Affiliations of authors: M. V. Relling, E. Y. Krynetski, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, and College of Pharmacy, University of Tennessee, Memphis; M. L. Hancock, Department of Biostatistics and Epidemiology, St. Jude Children's Research Hospital, and Department of Preventive Medicine, University of Tennessee; G. K. Rivera, J. T. Sandlund, R. C. Ribeiro, C.-H. Pui, Department of Hematology/Oncology, St. Jude Children's Research Hospital, and College of Medicine, University of Tennessee; W. E. Evans, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, and Colleges of Medicine and Pharmacy, University of Tennessee.
Correspondence to: Mary V. Relling, Pharm.D., St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105 (e-mail: mary.relling{at}stjude.org).
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ABSTRACT |
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INTRODUCTION |
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TPMT exhibits genetic polymorphism in all large ethnic groups studied to date, including Caucasians, Africans, African-Americans, and Asians. Approximately one in 300 inherit two mutant TPMT alleles and are TPMT deficient, and about 5%-10% are heterozygotes at the TPMT gene locus and have intermediate enzyme activity (9-11). The rare TPMT-deficient individual probably accounts for most of the thiopurine-intolerant patients who were previously considered to have "idiosyncratic" toxic effects. Little is known, however, about thiopurine tolerance in TPMT heterozygotes, who constitute approximately 10% of the patients who receive these medications. If these heterozygotes have intermediate intolerance to thiopurines, due to their intermediate level of TPMT enzyme activity, this would provide a compelling rationale for routinely assessing TPMT phenotype or genotype in all patients before initiating thiopurine therapy. This study was, therefore, undertaken to characterize 6-mercaptopurine metabolism and tolerance in acute lymphoblastic leukemia patients with each TPMT phenotype and to determine whether TPMT heterozygotes differ from patients who are homozygous wild-type or homozygous deficient at the TPMT gene locus. (Throughout this article, abbreviations referring to the gene encoding TPMT enzyme are italicized.)
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PATIENTS AND METHODS |
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Children with acute lymphoblastic leukemia were treated on St. Jude Children's
Research Hospital Protocol Total XII after written informed consent was obtained from the
parent or guardian (as appropriate). All research procedures were approved by our institutional
review board for ethical standards. Therapy has been described previously (12) and is outlined in Fig. 1. In brief, remission induction
therapy consisted of prednisone, vincristine, L-asparaginase, daunorubicin, teniposide,
and cytarabine given over a 4-week period. Patients were then randomly assigned to receive
"pulse" therapy with high-dose methotrexate at a dose of 1.5 g/m2
over a 24-hour period in the conventional group and individualized to achieve a target
area-under-the-concentration Z time (AUC) curve in the targeted group alternating with
teniposide plus cytarabine [see (12) and Fig. 1
for details] every 6 weeks, with doses based on either body surface area or
doses individualized on the basis of pharmacokinetic parameters. During other weeks, patients
received weekly methotrexate at a dose of 40 mg/m2 (intravenously or
intramuscularly) and daily oral 6-mercaptopurine at a dose of 75 mg/m2, for a total
of 2.5 years. Complete blood cell counts were obtained weekly. Chemotherapy was given every
week, provided that the absolute neutrophil count was greater than 300 cells/µL and that the
patient did not exhibit other complications, such as mucositis, fever, or hepatotoxicity. If toxic
effects or neutropenia in any given week precluded administration of chemotherapy, the scheduled
therapy with high-dose methotrexate or teniposide plus cytarabine was delayed until the patient
recovered, whereas the scheduled low-dose methotrexate plus 6-mercaptopurine was omitted
altogether.
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Erythrocyte concentrations (pmol/8 x 108 erythrocytes) of thioguanine nucleotides and of thioinosine monophosphate were measured by hydrolyzing erythrocyte lysates with acid and heat to the respective thioguanine and 6-mercaptopurine bases, as previously described (13). Methylated metabolites of methylthioinosine monophosphate were measured by hydrolyzing to methyl-6-mercaptopurine in a subset of patients in a separate high-pressure liquid chromatography (HPLC) assay (14). Patients were scheduled to have thiopurine metabolite concentrations measured in erythrocytes at weeks 7, 31, 55, 82, 106, and 120 of continuation therapy. At each of these times, the treatment protocol specified that patients should have received daily 6-mercaptopurine for at least the prior 5 weeks. Patients were instructed to take their 6-mercaptopurine on an empty stomach in the evening, and all samples were obtained at least 8 hours after the preceding 6-mercaptopurine dose. Because of acute toxicity, noncompliance, or other unusual reasons (e.g., misunderstanding directions, vacations, etc.), some patients might not have received 6-mercaptopurine daily during this time period. Lack of dosing was not a reason for not obtaining a sample at the scheduled time. For each sample, a research nurse reviewed with the patient and his/her guardian the dosing history of 6-mercaptopurine for the preceding 6 weeks and documented her subjective assessment of compliance, the time of day that the child had taken 6-mercaptopurine in the prior dosing interval, and the reason for obtaining the erythrocyte sample (specified by the protocol or for suspected toxicity or noncompliance). Ninety-seven percent of the samples were obtained as specified by the protocol, with 3% for toxicity or suspected noncompliance. Only samples obtained at times specified by the protocol were included in statistical analyses to assess pharmacologic measures versus toxicity or sex; all samples were eligible for inclusion for the assessment of thioguanine nucleotide concentrations versus compliance.
Plasma AUC-Versus-Time Curves
Plasma AUCs for methotrexate, cytarabine, and teniposide were measured in patients for every course of pulse chemotherapy, as previously described (12).
TPMT Phenotype and Genotype
Erythrocyte TPMT activity was measured by use of blood collected in heparinized tubes, as previously described (11). Erythrocyte TPMT activity was measured greater than or equal to 90 days following the last erythrocyte transfusion in 109 patients during their continuation therapy (1-843 days following achievement of complete remission) and in 45 patients after completion of continuation therapy (499-1602 days following achievement of complete remission). If a patient had TPMT measured while on therapy, the lowest value was used to assign phenotype as follows: less than or equal to 5 U/mL of packed erythrocytes, homozygous mutant; greater than 5 but less than 13.5 U/mL of packed erythrocytes, heterozygotes; and greater than or equal to 13.5 U/mL of packed erythrocytes, wild-type. If the TPMT was measured only after completion of continuation therapy, the lowest value was used to assign phenotype as follows: less than or equal to 5 U/mL of packed erythrocytes, homozygous mutant; greater than 5 but less than 10.2 U/mL of packed erythrocytes, heterozygous; and greater than or equal to 10.2 U/mL of packed erythrocytes, homozygous wild-type. If patients did not have TPMT activity measured either during or after completion of therapy but had erythrocyte thioguanine nucleotide concentrations below the 90th percentile for maximum thioguanine nucleotides for the entire group (1120 pmol/8 x 108 erythrocytes), they were considered to be wild-type; above that level, they were considered to have been heterozygotes. All 26 children who had no measures of TPMT activity were classified as wild-type, whereas all of the children classified as heterozygotes or mutant had their TPMT values measured to substantiate that classification. The average thioguanine nucleotides among the children assigned to the wild-type group on the basis of low thioguanine nucleotides were not different from the average thioguanine nucleotides in patients who were classified as wild-type on the basis of measured TPMT activity (P = .857). Of the 182 patients who entered remission, either thioguanine nucleotides or TPMT activity was evaluable in 180 patients (for purposes of assigning phenotype). TPMT genotype was determined in a subset of patients with each phenotype by use of leukocyte DNA and polymerase chain reaction-based methods specific for the TPMT *2, *3A, *3B, and *3C mutant alleles, as previously described (15).
Doses of Continuation Chemotherapy
A patient-specific treatment calendar, specifying doses of chemotherapy for all 120 weeks of
continuation therapy, was kept in the patient's medical record and updated regularly by
clinical and research staff. All pulses of high-dose methotrexate, teniposide, and cytarabine were
administered at St. Jude Children's Research Hospital. The exact doses and reasons for any
deviations from the planned protocol therapy for every dose of every antileukemic medication
were compiled into an institutional database. One of the patients with extreme intolerance to
continuation chemotherapy was identified to be homozygous deficient for TPMT (3). A drastic dose reduction (from 75 mg/m2 per day to 10 mg/m2 given 3 days per week) resulted in excellent tolerance and allowed administration of full
doses of the remainder of continuation therapy. From that point forward, if clinicians asked for a
pharmacokinetic consultation on the TPMT status and thioguanine nucleotide concentrations of a
patient experiencing unusual toxicity to therapy, consultations on thiopurine status were provided.
Doses of 6-mercaptopurine were decreased gradually in patients with likely heterozygous status
until reaching a dose that resulted in the desired degree of leukopenia (<4000 cells/µL but
absolute neutrophil count >300 cells/µL) and allowed full doses of other antileukemic
agents. Doses were decreased only in those patients experiencing myelosuppression. In addition,
the 6-mercaptopurine dose was increased after week 60 of continuation therapy in case of
persistently high leukocyte counts (4000/µL and absolute neutrophil counts
1500/µL for 4 consecutive weeks). No dose changes in weekly methotrexate were
dictated by the protocol.
Evaluation of Toxic Effects
For each week that therapy was withheld because of toxicity, the primary reason was documented (e.g., neutropenia, hepatotoxicity, thrombocytopenia, etc.). Hospitalizations for fever or infection were also considered to be toxic effects of therapy. If the 6-mercaptopurine dose was reduced from the protocol-specified dose of 525 mg/m2 per week (75 mg/m2 per day), toxicity was assessed only for the time period up until a dose reduction was required.
Statistical Analysis
The interpatient coefficient of variation for average values of the 6-mercaptopurine metabolites (thioguanine nucleotides, thioinosine monophosphates, and methylthioinosine monophosphate) as well as TPMT activity was computed as the ratio of the standard deviation (SD) to the mean from all contributed measurements and expressed as a percentage. The average intrapatient coefficient of variation was computed as the ratio of the SD to the mean for all measurements contributed by an individual patient and then averaged across all patients and expressed as a percentage.
Generalized estimating equations for longitudinal correlated binary data (16) were used to test for differences between heterozygotes and homozygous wild-types with respect to the incidence of primary toxic effects, including missed doses of mercaptopurine, hospitalizations for fever and neutropenia, neutropenia, or episodes of hepatotoxicity or thrombocytopenia. For each of the end points, each week of continuation therapy was coded with a binary variable representing the occurrence of the toxicity of interest.
Differences in doses and areas under the time-concentration curves for high-dose methotrexate, teniposide, and cytarabine among the three TPMT phenotypes were modeled and compared with the method of Diggle et al. (16) to account for repeated measures with missing data. Each of the models included treatment arm as a covariate. The same model was used to test for differences in thioguanine nucleotide levels between the sexes, between compliant and noncompliant patients, and between patients whose TPMT phenotype was assigned on the basis of thioguanine nucleotide levels and those assigned on the basis of measured TPMT activity and to test for differences in 6-mercaptopurine doses and TPMT activity between the sexes. Fisher's exact test was used to test for an association of TPMT phenotype with sex.
The cumulative incidences of patients who required 6-mercaptopurine dose adjustments to prevent toxicity were estimated for each of the three TPMT phenotypes by the method of Kalbfleisch and Prentice (17) and were compared with Gray's test (18). All statistical tests were two-sided.
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RESULTS |
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Fig. 2 is a frequency histogram showing the average (within a patient)
of all thioguanine nucleotide concentrations measured immediately after a period during which
patients received at least 65 mg/m2 per day for 12 of the preceding 14 days.
Erythrocyte concentrations of thioguanine nucleotides were higher and those of methylthioinosine
monophosphate were lower among TPMT homozygous-deficient patients, while metabolite
concentrations were intermediate among heterozygotes (Fig. 3
). There
was a statistically significant (P<.01) inverse relationship between concentration of
thioguanine nucleotides (Fig. 4
) and TPMT, with an average (SD)
concentration (pmol/8 x 108 erythrocytes) of 417 (179), 963 (752), and 3565
(1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and
homozygous-deficient (n = 2) patients, respectively. There was also a positive relationship
between thioinosine monophosphate and TPMT (P<.01).
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Neither thioguanine nucleotides (P = .24) nor prescribed 6-mercaptopurine dose (P = .49; not shown) differed between boys and girls. The average (SD) TPMT value did not differ statistically (P = .22) in boys (17.1 ± 5.5 U/mL of packed erythrocytes) versus girls (18.2 ± 5.2 U/mL of packed erythrocytes), nor was there a statistically significant difference in the proportion of boys versus girls who were TPMT heterozygous or homozygous deficient (14 [14%] of 98 boys versus five [6.1%] of 82 girls) (P = .091).
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DISCUSSION |
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This study has shown that, at conventional 6-mercaptopurine doses of 75 mg/m2
per day, TPMT heterozygotes accumulate approximately twofold more thioguanine nucleotides in
their erythrocytes when compared with homozygous wild-type patients. This difference in
thioguanine nucleotide accumulation translated into a fivefold greater cumulative incidence of
6-mercaptopurine dose-limiting toxicity in TPMT heterozygotes compared with TPMT wild-type
patients (Fig. 6; 35% versus 7% cumulative incidence).
Consistent with this finding, TPMT wild-type patients tolerated 75 mg/m2 per day of
6-mercaptopurine during 84% of scheduled therapy compared with 65% in
heterozygous patients and only 7% in TPMT-deficient patients (Fig. 5
). These data indicate that no TPMT-deficient patient will tolerate full-dose
6-mercaptopurine and that TPMT heterozygotes will require 6-mercaptopurine dose reductions
significantly more often than TPMT-homozygous wild-type patients. While it is true that clinicians
were encouraged to decrease the 6-mercaptopurine dose alone (rather than the methotrexate
doses) in patients who had experienced toxicity, blood cell counts ultimately determined how
much 6-mercaptopurine patients were able to tolerate. Thus, the polymorphic nature of the human
TPMT gene identifies about 10% of patients who are at higher risk of acute
6-mercaptopurine toxicity because of an inherited deficiency in 6-mercaptopurine metabolism.
It is interesting that the average dose eventually tolerated by TPMT heterozygotes was only 15% lower than the protocol dose tolerated by the patients with the wild-type TPMT phenotype, despite accumulating twice as high a concentration of thioguanine nucleotides in their red blood cells. The ability of patients with TPMT defects (homozygous deficient or heterozygous) to tolerate higher thioguanine nucleotide levels than those with wild-type TPMT (3,7,22) may be related to the substantially lower methylthioinosine monophosphate levels in these patients, since methylthioinosine monophosphate can be cytotoxic via inhibition of de novo purine synthesis (23). Consistent with this notion, very few patients with the wild-type TPMT phenotype could tolerate 6-mercaptopurine doses above 75 mg/m2 per day (in our setting of relatively intense methotrexate dosing at 40 mg/m2 per week parenterally), possibly because of high methylthioinosine monophosphate concentrations. Moreover, dose escalation can cause neutropenia, necessitating withholding of therapy until blood cell counts recover, which may compromise acute lymphoblastic leukemia outcome (24). In addition to being at higher risk of acute hematopoietic toxic effects, as described herein, patients with TPMT defects may also be at higher risk for irradiation-associated brain tumors (25) and etoposide-induced myeloid leukemia (26). Together, these data suggest that there is a subset of patients with TPMT defects who requires reductions in 6-mercaptopurine dose to avoid acute and long-term toxic effects, whereas increased doses in those wild-type for TPMT should be undertaken cautiously so as to avoid inducing excessive neutropenia.
Although there are data suggesting that intravenous 6-mercaptopurine is associated with
acute hepatotoxicity (27), we found no evidence that hepatotoxicity was
more frequent in those with TPMT defects. In fact, hepatotoxicity tended to be more frequent
among those with higher TPMT activity (Table 2). Because
hepatotoxicity followed administration of 6-methylmercaptopurine riboside (28-30), it is possible that methylated metabolites contribute to hepatotoxicity.
There are two strategies for prospectively identifying TPMT-deficient and heterozygous patients: either measure TPMT activity in erythrocytes (31,32) or determine TPMT genotype using genomic DNA (15,33). Measurement of erythrocyte TPMT activity is accomplished by either radiochemical (31) or HPLC (32) assays by use of a small volume of peripheral blood, but results can be spurious if patients have received allogeneic erythrocyte transfusions within the previous 60-90 days. Because it is not uncommon for newly diagnosed acute lymphoblastic leukemia patients or those experiencing hematopoietic toxicity to receive erythrocyte transfusions, this is frequently a serious limitation of diagnosing TPMT phenotype on the basis of TPMT activity. Alternatively, polymerase chain reaction-based methods have been developed to detect the signature mutations in the predominant TPMT mutant alleles in humans (10,15,20,21,34). Detection of the three most prevalent TPMT mutations yielded greater than 95% concordance between TPMT genotype and phenotype in a Caucasian population (15), and one can anticipate that the molecular diagnosis of TPMT deficiency and heterozygosity will continue to improve as additional mutations are discovered and incorporated into automated high throughput methods (e.g., DNA arrays).
Noncompliance, as assessed by undetectable erythrocyte thioguanine nucleotide concentrations, was rare (three of 180 patients) and comparable to rates reported in the U.K. (35). Only one of these three cases was suspected clinically, illustrating the utility of pharmacologic measures in documenting noncompliance.
Defining cut points to divide patients into phenotypes according to their TPMT activity is challenging because of the increase in activity of TPMT that occurs while patients are receiving chemotherapy (4,36,37). We acknowledge that our sample size was too small to apply statistical methods to accurately identify an antimode dividing heterozygotes from wild-type for TPMT, as we have done previously in healthy volunteers (11). By the use of cut points previously validated in large family studies (9) and against genotype (15) for those who had already completed therapy and by the use of cut points that identified the intermediate 10% of the group as presumed heterozygotes for those measures taken while patients were receiving therapy, phenotype was consistent with genotype and our cut points are similar to those reported by others (34).
Whether boys differ from girls in amount of 6-mercaptopurine prescribed, TPMT activity, or thioguanine nucleotide concentrations has differed in different studies (38-40), with lower dosing in boys postulated to contribute to their worse acute lymphoblastic leukemia outcome. However, we did not observe any differences in thioguanine nucleotides, TPMT (41), or in 6-mercaptopurine dosing between boys and girls.
It is important to recognize that, when full doses of 6-mercaptopurine are prescribed to patients with undiagnosed TPMT deficiency or heterozygosity, this can compromise the ability to deliver all forms of acute lymphoblastic leukemia chemotherapy and thereby jeopardize the chance for cure. However, with the appropriate dose adjustment of 6-mercaptopurine (or thioguanine or azathioprine), TPMT-deficient and heterozygous patients can be successfully treated with all components of acute lymphoblastic leukemia therapy including thiopurines (3). This study establishes that this inherited trait is a significant determinant of tolerance to acute lymphoblastic leukemia chemotherapy that contains 6-mercaptopurine (or other thiopurines). Because this common genetic polymorphism places approximately 10% of the patients at risk for excessive toxicity, we suggest that TPMT phenotype should be established in patients to optimize their thiopurine therapy.
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NOTES |
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We thank our clinical staff for their scrupulous attention to patient care and documenting doses; Ms. Nancy Kornegay for her computer assistance; Ms. Sheri Ring, Lisa Walters, Terri Kuehner, and Margaret Edwards, our research nurses; Dr. James Boyett for his statistical advice; Ms.YaQin Chu, Eve Su, Natasha Lenchik, and May Chung, our technical staff; and the patients and their parents for their participation in these studies.
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Manuscript received April 21, 1999; revised September 8, 1999; accepted October 1, 1999.
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