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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2817-2823
Prognostic Importance of 6-Mercaptopurine Dose Intensity in Acute
Lymphoblastic Leukemia
By
Mary V. Relling,
Michael L. Hancock,
James M. Boyett,
Ching-Hon Pui, and
William E. Evans
From the Departments of Pharmaceutical Sciences, Hematology/Oncology,
and Biostatistics and Epidemiology, St Jude Children's Research
Hospital, Memphis; and the Colleges of Medicine and Pharmacy, The
University of Tennessee, Memphis.
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ABSTRACT |
6-Mercaptopurine (6MP) and methotrexate are the
backbone of continuation therapy for childhood acute lymphoblastic
leukemia (ALL). In studies of oral 6MP and methotrexate, indices of
chronic systemic exposure to active metabolites of these agents,
namely, red blood cell (RBC) concentrations of methotrexate
polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have
positively correlated with event-free survival (EFS). Our objective was
to evaluate whether MTXPGs, TGNs, and the dose intensity of
administered methotrexate and 6MP were prognostic in the setting of a
treatment protocol in which all treatment was coordinated through a
single center, and the weekly doses of methotrexate were given
parenterally. On protocol Total XII, 182 children achieved remission
and received weekly methotrexate 40 mg/m2 parenterally and
daily oral 6MP, interrupted every 6 weeks during the first year by
pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine
methyltransferase (TPMT) measurements, along with complete dose
intensity information (dose received divided by protocol dose per week)
for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate
analyses, only higher dose intensity of 6MP and of weekly methotrexate
were significant predictors of overall EFS (P = .006 and
.039, respectively). The occurrence of neutropenia was associated with
worse outcome (P = .040). In a multivariate analysis, only
higher dose intensity of 6MP (P = .020) was a significant
predictor of EFS, with lower TPMT activity (P = .096) tending
to associate with better outcome. 6MP dose intensity was also
associated (P = .007) with EFS among patients with homozygous
wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to
missed weeks of therapy and not to reductions in daily dose. We
conclude that increased dose-intensity of oral 6MP is an important
determinant of EFS in ALL, particularly among those children with a
homozygous wild-type TPMT phenotype. However, increasing intensity of
therapy such that neutropenia precludes chemotherapy administration may
be counterproductive.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE "BACKBONE" of continuation
chemotherapy for childhood acute lymphoblastic leukemia (ALL) protocols
comprises oral daily 6-mercaptopurine (6MP) and weekly methotrexate
(MTX). It is widely held that treatment outcome is related to treatment intensity in many drug sensitive cancers, including childhood ALL. In
this regard, several treatment groups have positively correlated
indices of red blood cell (RBC) antimetabolite concentrations, either
thioguanine nucleotides (TGNs)1 or methotrexate
polyglutamates (MTXPGs),2,3 with long-term event-free
survival (EFS). Because two of these prior treatment protocols involved
oral administration of both weekly methotrexate and daily 6MP, it is
possible that the association of higher RBC TGNs and/or MTXPGs with
favorable outcome was due to patient compliance in taking oral
medications. In addition, in patients experiencing hematopoietic
toxicity due to a genetic defect in thiopurine methyltransferase
(TPMT), dosages of methotrexate may have been reduced along with the
dosages of 6MP, thus further compromising delivery of
therapy.2,4 The importance of RBC indices of 6MP and
methotrexate active metabolites has not previously been evaluated in a
setting in which the delivery of all other components of ALL therapy
are documented and incorporated into the outcome analysis.
In St Jude Children's Research Hospital (SJCRH) protocol Total XII, we
prospectively measured RBC TGNs and MTXPGs, along with plasma
exposure to every dose of "pulse" chemotherapy, in 182 children
with ALL. We documented and analyzed the exact dosage of weekly
parenteral methotrexate and daily oral 6MP for the entire 120 weeks of
chemotherapy and assessed whether RBC TGNs or MTXPGs have prognostic
significance in this setting.
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MATERIALS AND METHODS |
Treatment.
Children with ALL were treated on SJCRH Protocol Total XII after
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 previously5 and is outlined in
Fig 1. Briefly, after six-drug remission
induction therapy, patients were randomized to receive every-6-week
pulses of high-dose methotrexate alternating with teniposide plus
cytarabine that were either dosed conventionally (based on body surface
area) or individualized (based on pharmacokinetic parameters).5 Other than the weeks of pulse therapy,
patients received weekly methotrexate 40 mg/m2
(intravenously [IV] or intramuscularly [IM]) and daily oral 6MP 75 mg/m2. Complete blood counts were obtained weekly.
Chemotherapy was given every week, provided that the absolute
neutrophil count (ANC) was >300 cells/µL and that the patient did
not exhibit other complications such as mucositis, fever, or
hepatotoxicity. If toxicity or neutropenia in any given week precluded
administration of chemotherapy, the scheduled pulse therapy was delayed
until the patient recovered, whereas the scheduled low-dose
methotrexate plus 6MP was omitted altogether.
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| Fig 1.
Schema for Total XII protocol continuation therapy.
Abbreviations: P, prednisone; V, vincristine; D, daunomycin; Asp,
Escherichia coli asparaginase; VM, teniposide; ARA-C,
cytarabine; HDMTX, high-dose methotrexate; 6MP QD, daily oral
6-mercaptopurine; Mtx QWK, methotrexate given IV or IM every week; CNS,
central nervous system; IT MHA, intrathecal methotrexate,
hydrocortisone, and cytarabine.
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RBC thiopurine metabolites.
RBC concentrations of TGNs and of thioinosine monophosphate (TIMP) were
measured by hydrolyzing RBC lysates with acid and heat to the
respective 6TG and 6MP bases, as described.6 Methylated metabolites of TIMP (meTIMP) were measured by hydrolyzing to methyl-6MP in a subset of patients in a separate high-performance liquid chromatography (HPLC) assay.7 Patients were
scheduled to have thiopurine metabolite concentrations measured in RBCs
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 6MP for at least the prior 5 weeks. Patients were
instructed to take their 6MP on an empty stomach in the evening, and
all samples were obtained at least 8 hours after the preceding 6MP
dose. Because of acute toxicity, noncompliance, or other unusual reasons (eg, misunderstanding directions, vacations, etc), some patients might not have received 6MP 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 6MP for the
preceding 6 weeks, the reason for obtaining the RBC sample (specified
by the protocol or for suspected toxicity or noncompliance), and the
time of day that the child had taken 6MP in the prior dosing interval.
For purposes of evaluating RBC TGN, TIMP, and MeTIMP as possible
prognostic factors, only samples that were collected as specified by
the protocol were included in the analysis.
RBC MTXPG.
MTXPGs were measured as previously described8 in the same
RBC samples used for thiopurine metabolite measures. If the volume of
RBCs was inadequate, processing for TGNs took precedence over MTXPGs.
At each sampling time, the treatment protocol specified that patients
should have received weekly low-dose parenteral methotrexate (40 mg/m2; IV or IM for the first 60 weeks and IM thereafter in
those who received cranial irradiation at 60 weeks) for every week for
at least the prior 5 weeks. All samples were obtained at least 6 days
after the last dose of methotrexate.
Plasma area under the curve (AUC).
Plasma area under the concentration versus time curve for methotrexate,
cytarabine, and teniposide was measured in patients for every pulse
chemotherapy as previously described.5
TPMT phenotype and genotype.
RBC TPMT activity was measured using blood collected in heparinized
tubes as previously described.9 RBC TPMT activity
measurements were made  90 days after the last RBC transfusion in 109 patients during their continuation therapy (1 to 843 days after
achievement of complete remission) and in 45 patients after completion
of continuation therapy (499 to 1,602 days after achievement of
complete remission). If a patient had TPMT measured while on therapy,
the lowest value was used to assign phenotype as follows:  4 U/mL packed RBCs, homozygous mutant; 4 to 13.5 U/mL packed RBCs,
heterozygotes; 13.5 U/mL packed RBCs, wild-type. If the TPMT was
measured only after completion of continuation therapy, the lowest
value was used to assign phenotype as follows: 4 U/mL packed RBCs,
homozygous mutant; 4 to 10.2 U/mL packed RBCs, heterozygous; 10.2
U/mL packed RBCs, homozygous wild-type. If a patient had no TPMT
measured either during or after completion of therapy, but had RBC TGN concentrations above the 90th percentile for maximum TGNs for the
entire group (1,120 pmol/8  108 RBCs),
they were considered heterozygotes. For outcome analyses, TPMT
homozygous mutant and heterozygous individuals were pooled into a
single group (termed "TPMT defective"). Of the 182 patients who
entered remission, either TGN or TPMT activity was evaluable in 180 patients (for purposes of assigning phenotype). TPMT genotype was
evaluated, using somatic cell DNA, from a subset of patients, using
polymerase chain reaction (PCR)-based methods specific for the
TPMT*2, *3A, *3B, and *3C mutant
alleles as previously described.10
Dosages of continuation chemotherapy.
A patient-specific treatment calendar, specifying dosages 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 SJCRH. The exact dosages of every dose
of every antileukemic medication were compiled into an institutional
database, with reasons for any deviations from the planned protocol
therapy documented at each week. One of the patients with extreme
intolerance to continuation chemotherapy was identified to be
homozygous deficient for TPMT.11 A drastic dosage reduction
(from 75 mg/m2/d given daily to 10 mg/m2 given
3 days per week) resulted in excellent tolerance and allowed administration of full dosages of the remainder of continuation therapy
medications. From that point forward, if physicians asked for a
pharmacokinetic consult on the TPMT status and TGN concentrations of a
patient experiencing unusual toxicity, consults on thiopurine status
were provided. Dosages of 6MP were decreased gradually in patients with
likely heterozygous status until reaching a dosage of 6MP that resulted
in the desired degree of leukopenia (<4,000 cells/µL, but ANC
>300 cells/µL) and allowed for full dosages of other antileukemic
agents. Dosages were only decreased in those experiencing
myelosuppression. In addition, 6MP dosage was increased after week 60 of continuation therapy in case of persistently high leukocyte counts
(4,000/µL and ANCs 1,500/µL for 4 consecutive weeks). No dosage
changes in weekly methotrexate were dictated by the protocol.
Dose intensity for 6MP and methotrexate.
To assess the importance of maintaining dosages of 6MP and low-dose
methotrexate, dose-intensity variables were estimated for each drug.
The ratio of the cumulative dose of 6MP (or methotrexate) actually
received to the maximum dose that could have been received was
calculated for each patient for each week, so that the information could be properly entered into a time-dependent Cox proportional hazards model. The numerator for estimating 6MP dose intensity was
defined as the mg/m2/d dose of 6MP the number of days
that 6MP was taken that week. The denominator for 6MP dose intensity
was the planned protocol dosage (75 mg/m2/d 7 = 525 mg/m2/wk). The numerator for methotrexate dose intensity
was defined as the mg/m2 dose per week of methotrexate
actually administered; the denominator for methotrexate dose intensity
was the planned protocol dosage (40 mg/m2/wk). The
denominator excluded only the weeks of the pulses (ie, for a patient
who completed therapy and received all 10 pulses, the denominator for
the final cumulative methotrexate dose intensity was 120  10 = 110 weeks 40 mg/m2 = 4,400 mg/m2).
Statistical analyses.
The Cox Proportional Hazards model12 was used to assess the
prognostic significance of pharmacologic parameters on the complete remission experiences (because the analysis is restricted to patients who entered remission, EFS is used to indicate complete remission). Parameters that were measured repeatedly were treated as time-dependent covariates and included: average and maximum TGN levels, TIMP, MeTIMP;
average MTXPG, methotrexate, teniposide, and cytarabine AUCs; and
cumulative dose intensities of weekly 6MP and methotrexate. TPMT
phenotype was considered a fixed covariate. Factors that were
significant at the 0.20 level in univariate analyses and TPMT phenotype
were included in the multivariate analyses. In addition, the occurrence
of neutropenia in any given week, defined as an ANC of <300
cells/µL that precluded administration of therapy, was evaluated as a
predictor of EFS. EFS duration was defined as the time between
achievement of complete remission to the first adverse event: leukemic
relapse, second malignancy, or death, for those who failed, or to the
date of last contact for those patients who were censored. Models were
stratified according to treatment arm (individualized or conventional
dosing of the pulses) and risk group (better or worse; better risk was
defined as initial leukocyte count <50,000 cells/mL in conjunction
with either ETV6/CBFA2 [TEL/AML1] gene rearrangement
or DNA index 1.16 to 1.60, and the absence of central nervous system
[CNS] disease at diagnosis, T lineage, Philadelphia
chromosome positivity and MLL rearrangement). Models involving methotrexate, teniposide, and cytarabine AUCs were
stratified by risk criteria only because the plasma AUCs were
significantly associated with treatment arm.5 Kaplan-Meier curves of the estimated complete remission duration starting from the
end of continuation therapy for the 142 patients who completed the
120-week continuation treatment were constructed using the coefficients
and the baseline survivor function13 from a Cox proportional hazards model that included TPMT phenotype, treatment arm,
and cumulative dose intensity of weekly 6MP at the end of continuation
therapy, and then selecting two hypothetical dose intensity levels of
6MP (70% and 85%). The curves represent the weighted average of the
estimates among the two risk groups. The prognostic significance of the
product of the mean MTXPG and the mean TGN dichotomized at its median,
among the subset of patients aged 1 to 15 years who had a minimum of
three TGN and three MTX-PG measurements (as reported by Schmiegelow et
al2), was assessed using the Cox model.
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RESULTS |
Of the 188 patients enrolled on Total XII, 182 achieved a complete
remission. Their demographic characteristics have been described
previously.5 The number of patients with pharmacologic variables measured and the total number of measurements are indicated in Table 1.
TPMT was measured in 154 patients; 26 other patients never had an
interpretable RBC TPMT measurement, but did have TGN measurements that
were used to classify them as either TPMT homozygous wild-type or
heterozygous individuals. Of the 182 patients achieving complete remission, two were homozygous mutants, 17 were heterozygotes, 161 were
homozygous wild-type, and two were not classified because they had
neither informative TPMT nor RBC TGN measured. TPMT genotype was
evaluated in 28 patients and was in complete concordance with assigned
phenotype (18 homozygous wild-type [all TPMT*1/*1], eight heterozygous [all TPMT*1/*3A], and two homozygous mutant
individuals [one *2/*2, one *3A/*2]).
Descriptive summaries for TGNs, TIMP, MeTIMP, MTXPGs, methotrexate AUC,
teniposide AUC, cytarabine AUC, 6MP dose intensity, methotrexate dose
intensity, and RBC TPMT activity are provided in Table 1. Univariate
analyses showed that the only factors associated with EFS for the
entire follow-up period (Table 1) were 6MP (P = .006) and
methotrexate dose intensity (P = .039). When the analysis was
restricted to a follow-up period only extending to the end of the pulse
therapy, higher methotrexate AUC was significantly (P = .0187)
associated with improved EFS among the B-lineage cases, as previously
reported.5 Because doses of 6MP were adjusted in some
patients based on TPMT defects (heterozygotes and homozygous mutants),
the impact of 6MP dose intensity was also evaluated among only the 161 patients with homozygous wild-type TPMT phenotypes, and it maintained
prognostic importance (P = .007).
In a multivariate analysis, including 6MP dose intensity, methotrexate
dose intensity, and maximum RBC concentrations of methotrexate polyglutamates, adjusting for TPMT status, only 6MP dose intensity (P = .022) was a significant predictor of EFS (Table 1).
Patients with defects in TPMT activity (homozygous mutant and
heterozygous patients) tended to have improved EFS in this model
(P = .096, Fig 2). When MTX AUC was
forced into a multivariate model for predicting overall EFS, it was not
a statistically significant predictor (P = .143) and did not
substantially change the prognostic importance of 6MP dose intensity
(P = .001) and TPMT activity (P = .053).
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| Fig 2.
Kaplan-Meier curves for EFS according to TPMT status
(homozygous mutant plus heterozygotes versus homozygous wild-type
phenotype), indicating a tendency for better outcome among those with
TPMT defects (P = .096) in a multivariate model in which dose
intensity for 6MP was the most important predictor (P = .022).
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Because the pharmacologic predictors evaluated, including the
cumulative 6MP dose intensity variable, were time-dependent variables,
it is not possible to construct Kaplan-Meier survival curves that
visually depict the importance of 6MP dose intensity to risk of
failure. Therefore, to depict the influence of 6MP dose intensity on
treatment outcome, two approaches were taken. First, patients were
divided into those who remain in continuous remission and those who
eventually failed. At 30, 60, 90, and 120 weeks of continuation
therapy, the cumulative dose intensity for 6MP for each patient was
determined, and the results are depicted in
Fig 3. This figure illustrates that the
average 6MP dose intensity was slightly higher among those who never
failed than those who eventually failed at all time points in therapy.
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| Fig 3.
Average (standard deviation) cumulative 6MP dose
intensity, expressed as a percentage of the protocol-specified dosage
of 6MP, evaluated at 30, 60, 90, and 120 weeks from the start of
continuation therapy in those who remained in continuous remission
( ) and those who eventually failed ( ). The numbers of patients at
each of the four time points are 165, 156, 150, and 142, respectively.
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For the second approach, an analysis was conducted that was limited
only to those patients who completed all 120 weeks of therapy (n = 142). The median (range) cumulative 6MP dose intensity was 84% (57%
to 170%) in the 124 patients with wild-type TPMT phenotype and 70%
(11% to 100%) in the 18 patients with a TPMT defect (heterozygotes
and homozygous mutant). 6MP cumulative dose intensity at 120 weeks
remained a significant predictor of EFS (P = .014) in a
multivariate analysis including TPMT phenotype. Using estimates from
the Cox proportional hazards model, Kaplan-Meier curves were estimated
separately within each TPMT phenotypic group (wild-type v
defective), pulse treatment arms (conventional v targeted), and
at two cumulative 6MP dose intensities (70% and 85%)
(Fig 4). It can be observed that within
each treatment arm, patients receiving a higher 6MP dose intensity are
estimated to have an improved EFS compared with those receiving a lower
6MP dose intensity. Moreover, at any given 6MP dose intensity, patients in the TPMT defective group do better than those who are wild-type for
TPMT. Finally, patients who were randomized to the targeted systemic
therapy arm do better than those randomized to the conventional arm, in
accordance with our prior analysis.5
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| Fig 4.
Using estimates from the Cox proportional hazards model
limited to the patients who completed all 120 weeks of continuation
therapy, Kaplan-Meier curves were projected for each TPMT phenotypic
group and for each treatment arm (conventional v targeted) at
each of two cumulative 6MP dose intensities (70% v 85% of
possible 6MP dosages). The curves projected for those with wild-type
TPMT phenotype are depicted in the left panel, and those with either
heterozygous or mutant TPMT phenotype are depicted in the right
panel.
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Mean thiopurine pharmacologic parameters in patients who received the
lowest, intermediate, and highest 6MP dose intensity are summarized in
Table 2. Patients with wild-type TPMT
phenotype who were in the lowest dose intensity quartile had (on
average) over three times as many weeks with no 6MP therapy as those
who got the highest dose intensity (24% v 7% of weeks
missed). However, the average 6MP weekly dose, estimated only for the
weeks that 6MP was given, was only marginally lower (504 v 561 mg/m2/wk) in those in the lowest versus the highest
quartiles for dose intensity. Thus, the major reason that dose
intensity was compromised was due to missing entire weeks of therapy,
not due to reduced daily 6MP doses.
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Table 2.
Mean (Standard Deviation) Thiopurine Pharmacologic
Parameters by Dose Intensity Quartiles and TPMT Phenotype in
Patients Who Completed 120 Weeks of Therapy
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Missing entire weeks of therapy was often due to neutropenia
(accounting for about 45% of all the weeks that therapy was missed). Neutropenia tended to be associated with worse EFS in a stratified univariate analysis (P = .040). In a multivariate analysis with 6MP dose intensity and TPMT activity, only 6MP dose intensity remained
a significant predictor (P = .004 for dose intensity, P = .119 for neutropenia, and P = .067 for TPMT).
To enable a comparison of these results with prior
studies,1,2 we analyzed our data using procedures similar
to those used previously. A total of 73 patients met the age and
sampling criteria set out by Schmiegelow et al.2 In these
patients, the product of the median RBC MTX-PG and the median TGN was
not a predictor of EFS (P = .95) or of CNS relapse-free
survival (P = .24). In addition, EFS was not different between
patients whose maximum TGN reading fell above or below our median value
of 594 pmol/8 108 RBCs (P = .64) or when
divided according to a value of 284 pmol/8 108 RBCs
(previously reported to be associated with EFS1) (P = .99). These results are consistent with our Cox proportional hazards model analysis in which TGN values were evaluated as a continuous variable (Table 1).
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DISCUSSION |
These data represent a comprehensive analysis of pharmacologic
determinants of outcome in childhood ALL. Systemic exposure to every
dose of the three agents (methotrexate, cytarabine, and teniposide)
repeatedly given as pulse therapy during year 1, as well as multiple
measures of chronic exposure to thiopurine and methotrexate active
metabolites (RBC TGN and MTX-PG concentrations), were evaluable in 180 of 182 patients who entered complete remission on a single protocol.
Among all of these pharmacologic parameters, the most important
determinant of overall EFS was the 6MP dose intensity. This treatment
protocol, SJCRH Total XII, was highly dependent on daily 6MP and weekly
low-dose methotrexate, as these two drugs were the only chemotherapy
administered from weeks 60 to 120 of continuation therapy. Having more
weeks in which chemotherapy is administered or receiving higher dosages
has been suggested to be important in other studies of ALL that are
heavily antimetabolite-based.14-16
In contrast to prior reports,1 we did not find that RBC
TGNs (or other 6MP metabolite indices) were predictive of EFS. Several
reasons may account for this. First, the median and maximum RBC TGNs in
our population were substantially higher than levels reported
previously.1 Thus, it is possible that the vast majority of
the patients reported herein had active thiopurine metabolite concentrations which exceeded a minimum threshold value for efficacy. Second, it is possible that prior associations of RBC
thiopurine1 and MTX-PGs2,3 with EFS were more
indicative of good compliance with chemotherapy (including 6MP,
methotrexate, and other elements of ALL therapy) than they were
indicators of a minimum required level of exposure to antimetabolite
therapy. This latter explanation is particularly a possibility because
low-dose weekly methotrexate was given orally in the prior
protocols,1-3 but was given solely by the parenteral route
on the protocol reported herein. Thus, RBC thiopurine metabolite
indices would not be expected to reflect compliance with methotrexate
therapy in our study.
It is not clear why we observed relatively high TGN concentrations in
our patients. It is possible that the close follow-up with medication
histories by our research nurses, pharmacists, and physicians resulted
in improved compliance with oral 6MP. It is also possible that the
increased exposure to low-dose methotrexate, due to parenteral dosing
of 40 mg/m2 (rather than 20 mg/m2 used by most
other groups), was more effective at inhibiting de novo purine
synthesis, resulting in increased levels of phosphoribosyl pyrophosphate, and thereby increasing availability of a rate-limiting cofactor for TGN formation by hypoxanthine phosphoribosyl
transferase.17 In any case, the high TGNs we observed in
our patients may indicate that we exceeded a "threshold" value
for TGNs in most patients, and may partly explain why 6MP dose
intensity was prognostically important, whereas TGNs were not. Because
our assessment of dose intensity provides data on all weeks of
continuation therapy and TGNs were only measured a few times (and were,
putatively, above some minimum threshold when they were measured), it
is plausible that 6MP dose intensity could provide more information on
overall treatment intensity and correlate with EFS, while TGNs did not.
There has been controversy as to whether EFS can be improved by
advancing the weekly dosage of 6MP to the point of toxicity (in which
case subsequent weeks of therapy may be omitted due to neutropenia), or
whether it is better to proceed with smaller dosage increments, thereby
causing less severe neutropenia.1,14-16,18-21 Our study
shows that among patients with wild-type TPMT phenotype who were in the
lowest quartile for dose intensity of 6MP (and thus most likely to
fail), 24% of weeks of therapy were completely omitted, compared to
only 7% of weeks of therapy omitted among those with higher dose
intensity (see Table 2). However, the weekly dose of 6MP (when 6MP was
given) among such children with low-dose intensity appeared to be only
modestly lower compared to those with the highest dose intensity (504 v 561 mg/m2/wk). Was this lower dose intensity due
to our failure to prescribe enough 6MP, or because neutropenia
precluded administration of 6MP? To partially address the latter
possibility, we examined whether neutropenia was associated with
outcome and found that in a univariate analysis, neutropenia was
associated with worse EFS. In addition, we evaluated an alternative
estimate of 6MP dose intensity, ie, each week was scored dichotomously
as to whether any dose of 6MP was given for at least 3 of the 7 days or
not. This measure of 6MP dose intensity was also prognostic for EFS (P = .0295, data not shown). Thus, although caution must be
used in drawing conclusions from these retrospectively analyzed data, our findings are consistent with the notion that neutropenia which compromises the ability to deliver 6MP worsens EFS, and that EFS is
improved by ensuring that some 6MP is given every week. We hypothesize
that every effort should be made to administer maximal doses of 6MP,
especially in individuals with TPMT wild-type phenotype, but that such
dosing should not be advanced at the expense of toxicity which
precludes administration of subsequent therapy. The notion that too
much toxicity may compromise outcome by resulting in too many
interruptions of therapy has been suggested by other investigators, as
well.16,20 Efficacy of 6MP therapy appears to be dependent
on adequate chronic exposure to the drug over a high percentage of the
weeks of continuation therapy.
The importance of dose intensity of 6MP therapy as a determinant of ALL
outcome is somewhat surprising, given that the difference in the 6MP
dose intensity between children who remained in remission and those who
failed, examined at any time point in therapy, appears to be very
modest (Fig 3). These data suggest that intensive monitoring and
scrupulous attention to weekly continuation therapy dosing may be
necessary to optimize therapy for children with ALL. Whether intensifying the administration of 6MP will be necessary in the context
of contemporary ALL protocols, which often include therapy other than
antimetabolites, such as monthly pulses of glucocorticoid and
vincristine, is uncertain. However, cumulative dose of 6MP was an
important prognostic determinant in at least one study16 which included monthly glucocorticoid plus vincristine.
Our data indicate that dosage individualization of 6MP therapy in ALL
is dependent on TPMT phenotype. TPMT is subject to a genetic
polymorphism, with about 10% of white and American black populations
exhibiting a heterozygous phenotype.9,22 Despite the fact
that heterozygous and homozygous mutant patients received lower 6MP
dose intensity than patients with wild-type TPMT, TPMT defective
phenotype tended to be associated with improved EFS (Figs 2 and 4). Our
hypothesis is that advancing 6MP dose intensity may be more important
for patients with wild-type phenotype. We11 and
others23,24 have demonstrated that substantial ( 10-fold) dosage decreases are required in patients with homozygous mutant TPMT
phenotype; we caution that the appropriate degree of dosage alteration
in those with heterozygous phenotype is not known.
Our data support a balanced approach to dosage individualization in
childhood ALL. Administration of maximum doses of 6MP is important in
childhood ALL, particularly in patients with wild-type TPMT phenotype,
but dosage increases should be tempered by the fact that resulting
toxicity may compromise the ability to give 6MP during all scheduled
weeks, thereby reducing overall dose intensity and worsening outcome.
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ACKNOWLEDGMENT |
We thank our clinical staff for scrupulous attention to patient care
and documenting dosages; Nancy Kornegay for computer assistance; our
research nurses, Sheri Ring, Lisa Walters, Terri Kuehner, and Margaret
Edwards; our technical staff, YaQin Chu, Eve Su, Natasha Lenchik, and
May Chung; and the patients and their parents for their participation
in these studies.
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FOOTNOTES |
Submitted October 12, 1998; accepted December 22, 1998.
Supported by Grants No. CA51001, CA20180, and CA36401 from the National
Institutes of Health; Cancer Center CORE Grant No. CA21765; by a Center
of Excellence grant from the State of Tennessee; and by American
Lebanese Syrian Associated Charities (ALSAC).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Mary V. Relling, PharmD, St
Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN
38105.
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ABSTRACT
INTRODUCTION