Diagnostic Cerebrospinal Fluid Examination in Children With

A c u t e L y m p h o b l a s t i c L e u k e m i a : S i g n i fi c a n c e o f L o w L e u k o c y t e
Counts With Blasts or Traumatic Lumbar Puncture

By Britta Bürger, Martin Zimmermann, Georg Mann, Joachim Kühl, Lutz Löning, Hansjörg Riehm,
Alfred Reiter, and Martin Schrappe

Purpose: To determine the significance of leukemic nostically significant (CNS3): risk ratio (RR) ⴝ 2.3; 95% confi-
blasts or traumatic lumbar puncture (TLP) in diagnostic CSF dence interval [CI], 1.4 to 3.6; P ⴝ .0005; TLPⴙ: RR ⴝ 1.5; 95%
of children enrolled in the Berlin-Frankfurt-Münster (BFM) CI, 1.02 to 2.2; P ⴝ .04. Overall 5-year event-free survival
Acute Lymphoblastic Leukemia–BFM-95 trial. (EFS) is 79%, for CNS1 it is 80%, and for TLPⴚ it is 83%. CNS2
Patients and Methods: A total of 2,021 patients were patients have an EFS of 80%, but the cumulative incidence of
retrospectively evaluated according to initial central ner- relapses with CNS involvement is higher compared with CNS1
vous system (CNS) status. Patients were classified as fol- patients (0.10 v 0.04). TLPⴙ patients have a significantly
lows: CNS1 (CNS negative, n ⴝ 1,605), CNS2 (< 5 WBC/␮L reduced EFS (73%, P ⴝ .003) because of an increased incidence
CSF with blasts, n ⴝ 103), CNS3 (CNS positive, n ⴝ 58), TLPⴙ of CNS relapses. CNS3 patients suffer from more systemic and
(TLP with blasts, n ⴝ 135), or TLPⴚ (TLP without blasts, n ⴝ CNS relapses (EFS 50%).
111). Patients with CNS2 and TLPⴙ status were eligible for Conclusion: CNS2 patients have the same prognosis as
two additional doses of intrathecal (IT) methotrexate (MTX). patients with CNS1 status, whereas the EFS of TLPⴙ patients is
CNS3 patients received additional IT MTX and cranial irra- inferior to CNS1 but superior to CNS3 patients (P ⴝ .001). Both
diation (18 Gy). subgroups may have benefitted from additional IT MTX.
Results: CNS2, CNS3, and TLPⴙ groups contained a higher J Clin Oncol 21:184-188. © 2003 by American
percentage of patients with unfavorable characteristics. Cox Society of Clinical Oncology.
regression analysis identified TLPⴙ and CNS3 status as prog-

OR SUCCESSFUL treatment of childhood acute lympho- There has been controversy about the significance of blasts
F blastic leukemia (ALL), it is mandatory to give sufficient
therapy directed to the central nervous system (CNS) to treat
detected in CSF without pleocytosis. Investigators from the
Children’s Cancer Group reported that patients with blasts in
subclinical or overt CNS leukemia. Without CNS-directed ther- CSF preparations, in the presence of five or fewer WBCs per
apy, relapses originating from the CNS in up to 75% of cases can microliter CSF, are not at greater risk for CNS or other relapse
be expected.1 With the introduction of effective prophylactic compared with CNS-negative patients.8,9 In contrast, investiga-
CNS treatment, such as intrathecal chemotherapy and cranial tors from St. Jude Children’s Research Hospital have shown that
irradiation, up to 80% of patients in current studies are finally CNS2 status (⬍ 5 WBC/␮L CSF with blasts) resulted in a higher
regarded as cured and only about 5% relapse with involvement risk of relapse and would, thus, require more intensive intrathe-
of the CNS.2 Patients with CNS leukemia, however, which is cal therapy.10,11 In addition, most studies looking at outcome
commonly defined as more than five leukocytes per microliter within CNS status subgroups, to date had not evaluated that
CSF in the presence of lymphoblasts after cytocentrifugation, particular subset of patients with traumatic lumbar punctures at
suffer from more relapses with CNS involvement and have a diagnosis. Gajjar et al11 recently published data demonstrating
significantly poorer outcome compared with CNS-negative pa- that initial traumatic lumbar punctures (TLPs) combined with the
tients.3-5 At a time when the intensity of CNS-directed therapy is presence of blasts negatively affect treatment outcome. In this study,
we wanted to elucidate the prognostic significance of blast cells in
being reduced, it is even more important to identify patients with
CSF without pleocytosis and of TLPs at the time of initial diagnosis
meningeal leukemia at the time of initial diagnosis, as they
for event-free survival (EFS) and types of relapse.
require more CNS-directed therapy.6,7
PATIENTS AND METHODS
A total of 2,021 patients (from 85 centers in Germany, Austria, and
From the Department of Pediatric Hematology/Oncology, Hannover Switzerland) with newly diagnosed ALL were enrolled in trial Acute
Medical School, Hannover; University Children’s Hospital, Würzburg; Lymphoblastic Leukemia–Berlin-Frankfurt-Münster-95 (ALL-BFM 95) of
Children’s Hospital, Klinikum Oldenburg; Department of Pediatric Hema- the Berlin-Frankfurt-Münster Study group between April 1995 and June
tology/Oncology, University of Giessen, Germany; and St. Anna Children’s 1999. Informed consent was obtained from the guardians of all patients, and
Hospital, Vienna, Austria. the protocol was approved by local and central ethical committees. Only
Submitted April 15, 2002; accepted October 5, 2002. patients with a minimum follow-up of 2 years were included in this
Supported by grants from the Deutsche Krebshilfe. retrospective analysis. Nine patients had to be excluded from the analysis
Address reprint requests to Britta Bürger, MD, Department of Pediatric because of missing CNS data. According to protocol, patients underwent
Hematology/Oncology, Hannover Medical School, Carl-Neuberg-Str 1, diagnostic lumbar puncture and received their first intrathecal (IT) metho-
30625 Hannover, Germany; email: [email protected]. trexate (MTX) on day 1 of induction therapy. CSF evaluation was done at the
© 2003 by American Society of Clinical Oncology. treating hospitals. A total of 974 patients (48%) had centrally reviewed CSF
0732-183X/03/2102-184/$20.00 cytocentrifuge preparations. CNS status was defined as follows: CNS1

184 Journal of Clinical Oncology, Vol 21, No 2 (January 15), 2003: pp 184-188
DOI: 10.1200/JCO.2003.04.096
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
130.113.86.233
CNS INVOLVEMENT IN CHILDREN WITH ALL 185

Table 1. Patient Characteristics According to CNS Status in the ALL-BFM 95 Trial

All CNS1 CNS2 CNS3 TLP⫹ TLP⫺

All 2,012 (100) 1,605 (80) 103 (5) 58 (3) 135 (7) 111 (6)
Sex
Male 1,139 (57) 890 (56) 59 (57) 40 (69)* 79 (59) 71 (64)
Female 873 (43) 715 (45) 44 (43) 18 (31)* 56 (42) 40 (36)
Age
⬍ 1 year 40 (2) 20 (1) 6 (6) 6 (10) 6 (4) 2 (2)
1-9 years 1,575 (78) 1,286 (80) 74 (72) 38 (66) 89 (66)* 88 (79)
ⱖ 10 years 397 (20) 299 (19) 23 (22) 14 (24) 40 (30)* 21 (19)
WBC (per ␮L)
⬍ 20,000 1,286 (64) 1,081 (67) 44 (42)* 19 (33)* 56 (42)* 86 (78)
20,000-100,000 502 (25) 377 (24) 37 (36)* 13 (22)* 57 (42)* 18 (16)
ⱖ 100,000 224 (11) 147 (9) 22 (21)* 26 (45)* 22 (16)* 7 (6)
Immunology
pro-B 74 (4) 51 (3) 12 (12)* 4 (7) 5 (4) 2 (2)
pre-B/common 1,586 (79) 1,299 (81) 67 (65) 26 (45) 104 (77) 90 (81)
T-ALL 256 (13) 178 (11) 22 (21)* 28 (48)* 20 (15) 8 (7)
Predicted response
Good 1,807 (90) 1,453 (91) 89 (86) 40 (69)* 117 (87) 108 (97)
Poor 170 (8) 123 (8) 13 (13) 15 (26)* 16 (12) 3 (3)
Risk Group
SR 694 (35) 592 (37) 22 (21)* 8 (14)* 24 (18)* 48 (43)
MR 1,073 (53) 833 (52) 63 (61)* 31 (53)* 92 (68)* 54 (49)
HR 245 (12) 180 (11) 18 (18)* 19 (33)* 19 (14)* 9 (8)

NOTE. Percentages are in parentheses. In the first column, where percentages refer to the whole group, all other percentages are calculated within the CNS status groups.
Statistically significant differences, compared with the CNS1 group, are marked with an asterisk (␹2 test for categorized variables, Wilcoxon rank sum test for continuous
variables; eg, WBC count).
Abbreviations: TLP, traumatic lumbar puncture; SR, standard risk; MR, medium risk; HR, high risk.

(puncture nontraumatic without leukemic blasts after cytocentrifugation), who did not attain a complete remission were considered failures at time zero.
CNS2 (puncture nontraumatic, ⱕ 5 WBC/␮L CSF with identifiable blasts), Duration of disease-free survival for patients who achieve remission is defined
CNS3 (puncture nontraumatic, ⬎ 5 WBC/␮L CSF with identifiable blasts), as the time from attainment of a complete remission until the date of an adverse
TLP⫹ (TLP with blasts), and TLP⫺ (TLP without blasts). CNS3 definition event (relapse, death, second malignancy) or, if no such event occurred, until the
was derived from Mastrangelo et al.12 A TLP was defined as 10 or more date of last contact. Distributions of EFS and continuous complete remission
erythrocytes per microliter CSF or macroscopically contaminated CSF. In were estimated by the methods of Kaplan and Meier with SE according to
addition to the CNS3 group as defined above, patients with a cerebral mass Greenwood,14 and were compared using the log-rank test.14,15 All analyses were
or patients with cranial nerve palsy in combination with blasts after performed on the basis of “intent-to-treat.” Cumulative incidence functions of
cytocentrifugation were regarded as having CNS3 disease. CNS relapse were constructed by the method of Kalbfleisch and Prentice16 for
patients who achieved a complete remission.16 Incidence functions for all
Treatment competing factors of failure were also calculated. Functions were compared with
Gray’s test.17 A CNS relapse is defined as an isolated CNS relapse or a CNS
Patients were treated according to the protocols of the ALL-BFM 95 trial. In
relapse in combination with another type of relapse or failure.
contrast to the ALL-BFM 90 trial, which has been described previously,13 a new
Differences in the distribution of variables among patient subsets were
stratification system was introduced. In ALL-BFM 95, patients were stratified
analyzed using the ␹2 test for categorized variables and the Wilcoxon rank
according to age, initial WBC count, day 8 response to prednisone, T immu-
sum test for continuous variables. The prognostic relevance of the different
nology, and molecular rearrangements such as t(9;22) and t(4;11) into standard-
CNS groups compared with CNS-negative patients was examined by Cox
risk (SR), medium-risk (MR), and high-risk (HR) groups. SR and MR therapy
regression analysis with known prognostic factors as covariables.18 The
consisted of an eight-drug induction, consolidation with four times high-dose
database for all analyses was “frozen,” meaning that no data about patients
(HD) MTX, and an eight-drug reintensification, followed by maintenance
who became known to the study center were entered, on August 1, 2001.
therapy. HR patients were treated with a five-drug induction, followed by six
intensive multiagent blocks and the identical reintensification as SR and MR
RESULTS
patients. CNS-directed therapy consisted of 11 doses of IT MTX for both SR and
MR, whereas HR patients received five doses of IT MTX and six doses of triple The number of patients classified into each of the different
intrathecal therapy. Prophylactic cranial irradiation was given after reintensifi-
CNS status groups is shown in Table 1. CNS1 status was
cation only to patients with T immunology or to HR patients (12 Gy). Patients
with CNS2 and TLP⫹ disease received two additional doses of IT MTX during diagnosed in 79.77% of patients; 2.88% were found to have CNS
induction. Some TLP⫹ patients (n ⫽ 7) were treated as having CNS3 disease leukemia (CNS3). The remaining 17.34% of patients are divided
although CSF findings were not consistent with the CNS3 definition described among the other groups: CNS2 (5.12%), TLP⫹ (6.71%), and
previously. Patients with CNS3 status received four (five for HR patients) TLP⫺ (5.51%). Among the 58 patients diagnosed with CNS3
additional doses of IT therapy and therapeutic cranial irradiation with 18 Gy.
status, six were defined as having CNS leukemia by demonstra-
Maintenance therapy was without IT therapy.
tion of a cerebral/meningeal mass only, and three could be
Statistical Analysis defined as having CNS3 status by presence of blasts without CSF
The duration of EFS is defined as the time from diagnosis until the date of the pleocytosis in combination with cranial nerve palsy.
first adverse event (relapse, death for any reason, or the development of a second Evaluation of the patient characteristics among the different
malignancy) or, if no such event occurred, until the date of last contact. Patients CNS status groups revealed that CNS2, CNS3, and TLP⫹
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130.113.86.233
186 BÜRGER ET AL

Table 2. CNS Treatment According to CNS Status

All CNS1 CNS2 CNS3 TLP⫹ TLP⫺

(n ⫽ 2,012) (n ⫽ 1,605) (n ⫽ 103) (n ⫽ 58) (n ⫽ 135) (n ⫽ 111)

Treatment, CNS negative 1,716 1,560 26 0 36 94

Additional IT MTX in protocol I 201 17 76 3 88 17
Treatment, CNS positive 62 3 0 52 7 0
Unknown 33 25 1 3 4 0

Abbreviations: TLP, traumatic lumbar puncture; IT MTX, intrathecal methotrexate; CNS, central nervous system.

groups include a higher percentage of unfavorable characteris- patients with T-ALL showed a result similar to that for the
tics, as shown in Table 1. Compared with CNS1 patients, CNS2, overall CNS status groups, but because of small numbers,
CNS3, and TLP⫹ groups had significantly higher WBC counts these differences were not statistically significant.
at diagnosis (Wilcoxon test, P ⫽ .0001) and significantly fewer Regarding CNS-directed therapy, we compared the TLP⫹
SR patients and more HR patients (␹2 test, P ⱕ .01). A patients (B-precursor and T-ALL combined) treated as CNS
statistically significant difference in platelet count could not be negative (n ⫽ 36) with those who received two additional doses
identified (median platelet count in TLP⫹ patients: 46,500/␮L; of IT MTX (n ⫽ 88). No statistically significant difference could
median platelet count in CNS1 patients: 55,000/␮L; Wilcoxon be demonstrated, although there was a tendency toward higher
test, P ⫽ .13). Regarding immunology, in the CNS2 group, there EFS with additional IT MTX (77% [SE 5%] v 66% [SE 9%],
were significantly more patients with T- and pro-B-ALL. T- P ⫽ .69). The same was also observed for the CNS2 group: 73%
lineage ALL was significantly more frequent in CNS3 patients EFS (SE 10%) for patients treated as CNS negative (n ⫽ 26)
(␹2 test, P ⱕ .01). The CNS-directed therapy in the different versus 82% EFS (SE 5%) for patients treated with two additional
groups is shown in Table 2. doses of IT MTX (n ⫽ 76, P ⫽ .36).
The 5-year EFS estimates (⫾ SE) for patients in each group The distribution of relapses within the different CNS status
were as follows: CNS1, 80% (⫾ 1%); CNS2, 80% (⫾ 4%); groups is shown in Table 3. From 2,012 patients, 20 were excluded
CNS3, 50% (⫾ 8%); TLP⫹, 73% (⫾ 4%); and TLP⫺, 83% (⫾ from the analysis because of death before complete remission (n ⫽
4%; Fig 1). The EFS for CNS1, CNS2, and TLP⫺ groups were 15) or nonresponse (n ⫽ 5). For CNS1 patients, the cumulative
almost identical at 80%. Compared with CNS1 patients, the incidence (CI) for any relapse is 0.17, of which the CI for an isolated
prognosis of the TLP⫹ group was significantly worse (73%, P ⫽ or combined CNS relapse is 0.04 and for other relapses (bone
.003). CNS3 status had the worst prognosis, with a 5-year EFS marrow, testes, other) it is 0.13. This distribution is also found
estimate of 50% (P ⫽ .0001). If analyzed by the Cox regression among TLP⫺ patients. For CNS2 patients, the overall CI for
analysis (covariables: age ⬎ 10 years, sex, WBC count ⬎ relapses is identical to that of the CNS1 group. However, among the
100,000, response to prednisone, and T immunology versus CNS2 group, there is a higher proportion of relapses with CNS
B-precursor immunology), TLP⫹ and CNS3 status maintain involvement (CI 0.10) and a reduction in CI regarding other
prognostic significance (TLP⫹: RR ⫽ 1.5; 95% confidence relapses (0.07). For the TLP⫹ group, an increase in CI for all
interval, 1.02 to 2.2; P ⫽ .04; CNS3: RR ⫽ 2.3; 95% relapses is observed (0.20), the CI for relapses with CNS involve-
confidence interval, 1.4 to 3.6; P ⫽ .0005). Subset analysis for ment (0.08) being comparable to the CNS2 group, whereas the CI
for other relapses (0.12) is closer to the CNS1 group. As expected,
the CNS3 status patients experience the highest overall relapse rate
(CI 0.35), relapses without CNS involvement being the major
problem in this subgroup (CI 0.22).

DISCUSSION

In this study, we have shown that patients with five or fewer

WBCs per microliter in initial diagnostic CSF with blasts
(CNS2) have the same prognosis regarding EFS as CNS-
negative patients if treated with two additional doses of IT MTX
(EFS for both groups, 80%; SE 1% and 4%, respectively). TLP⫺
patients had the same overall outcome (EFS 83%) as CNS1 and
CNS2 groups. TLP⫹ patients, however, were found to have an
EFS of 73%, which is inferior to that of CNS1 patients (P ⫽
.003) but superior to CNS3 patients (EFS 50%, P ⫽ .001).
The distribution of patients within CNS status groups is
similar to the distribution reported by Gajjar et al,11 although
group sizes of CNS2, TLP⫺, and TLP⫹ patients are smaller in
Fig 1. Event-free survival (EFS) for the five CNS status groups is shown. Only our study (5%, 6%, and 7% v 15%, 10%, and 11%). This might
patients enrolled in the ALL-BFM 95 trial with a minimum follow-up of 2 years were
evaluated. The EFS of TLPⴙ patients is significantly inferior to CNS1 patients be the effect of our study being a multicenter study with 85
(P ⴝ .003), but superior to CNS3 patients (P ⴝ .001). participating institutions in Germany, Austria, and Switzerland,
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CNS INVOLVEMENT IN CHILDREN WITH ALL 187

Table 3. Distribution of Relapses According to CNS Status Groups in ALL-BFM 95 Trial

All CNS1 CNS2 CNS3 TLP⫹ TLP⫺

(n ⫽ 2,012) (n ⫽ 1,605) (n ⫽ 103) (n ⫽ 58) (n ⫽ 135) (n ⫽ 111)

All relapses 269 (0.17) 203 (0.17) 15 (0.17) 16 (0.35) 23 (0.20) 12 (0.12)
Relapses with CNS involvement 71 (0.043) 44 (0.035) 8 (0.10)* 7 (0.13)* 10 (0.08)* 2 (0.02)
Isolated CNS relapse 33 22 4 2 4 1
BM ⫹ CNS relapse 38 22 4 5 6 1
Other relapses 198 (0.131) 159 (0.134) 7 (0.07) 9 (0.22) 13 (0.12) 10 (0.10)
Other events (death during CCR, 61 (0.03) 42 (0.03) 2 (0.02) 5 (0.10) 6 (0.05) 6 (0.06)
second malignancy, LFU)

NOTE. Cumulative incidences are given in parentheses. Statistically significant differences compared with CNS1 patients are marked with an asterisk.
Abbreviations: BM, bone marrow; CCR, continuous complete remission; LFU, lost to follow up in CCR; CNS, central nervous system.

in which CSF samples have not always been centrally evaluated. (weekly for CNS2, CNS3, and TLP⫹ patients) and, second, by
Another explanation could lie in the fact that thrombocytopenic increasing the total number of IT chemotherapy applications
patients in most participating institutions of the ALL-BFM trials from 21 to 26. Another difference between the ALL-BFM 95
usually receive platelet transfusions before lumbar puncture, trial and the St. Jude studies XI and XII is the number of courses
especially if platelet counts are below 50,000/␮L, although with HD MTX. In the BFM trial, patients are exposed to HD
serious complications are an extremely rare event.19 However, MTX (5 g/m2) four times, whereas patients received two courses
the size of the CNS3 group (3%) is identical in both studies and HD MTX (2 g/m2) in study XI and five courses of MTX (1.5
matches that of most other reported trials, indicating that a g/m2) in study XII.10,22
multicenter approach allows a valid data collection. Compared with CNS1 patients, of whom the majority are
The CNS2 group contains higher percentages of patients with suffering systemic relapses, the relapses among CNS2 patients seem
unfavorable prognostic parameters. In this group, there are fewer to be more equally divided between those with CNS involvement
SR and more HR patients, more T and pro-B immunology, and and all other relapses. This distribution (50% relapses with CNS
more patients with higher WBC counts at diagnosis. The CSF involvement, 50% bone marrow and other relapses) was also found
findings can be interpreted as an expression of “minimal men- by Children’s Cancer Group investigators.9 As overall outcome is
ingeal leukemia,” which might correlate with a poorer prognosis. identical when compared with the CNS1 group, a modification of
However, with additional IT therapy and a total of four courses the treatment strategy for CNS2 patients does not seem mandatory.
HD MTX, these patients have a good prognosis, as previously It could be of interest, however, to examine whether the percentage
described by the Children’s Cancer Group and van den Berg et of blasts in CSF differential cell counts can identify a subgroup
al.8,9,20 Our result of an EFS of 80% is strikingly different than among CNS2 patients with an inferior prognosis compared with the
the experience from St. Jude’s Hospital, where CNS2 patients overall CNS2 group.
with regular CNS therapy had a survival of only 55%11 or The outcome for the TLP⫹ group also differs from the results
53%,10 respectively. This result is remarkable, as the number of reported by Gajjar et al,11 although the variation is not as
IT chemotherapy applications (nine to 13 times for lower-risk pronounced as for the CNS2 group. Reasons for this may be the
and 13 to 20 times for higher-risk patients) is comparable to trial time interval between diagnostic and TLP and the interval to the
ALL-BFM 95, and the percentage of patients receiving cranial second instillation of IT therapy. One has to ask, however, why
radiotherapy (RT) is higher in the St. Jude trials (21% in TLP⫹ patients have an inferior outcome, especially when
BFM-ALL 95 v 63% in study XI and 30% in study XII).5 One compared with CNS2 patients. One explanation could be that
explanation for this difference might be the fact that, in the St. this difference is the result of an iatrogenic introduction of blasts
Jude trials, IT therapy was generally not given at the time of the into the CSF. But it is not easy to understand why a single,
diagnostic lumbar puncture, but 24 to 48 hours later, and the iatrogenic introduction of blasts should cause a difference in
second IT therapy was not given until 3 weeks later, whereas in overall outcome, when patients with “minimal meningeal leuke-
our study, the second IT MTX was always instilled on day 12. mia,” as in the CNS2 group, can be handled quite easily with two
One could also argue that systemic treatment has improved with additional applications of IT MTX. Another hypothesis to
time; thus, a comparison between trials from 1984 up to 1991 explain the inferior outcome in TLP⫹ patients could be more
and one starting in 1995 is not appropriate. However, in the advanced disease, for example, with more perivenular or para-
ALL-BFM 90 trial (1990 to 1995), we found that survival of meningeal leukemic infiltrates, or a biologically different dis-
patients with CNS2 status was identical to the EFS in CNS1 and ease, permitting migration of leukemic blasts more easily.
TLP⫺ groups (80%, 80%, and 79% respectively; CNS2 group Bleyer23 reported that certain types of leukemia penetrate the
n ⫽ 30; M. Schrappe, unpublished data). In a subsequent study CNS with a higher rate (eg, T-cell leukemias) and that other
of 165 patients from 1991 to 1994, St. Jude investigators factors such as blast and platelet count, patient’s age, or maturity
reported that early intensification of IT therapy resulted in a of the blood-brain barrier are factors that influence ingress of
reduced cumulative risk for all relapses with CNS involvement leukemic cells into the CNS. We did not find significantly more
of 4.4%.21 This result, which is similar to our overall cumulative T-ALL or lower platelet counts among the TLP⫹ patients, but
incidence for relapses with CNS involvement (CI 0.043), was we did find a significant number of patients had higher initial
achieved, first, by intensifying IT therapy early in induction WBC counts compared with CNS1 patients. But by Cox regres-
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130.113.86.233
188 BÜRGER ET AL

sion analysis, TLP⫹ status maintains prognostic significance, What can we do for TLP⫹ patients? An introduction of
indicating that the higher incidence of unfavorable patient cranial RT for all patients with B-precursor ALL in this
characteristics cannot account for the observed difference in subgroup still remains an option in trying to improve outcome, as
EFS. Also, when comparing TLP⫹ patients with those in the the increased incidence of CNS relapses is the major problem
CNS2 group, which has a good prognosis, TLP⫹ patients do not among TLP⫹ patients. However, cranial RT might lead to
seem to have more advanced disease. On the contrary, the CNS2 significant toxicity or second malignancies in patients who
group comprises more patients with initial hyperleukocytosis, T otherwise have a good prognosis. There was also no statistically
immunophenotype, and prednisone poor-response or high-risk dis- significant difference in TLP⫹ patients treated as CNS negative
ease than does the TLP⫹ group. A third explanation for the inferior (EFS 66%) versus those treated with additional IT MTX (EFS
EFS in the TLP⫹ group could be that, among TLP⫹ patients, there 77%). However, we will continue to treat CNS2 and TLP⫹
are hidden CNS3 patients who are simply not identified at the time patients with two additional doses of IT MTX.
of initial diagnosis. Because the other possible explanations for the
In conclusion, this study has shown that CNS2 patients have
inferior outcome in TLP⫹ patients seem unlikely, we favor the
a good prognosis (EFS 80%) that does not require any intensi-
latter possibility— unidentified CNS3 patients—as the most likely
fication of CNS-directed therapy. TLP⫹ patients have an inferior
explanation for the observed difference in outcome.
prognosis compared with the CNS1 group (73% v 80%) but a
How can we identify true CNS3 patients within the TLP⫹
superior EFS compared with the CNS3 group (50%). In our
group? First, one could compare the CSF with the peripheral
blood differential cell count. If the percentage of blasts in the opinion, further intensification of CNS-directed therapy is not
CSF is significantly higher than in the peripheral blood, CNS3 mandatory at this time if the treatment schedule is comparable to
disease is likely. One could also compare the ratio of erythro- the ALL-BFM strategy. Evaluation of the ongoing ALL-BFM
cytes to leukocytes in the CSF and in peripheral blood. If this 2000 trial for CNS status and survival will further clarify the
ratio is smaller in the CSF compared with peripheral blood, prognostic significance of CNS2 and TLP⫹ findings.
CNS3 status might also be assumed. In our study, seven patients
in the TLP⫹ group were treated as having CNS disease because ACKNOWLEDGMENT
of their CSF findings. Among those, two suffered a relapse. We thank E. Odenwald, B. Puttkamer, and T. Büchner for expert cytology;
Although these numbers are small, one could expect more the data managers N. Götz, U. Meyer, I. Krämer, and K. Mischke for precise
relapses if this group consisted of true CNS3 patients. data management; and the nurses and doctors of all participating hospitals.

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