before the dose was administered and then 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 420 minutes later. Serum was immediately centrifuged and frozen at -20°C until analyzed, within seven days. The elimination half-life was calculated by fitting the data with use of the nonlinear ADAPT program.8 The area under the concentration-time curve was generated from the same program. The correlation between peak concentration and the area under the curve was calculated with least-squares regression analysis and used to generate the area under the curve in the 10 tested children.
The children were asked to drink 300 ml (a 10-oz can) of "Classic" Coke between noon and 3 p.m. on the day before the study. They collected the first urine sample the next morning (the day of the study). Aliquots of 10 ml were mixed with 200 mg of ascorbic acid to adjust the pH to 3.5. The specimens were then frozen until analyzed by the technique of high-performance liquid chromatography described by Grant and coworkers.10 Xanthine oxidase activity was expressed as the ratio between l-methyluric acid and l-methylxanthine. As a control group for xanthine oxidase activity, 14 siblings of the children with leukemia were studied in a similar manner.
Results
Pharmacokinetic Studies
Of the 30 enrolled children, 7 were excluded from analysis because of violation of their protocol: 5 received methotrexate intravenously, and 2 received daunorubicin. Of the 23 patients who could be evaluated, 3 of the 11 at low risk and 7 of the 12 at standard risk have relapsed (Table 2Table 2
Clinical and Pharmacokinetic Characteristics of Children at Low or Standard Risk of Relapse, According to Whether a Relapse Occurred.*).Those who relapsed did not differ from those who did not relapse in age, hemoglobin level at diagnosis, white-cell count during maintenance therapy, polymorphonuclear-cell count, mean dose of mercaptopurine or methotrexate, number of interruptions of therapy with these drugs, or total number of days with no therapy because of interruptions (Table 2).
There were significant differences between the children who relapsed and those who did not in the standard area under the curve achieved by a dose of 1 mg of mercaptopurine per square meter, in systemic exposure to mercaptopurine (the standard area under the curve times the mean dose of mercaptopurine), and in systemic exposure to mercaptopurine during the first 100 days of therapy (the standard area under the curve times the mean dose of mercaptopurine during the first 100 days of maintenance therapy) (Table 2). The same differences prevailed when patients at low risk and those at standard risk were analyzed separately (Table 3Table 3
Pharmacokinetic Values in Children with Acute Lymphocytic Leukemia Who Relapsed and Those Who Did Not, According to Risk Group.*).Relapse-free survival correlated significantly with the standard area under the curve (Fig. 1Figure 1
Relapse-free Survival in Children at Low or Standard Risk of Relapse, According to the Area under the Curve.) and with mean systemic exposure to mercaptopurine (Fig. 2Figure 2Relapse-free Survival in Children at Low or Standard Risk of Relapse, According to Area under the Curve.). Children with areas under the curve of less than 300 ng per milliliter X minutes (1974 nmol per liter X minutes) had a significantly lower chance of relapse-free survival (P<0.01 by MantelHaenszel test). Children having mean daily systemic exposure of 21,000 ng per milliliter X minutes (137,970 nmol per liter X minutes) or more had a significantly lower risk of relapse (P<0.005).Table 4Table 4
Xanthine Oxidase Activity and Area under the Curve of Mercaptopurine in Children with Acute Lymphocytic Leukemia.* shows the standard areas under the curve and xanthine oxidase activity in the 10 children tested. There was a good correlation between the peak concentration and the area under the concentration-time curve of mercaptopurine; the best fit is described by the formula Y = 529X + 41,115, where Y is the area under the curve and X is the units of concentration (r = 0.85, P<0.0001). There was a fourfold difference in the areas under the curve achieved by a standard dose of mercaptopurine (959 to 4093 nmol per liter per minute). The enzyme activity measured by the ratio between l-methyluric acid and l-methylxanthine varied threefold (0.6 to 1.88). Within this range, variability between patients in xanthine oxidase activity was between 0 and 211 percent. There was variability of 1 to 167 percent in the areas under the curve of mercaptopurine. There was no correlation between the standard area under the curve of mercaptopurine and xanthine oxidase activity. Within the two months of the repeated studies there was a significant correlation between the calculated areas under the curve (r = 0.65, P<0.01).Xanthine oxidase activity in the children with leukemia did not differ from that in their siblings (mean ratios between l-methyluric acid and l-methylxanthine, 0.947±0.063 and 0.927±0.044, respectively).
Discussion
A large number of biologic markers have been shown to predict the risk of relapse and mortality in childhood acute lymphocytic leukemia. Some of these are used clinically (Table 1) in an attempt to intensify chemotherapy and radiation treatment in children with a poorer prognosis. However, once assigned to a treatment protocol, children receive similar therapy during both the induction and maintenance phases.
During the past decade a large body of evidence has been accumulated to suggest that variability between patients in the pharmacokinetics of maintenance chemotherapy may be clinically important in acute lymphocytic leukemia. Zimm et al. have shown that in many children the oral bioavailability of mercaptopurine can be very low.4 We described a case in which no detected levels of mercaptopurine could be measured in a child with acute lymphocytic leukemia on two different occasions of supervised administration of the drug.11 The variability in systemic exposure to mercaptopurine may stem from a combination of differences in the rates of absorption, distribution, and elimination of the drug. Because the oral bioavailability of mercaptopurine can be both low and variable, it is conceivable that over several years of maintenance therapy some patients may be exposed to substantially lower amounts of the drug than others, despite similar oral doses per unit of body size. In view of similar data on the disposition of methotrexate (patients who have lower concentrations have a higher risk of relapse5), we wished to ascertain whether children exposed to lower systemic concentrations of mercaptopurine over time have a poorer prognosis.
Our data reveal a fivefold variation in systemic exposure to mercaptopurine, as evidenced by the variation in the area under the curve achieved by a standard dose of the drug. Both children who had relapses and those who did not were given mean doses of mercaptopurine and methotrexate very close to those recommended in the protocol, and the slight decrease in the dose of mercaptopurine in both groups was attributed to the interruption of therapy. On average, patients who relapsed, both those at low risk and those at standard risk, had only two thirds of the area under the curve produced by the patients who did not relapse, despite similar oral doses.
Recent work by Lennard and Lilleyman12 has shown correlation between the intracellular accumulation of active metabolites of mercaptopurine and the rate of relapse; it is conceivable that among several mechanisms that control such intracellular accumulation, plasma pharmacokinetics may have an important role.
Previous studies have shown that complete inhibition of xanthine oxidase totally eliminates the first-pass metabolism of mercaptopurine, resulting in its complete bioavailability. However, our findings indicate that the variation in enzyme activity in patients with acute lymphocytic leukemia is not likely to cause the variation seen in mercaptopurine pharmacokinetics. This antimetabolite is coadministered with methotrexate for several years, and methotrexate is known to inhibit xanthine oxidase activity. A recent study has revealed that levels of mercaptopurine are slightly higher when the drug is given with methotrexate rather than alone.13 Our data do not reveal less xanthine oxidase activity in children with acute lymphocytic leukemia who receive methotrexate intravenously than in their healthy siblings, and the data agree with our recent observations that higher systemic exposure to methotrexate does not result in high areas under the curve of mercaptopurine.14
Our data indicate that when mercaptopurine measurements are repeated within two months in patients receiving similar doses, the areas under the curve have a general tendency to reach an average at the same values; however, variation within patients may be as high as 50 percent. Therefore, any future estimate of exposure over time will have to include the repetition of such measurements every several months.
The results of the present study suggest that the ability of a child to achieve a suitable area under the curve of mercaptopurine should be studied at the outset of maintenance therapy and that the individual maintenance dose should be tailored to achieve an appropriate systemic exposure. Although our cohort was relatively small, a daily systemic exposure (the area under the curve achieved by a dose of 1 mg per square meter times the mean daily dose) of less than 21,000 ng per milliliter X minutes (137,970 nmol per liter X minutes) or a standard area under the curve of less than 300 ng per milliliter X minutes (1974 nmol per liter X minutes) was associated with a significantly poorer prognosis. Prospective studies are needed to confirm whether increasing the dose of mercaptopurine to achieve a targeted systemic exposure will improve the clinical outcome.
Supported in part by the Leukemia Research Fund, Toronto. Dr. Koren is a Career Scientist of the Ontario Ministry of Health.
Source Information
From the Divisions of Clinical Pharmacology (G.K., G.F., J. Klein) and Hematology/Oncology (H.S., A.M.L., J. Kapelushnik, M.G.), the Departments of Pediatrics (G.K., G.F., H.S., J. Kapelushnik, M.G.) and Biochemistry (E.G., S.S.), and the Research Institute (G.K., S.S.), Hospital for Sick Children, Toronto; and the Departments of Pediatrics (G.K., G.F., H.S., J. Kapelushnik, M.G.), Pharmacology (G.K., S.S.), and Biochemistry (S.S.), University of Toronto. Address reprint requests to Dr. Koren at the Division of Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
- References
References
1
Poplack
Web of Science | Medline2
Van Eys
CrossRef | Web of Science | Medline3
Bennett
CrossRef | Web of Science | Medline4
Zimm
Full Text | Web of Science | Medline5
Evans
Full Text | Web of Science | Medline6
Peeters
CrossRef | Web of Science | Medline7
Whalen
CrossRef | Web of Science | Medline8
D'Argenio
CrossRef | Medline9
Zimm
CrossRef | Web of Science | Medline10
Grant
CrossRef | Web of Science | Medline11
Sulh
CrossRef | Web of Science | Medline12
Lennard
CrossRef | Web of Science13
Balis
CrossRef | Web of Science | Medline14
Koren
CrossRef | Medline
- Citing Articles (29)
Citing Articles
1
Smita Bhatia. (2011) Disparities in cancer outcomes: Lessons learned from children with cancer. Pediatric Blood & Cancer 56:6, 994-1002
CrossRef2
Wendy Landier. (2011) Adherence to Oral Chemotherapy in Childhood Acute Lymphoblastic Leukemia: An Evolutionary Concept Analysis. Oncology Nursing Forum 38:3, 343-352
CrossRef3
Ahna L. H. Pai, Dennis Drotar, Eric Kodish. (2008) Correspondence Between Objective and Subjective Reports of Adherence Among Adolescents With Acute Lymphoblastic Leukemia. Children's Health Care 37:3, 225-235
CrossRef4
T L Lin, M S Vala, J P Barber, J E Karp, B D Smith, W Matsui, R J Jones. (2007) Induction of acute lymphocytic leukemia differentiation by maintenance therapy. Leukemia 21:9, 1915-1920
CrossRef5
Michelle T. Pritchard, Phyllis N. Butow, Michael M. Stevens, John A. Duley. (2006) Understanding Medication Adherence in Pediatric Acute Lymphoblastic Leukemia: A Review. Journal of Pediatric Hematology/Oncology 28:12, 816-823
CrossRef6
Yukari Sato, Yayoi Ishikawa, Hiroaki Matsuura, Kohei Uosaki, Fumio Mizutani, Osamu Niwa. (2005) Highly-Sensitive Determination of 6-Mercaptopurine and Its Metabolites by Electrochemical Reductive Desorption Measurements. Electroanalysis 17:11, 965-968
CrossRef7
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
CrossRef8
Christine M. Formea, Heather Myers-Huentelman, Rongling Wu, Janet Crabtree, Shiro Fujita, Alan Hemming, Alan Reed, Richard Howard, Janet L. Karlix. (2004) Thiopurine S-Methyltransferase Genotype Predicts Azathioprine-Induced Myelotoxicity in Kidney Transplant Recipients. American Journal of Transplantation 4:11, 1810-1817
CrossRef9
Richard Aplenc, Beverly Lange. (2004) Pharmacogenetic determinants of outcome in acute lymphoblastic leukaemia. British Journal of Haematology 125:4, 421-434
CrossRef10
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
CrossRef11
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
CrossRef12
Federico Innocenti, Romano Danesi, Claudio Favre, Margherita Nardi, Maria Christina Menconi, Antonello Di Paolo, Guido Bocci, Stefano Fogli, Cecilia Barbara, Serena Barachini, Gabriella Casazza, Pierantonio Macchia, Mario Del Tacca. (2000) Variable Correlation Between 6-Mercaptopurine Metabolites in Erythrocytes and Hematologic Toxicity: Implications for Drug Monitoring in Children With Acute Lymphoblastic Leukemia. Therapeutic Drug Monitoring 22:4, 375-382
CrossRef13
Robert C. W. Lau, Doreen Matsui, Mark Greenberg, Gideon Koren. (1998) Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia. Medical and Pediatric Oncology 30:2, 85-90
CrossRef14
Howard L. McLeod. (1997) Therapeutic drug monitoring opportunities in cancer therapy. Pharmacology & Therapeutics 74:1, 39-54
CrossRef15
Zeba Aziz, Maliha Zahid, Rashid Mahmood, Sajid Maqbool. (1997) Modified BFM protocol for childhood acute lymphoblastic leukemia: A retrospective analysis. Medical and Pediatric Oncology 28:1, 48-53
CrossRef16
Federico Innocenti, Romano Danesi, Antonello Paolo, Barbara Loru, Claudio Favre, Margherita Nardi, Guido Bocci, Denise Nardini, Pierantonio Macchia, Mario Tacca. (1996) Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate. Cancer Chemotherapy and Pharmacology 37:5, 409-414
CrossRef17
Alvin Zipursky. (1996) Hematology and Oncology at the Hospital for Sick Children. Pediatric Hematology-Oncology 13:5, 391-395
CrossRef18
Jorge E. Cortes, Hagop M. Kantarjian. (1995) Acute lymphoblastic leukemia a comprehensive review with emphasis on biology and therapy. Cancer 76:12, 2393-2417
CrossRef19
Donald H. Mahoney, Bruce M. Camitta, Brigid G. Leventhal, Jonathan J. Shuster, Curt J. Civin, Dorothy J. Ganick, Stephen J. Lauer, C. Philip Steuber, Barton A. Kamen. (1995) 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 75:10, 2623-2631
CrossRef20
J.S. Lilleyman, L. Lennard. (1994) Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. The Lancet 343:8907, 1188-1190
CrossRef21
Salvatore P. Dibenedetto, Vincenzo Guardabasso, Rosalia Ragusa, Andrea Di Cataldo, Vito Miraglia, Salvatore D'Arnico, Anna M. Ippolito. (1994) 6-Mercaptopurine Cumulative Dose: A Critical Factor of Maintenance Therapy in Average Risk Childhood Acute Lymphoblastic Leukemia. Pediatric Hematology-Oncology 11:3, 251-258
CrossRef22
Kathleen A. Skoglund, Stefan Söderhäll, Olof Beck, Curt Peterson, Mona Wennberg, Salah Hayder, Olle Björk. (1994) Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate. Medical and Pediatric Oncology 22:3, 187-193
CrossRef23
L. Lennard. (1992) The clinical pharmacology of 6-mercaptopurine. European Journal of Clinical Pharmacology 43:4, 329-339
CrossRef24
Kenneth Lucas, Mary Jean Gula, Julie Blatt. (1992) Relapse in Acute Lymphoblastic Leukemia as a Function of White Blood Cell and Absolute Neutrophil Counts During Maintenance Chemotherapy. Pediatric Hematology-Oncology 9:2, 91-97
CrossRef25
Gideon Koren, Gianmario Ferrazzini, Hassan Sohl, Isabelle Robieux, David Johnson, Esther Giesbrecht. (1992) Chronopharmacology of Methotrexate Pharmacokinetics in Childhood Leukemia. Chronobiology International 9:6, 434-438
CrossRef26
R.P. Gale, A. Buttunni. (1991) Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. The Lancet 338:8778, 1315-1318
CrossRef27
Jan Liliemark, Birgitta Pettersson, MÅRten Järnmark, Curt Peterson. (1991) On the Cellular Pharmacokinetics of 6-Thioguanine in Acute Myelogenous Leukemia. Leukemia & Lymphoma 4:4, 271-276
CrossRef28
Kjeld Schmiegelow. (1991) Prognostic Significance of Methotrexate and 6-Mercaptopurine Dosage During Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukemia. Pediatric Hematology-Oncology 8:4, 301-312
CrossRef29
(1990) Pharmacokinetics of Mercaptopurine in Children with Acute Lymphocytic Leukemia. New England Journal of Medicine 323:22, 1565-1566
Full Text
- Letters
