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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 411-415
Early Intensification of Intrathecal Chemotherapy Virtually
Eliminates Central Nervous System Relapse in Children With Acute
Lymphoblastic Leukemia
By
Ching-Hon Pui,
Hazem H. Mahmoud,
Gaston K. Rivera,
Michael L. Hancock,
John T. Sandlund,
Frederick G. Behm,
David R. Head,
Mary V. Relling,
Raul C. Ribeiro,
Jeffrey E. Rubnitz,
Larry E. Kun, and
William
E. Evans
From the Departments of Hematology-Oncology, Pathology and Laboratory
Medicine, Pharmaceutical Sciences, Biostatistics and Radiation
Oncology, St Jude Children's Research Hospital, and Department of
Pediatrics, Pharmacy and Radiation Oncology, University of Tennessee,
College of Medicine, Memphis, TN.
 |
ABSTRACT |
Central nervous system (CNS) relapse has been an obstacle to
uniformly successful treatment of childhood acute lymphoblastic leukemia (ALL) for many years. We therefore intensified intrathecal chemotherapy (simultaneously administered methotrexate, hydrocortisone, and cytarabine) for 165 consecutive children with newly diagnosed ALL
enrolled in Total Therapy Study XIIIA from December 1991 to August
1994. The 64 patients (39%) who had 1 or more blast cells in
cytocentrifuged preparations of cerebrospinal fluid at diagnosis, with
or without associated higher-risk features, received additional doses
of intrathecal chemotherapy during remission induction and the first
year of continuation treatment. Patients with higher-risk leukemia,
regardless of cerebrospinal fluid findings, also received additional
doses of intrathecal chemotherapy during the first year of continuation
treatment. Cranial irradiation was reserved for patients with
higher-risk leukemia (22% of the total). The 5-year cumulative risk of
an isolated CNS relapse among all 165 patients was 1.2% (95%
confidence interval, 0% to 2.9%), whereas that of any CNS relapse was
3.2% (0.4% to 6.0%). The probability of surviving for 5 years
without an adverse event of any type was 80.2% ± 9.2% (SE). Our
results suggest that early intensification of intrathecal chemotherapy
will reduce the risk of CNS relapse to a very low level in children
with ALL, securing a higher event-free survival rate overall.
| |
INTRODUCTION |
APPROXIMATELY 70% of children with acute
lymphoblastic leukemia (ALL) can be cured with contemporary forms of
chemotherapy.1 One approach to improving this result would
be to lower the incidence of central nervous system (CNS) relapse,
which in most studies ranges from 5% to 11%.2-12 Growing
appreciation that CNS irradiation can cause potentially serious
neurotoxicity, including brain tumors, has increased the emphasis on
stringent risk assessment to ensure that patients are neither
undertreated nor overtreated within this site.13 Thus, we
have reported that fewer than 5 leukocytes/µL with definable blast
cells in the cerebrospinal fluid (CSF) increases the CNS relapse hazard
in children with ALL.5 This suggests that any number of
leukemic cells in the CSF identifies patients who may benefit from
intensified intrathecal chemotherapy, which effectively prevents CNS
relapse in cases of intermediate- or high-risk ALL.10,14-16
In the study reported here, early intensification of triple intrathecal
chemotherapy (methotrexate, hydrocortisone, and cytarabine), especially
for patients with blast cells in the CSF and those with standard
higher-risk features, reduced the incidence of CNS relapse to a very
low level, improving clinical outcome overall.
| |
MATERIALS AND METHODS |
Patients.
From December 1991 to August 1994, 165 consecutive children and
adolescents, 18 years of age or younger, with newly diagnosed ALL were
enrolled in Total Therapy Study XIIIA at St Jude Children's Research
Hospital.17 The treatment protocol was approved by the
institutional review board, and signed informed consent was obtained
from the patients' parents or guardians.
The diagnosis of ALL was based on morphologic and cytochemical
evaluation of bone marrow smears as well as immunophenotyping and
cytogenetic analysis of lymphoid blast cells. Depending on the pattern
of blast cell reactivity to a panel of monoclonal antibodies, cases
were classified as T-cell or B-cell precursor, as previously
described.18
Samples of CSF (1.0 mL from cases with fewer than 500 cells/µL or a
smaller volume from cases with higher counts, increased to 1.0 mL with
normal saline) were mixed with one drop of 22% bovine albumin (Organon
Teknika, Durham, NC), placed in a cytospin sample chamber, and
centrifuged at 1,000 revolutions per minute for 5 minutes (Shandon
centrifuge; Shandon, Cheshire, UK). All slides were reviewed by two
examiners (a hematopathologist and a certified medical technician) who
classified cases as CNS-1, no definable blast cells;
CNS-2, fewer than 5 leukocytes/µL with definable blast cells;
CNS-3, 5 or more leukocytes/µL with definable blast cells or
the presence of cranial-nerve palsies; and contaminated, more
than 10 erythrocytes/µL with detectable blast cells. Cell counts in
the CSF were performed with a hemocytometer.
Treatment.
Initial treatment consisted of methotrexate alone19
followed 4 days later by remission induction therapy with prednisone, vincristine, daunorubicin, asparaginase, and etoposide plus cytarabine (Fig 1).17 All patients
received 2 weeks of consolidation therapy with high-dose methotrexate
and mercaptopurine upon attaining complete remission. Continuation
therapy for higher-risk cases consisted of drug pairs administered in
weekly rotation: etoposide plus cyclophosphamide, mercaptopurine plus
methotrexate, methotrexate plus cytarabine, prednisone plus vincristine
plus asparaginase, etoposide plus cyclophosphamide, mercaptopurine plus
high-dose methotrexate (replaced by low-dose methotrexate after 1 year
of therapy), etoposide plus cytarabine, and prednisone plus vincristine plus asparaginase. Reinduction therapy (similar to that used initially) was administered from weeks 32 to 37. Postremission treatment for
lower-risk cases consisted of daily mercaptopurine and weekly methotrexate reinforced by high-dose methotrexate every 8 weeks (for
the first year) and prednisone plus vincristine pulse every 4 weeks.
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| Fig 1.
Schema of remission induction, consolidation treatment,
and continuation therapy for the first year. Solid arrows indicate triple intrathecal treatment that was administered to all patients; hatched arrows, additional doses administered only to patients with a
CNS-2, CNS-3, or contaminated status; open arrows, additional doses
administered during the continuation phase of therapy to patients with
a higher risk of CNS relapse, as defined by CSF findings or other
features (Table 1). Cranial irradiation plus 5 triple intrathecal
treatments was administered only to patients with high-risk leukemia.
See the Materials and Methods for other details.
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The schedule of triple intrathecal chemotherapy (simultaneously
administered methotrexate, hydrocortisone, and cytarabine) is shown in
Fig 1. Briefly, the intensification plan specified additional
intrathecal treatments, in age-appropriate doses,20 on days
8 and 15 of remission induction for all patients whose CSF sample had a
CNS-2, CNS-3, or contaminated status. These subgroups then received
additional intrathecal doses every 4 weeks during the first 56 weeks of
continuation therapy, as did patients with a CNS-1 status who were
judged to have an increased risk of CNS relapse based on other features
(Table 1). Cranial irradiation was reserved
for patients in the higher-risk category (1,800 cGy or 2,400 cGy plus 5 intrathecal treatments from weeks 56 to 69). Intrathecal chemotherapy
was not administered after the first 59 weeks of continuation
treatment.
Statistical analysis.
Differences in the distribution of base-line characteristics among
subgroups defined by CNS status were assessed with Fisher's exact
test. To account for the competing effects of failures other than CNS
relapse, we estimated the cumulative incidence of CNS relapse (either
isolated or combined with relapse in any other site) as an initial
adverse event, using the method of Kalbfleisch and
Prentice21 as implemented by Gray.22 Survival
free of CNS relapse and event-free survival were estimated by the
Kaplan-Meier method. Follow-up times on the date of analysis ranged
from 3 to 5.7 years (median, 4.3 years).
| |
RESULTS |
Sixty-four patients (39%) had unequivocal lymphoblasts in their CSF
samples: 42 had CNS-2 status; 6 had CNS-3 status; and 16 had
contaminated status (Table 1). Twenty-five were considered to have a
higher risk of CNS relapse by standard criteria (B-cell precursor
immunophenotype with a leukocyte count of at least 100 × 109/L, a T-cell immunophenotype with a leukocyte count of
at least 50 × 109/L, or a karyotype with the
Philadelphia chromosome), whereas 39 were in the lower-risk category
(absence of higher-risk features). By comparison with the CNS-1
subgroup, patients with a CNS-2 status were significantly more likely
to have several adverse presenting features: leukocyte counts greater
than 100 × 109/L (33% v 5%, P < .001), a germline TEL status (76% v 58%, P < .01), or an MLL rearrangement (17% v 1%,
P < .001). There were too few patients with a CNS-3 status to
permit meaningful statistical testing.
One hundred sixty-three of the 165 patients entered complete remission.
Of the 28 adverse events that have occurred, 13 were hematologic
relapses, 2 were isolated CNS relapses, 3 were combined CNS and
hematologic relapses, and 2 were deaths in remission (1 accidental and
1 due to presumed sepsis). There have been 8 cases of therapy-induced
leukemia. The cumulative risk of an isolated CNS relapse at 5 years
postremission was 1.2% (95% confidence interval, 0% to 2.9%) and of
any CNS relapse was 3.2% (0.4% to 6.0%;
Fig 2A). The 5-year event-free survival
estimate for all 165 patients was 80.2% ± 9.2% (SE) (Fig 2B).
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| Fig 2.
(A) Cumulative risk of CNS relapse, either isolated or
combined with relapse in other sites. Numbers in parentheses are the 95% confidence intervals. (B) Event-free survival and survival free of
CNS relapse. Five-year estimates are the means ± SE. Three patients
did not achieve complete remission and therefore were not at risk for
CNS relapse during the immediate postinduction period.
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Two adolescent boys (with B-cell precursor leukemia and a CNS-2 or
contaminated CSF status) had isolated CNS relapses at 16 and 19 months
of continuation treatment. Both patients had relatively low presenting
leukocyte counts (17 and 18.9 × 109/L, respectively),
and neither had recognized high-risk genetic features. Three other
boys, 3 to 6 years of age with B-cell precursor leukemia and a CNS-1
status, had combined CNS and bone marrow relapses at 13, 19, and 37 months. Both cases of early relapse had high-risk genetic features,
either the Philadelphia chromosome with a leukocyte count of 271 × 109/L or a near-haploid karyotype with a leukocyte
count of 2.7 × 109/L. The 1 late relapse
occurred in a patient with hyperdiploid leukemia (>50 chromosomes per
leukemic cell). The patient with Philadelphia chromosome-positive ALL
relapsed just before scheduled cranial irradiation, and in this study
near-haploidy was not used as a criterion for cranial irradiation.
Hence, none of these 5 patients had received cranial irradiation before
relapse.
| |
DISCUSSION |
We attribute the very low incidence of CNS relapse in this study to
early intensification of intrathecal treatment in the context of
effective systemic chemotherapy. Although the need for intensive
CNS-directed therapy is well recognized in patients with a CNS-3
status,9 we are the first to have extended this requirement
to patients with a CNS-2 status. Our use of cranial irradiation was
limited to a subset of patients (22% of the total group) who were at
higher risk of CNS relapse, with or without positive CSF findings. The
efficacy of this strategy is supported by results from an interim
analysis of our ongoing Total Therapy trial: no CNS relapses among 200 patients observed for a median of 20 months (C.-H.P., unpublished
observation). Others have reported similarly low risks of
CNS relapse in recent years, but in each instance, a majority of the
patients received cranial irradiation.23-26 The high
event-free survival estimate in our study (80.2% ± 9.2% [SE] at
5 years) reflects at least in part the near elimination of CNS relapse
as a major adverse event in the clinical course of ALL patients and
represents improvement over previous results from this
center.2,5
In therapeutic trials that did not include early intensification of
intrathecal therapy, the isolated CNS relapse rates have ranged from
5% to 11%.2-12 Addition of cranial irradiation did not
appear useful in lowering the hazard of CNS relapse in several of these
studies.6,10,11 In the trial preceding Study XIIIA, we did
not administer intrathecal treatment during consolidation therapy or
early in the continuation phase, and neither did we intensify
CNS-directed therapy for patients in whom a CNS-2 status was the only
feature predicting relapse.5 Virtually all of the CNS
relapses in that study occurred during the first year of continuation
treatment, before scheduled administration of cranial irradiation.
In the future, it may be possible to avoid cranial irradiation in some
patients with high-risk leukemia, eg, those with a rapid early response
to induction chemotherapy.14,16 The use of dexamethasone,
which may penetrate into the CSF better than prednisolone,27 could further reduce the proportion of
patients requiring cranial irradiation.28 However, the
requirement for radiation in other subgroups remains controversial.
Among children with T-cell leukemia and an initial leukocyte count of
at least 100 × 109/L, those treated with intensive
intrathecal therapy alone had an inferior outcome compared with those
receiving cranial irradiation,15 although this comparison
was not based on patients treated with the same systemic regimen.
Nonetheless, it may be possible to reduce the dose of prophylactic
cranial irradiation to as low as 1,200 cGy without loss of therapeutic
efficacy.15 Some investigators use craniospinal irradiation
to treat patients with a CNS-3 status.11,12,23,29 We
suggest that cranial irradiation plus intensified intrathecal chemotherapy is sufficient therapy for this subgroup, because none of
the 13 patients with a CNS-3 status in the present study or our ongoing
trial has relapsed in the CNS.
The frequency of detection of a CNS-2 status has increased
significantly at this center (P < .01), from 17.6% (Mahmoud
et al5) to 25.5% in the present study. We would emphasize
that the distribution of other presenting features (eg, leukocyte
count, age, leukemic cell lineage or ploidy, and the presence of the Philadelphia chromosome) did not differ between study patients and the
historical comparison group (data not shown). However, even though the
median leukocyte count in the CSF (n = 1) was identical between these
two cohorts, the median percentage of blasts in cytospin preparations
was higher in the current study (6% v 3%, P = .03).
We attribute both the higher incidence of CNS-2 findings and the
increased percentage of blasts in the CSF to improved preparation of
cytospin samples (with an upgraded cytocentrifuge), more rapid delivery
of CSF samples to the laboratory (thus avoiding excessive degradation
of blast cells), and greater vigilance for leukemic blasts in CSF
samples. With immunologic assays, the proportion of children with
leukemic cells in their CSF may increase still further, to as high as
45%.30,31
Early intensification of systemic chemotherapy to prevent the emergence
of drug-resistant blast cells is the cornerstone of successful
treatment of ALL.1,13 As demonstrated in this report, the
same approach to intrathecal chemotherapy can reduce the CNS relapse
hazard to near zero, boosting the overall effectiveness of ALL
treatment programs. Additional study is needed to determine if patients
with a CNS-2 status require more intensive early intrathecal treatment
than do those with a CNS-1 status.
| |
FOOTNOTES |
Submitted December 1, 1997;
accepted March 16, 1998.
Supported by Grants No. CA-20180 and CA-21765 (CORE) from the National
Cancer Institute and by the American Lebanese Syrian Associated
Charities (ALSAC).
Address reprint requests to Ching-Hon Pui, MD, St Jude Children's
Research Hospital, 332 N Lauderdale, Memphis, TN 38105-0318.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank John Gilbert for critical comments and editing
assistance and Virginia Norris for preparing the manuscript.
| |
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Abstract
Introduction
Abstract