Leukemia & Lymphoma, February 2010; 51(2): 261–268

ORIGINAL ARTICLE: CLINICAL

Central nervous system involvement at presentation in childhood acute

lymphoblastic leukemia: management experience and lessons

RAM K. MARWAHA, KETAN P. KULKARNI, DEEPAK BANSAL, & AMITA TREHAN

Division of Pediatric Hematology–Oncology, Advanced Pediatric Center, PGIMER, Chandigarh, India

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(Received 28 July 2009; revised 30 October 2009; accepted 3 November 2009)

Abstract
This study was designed to analyze the spectrum of central nervous system (CNS) disease at diagnosis, traumatic lumbar
puncture (TLP), role of cranial irradiation, prognostic parameters, and survival outcome in patients with CNS involvement
amongst 747 patients with acute lymphoblastic leukemia managed at our center. Twenty-five and six patients had CNS
disease and TLP, respectively. Patients with CNS involvement had significantly higher mean presenting leukocyte count
( p ¼ 0.021) and incidence of hyperleukocytosis ( p ¼ 0.01) compared to those without it. The outcome was poor with three
For personal use only.

patients in continuous complete-remission, nine relapsers, eight deaths, and eight therapy defaulters. Three patients did not
opt for therapy. CNS involvement was significantly associated with inferior survival by log-rank ( p ¼ 0.03) analysis but not by
Cox-multivariate ( p ¼ 0.145) analysis. CNS involvement is a high-risk indicator. Poor outcome in our cohort indicates the
need for the revaluation of our treatment protocols with the inclusion of risk-stratified systemic therapy, categorization of
CNS involvement into CNS1/CNS2/CNS3, and appropriate use of intrathecal therapy.

Keywords: Central nervous system, event free survival, prognostic factors, relapse

PGIMER, Chandigarh from January 1990 to De-

Introduction
Acute lymphoblastic leukemia (ALL) with high-risk
features has an inferior outcome [1,2]. High-risk
indicators, factors influencing treatment and out-
come of ALL in developing countries have not been
adequately studied. Central nervous system (CNS)
disease at presentation and lumbar puncture (LP)
have been associated with increased risk and poorer
survival outcome [1–4]. However, data from devel-
oping nations describing CNS involvement at pre-
sentation and prognostic importance are scant [5,6].
In this communiqué, we describe the clinical
spectrum and our experience of managing patients
with ALL with CNS involvement at presentation and
lessons learnt thereby.
Material and methods
Seven hundred forty-seven children, age1–14 years,
with ALL enrolled in the pediatric oncology clinic of
cember 2005 were analyzed. Information concerning
demographic profile, symptoms, clinical features,
laboratory investigations, therapy administered, and
outcome was recorded. The study was approved by
Ethics Review Board of PGIMER, Chandigarh. The
follow-up data are as of February 2008 with a mean
follow-up duration of 66 months.
CNS status at presentation was classified into (a)
CNS1: absence of lymphoblasts in cerebrospinal
fluid (CSF) (b) CNS2/3: (i) presence of unequivocal
blasts in cytocentrifuged CSF irrespective of CSF cell
count (Group A) or (ii) overt CNS leukemia: the
presence of new onset focal neurological deficit or
raised intracranial pressure at presentation (Group
B), and (c) traumatic lumbar puncture (TLP):
defined as 10 or more erythrocytes/mL with identifi-
able lymphoblasts in CSF (Group C) [1].
Bulk disease was defined as the presence of one
or more of the following: enlarged lymph node
(42 cm), hepatomegaly (45 cm), and splenomegaly

Correspondence: Dr. Ram Kumar Marwaha, Professor, Division of Pediatric Hematology–Oncology, Advanced Pediatric Center, PGIMER, Sec 12,
Chandigarh 160012, India. Tel: þ91-172-2755303/09815466662. Fax: þ91-172-2744450. E-mail: rammarwaha1@rediffmail.com or
ketanpkulkarni@gmail.com

ISSN 1042-8194 print/ISSN 1029-2403 online ! 2010 Informa Healthcare USA, Inc.
DOI: 10.3109/10428190903470323
 262 R. K. Marwaha et al.

(45 cm). High-risk disease: Age 52 or 410 years,
presenting leukocyte count (PLC) 4 50.0 6 109/L,
bulk disease, T cell disease. Till recently, immuno-
phenotyping and cytogenetics were not routinely
available for risk assessment.
Treatment protocol
The treatment protocol used at our center was a
modified version of UKALL X protocol [7–9].
Remission induction chemotherapy consisted of
vincristine, prednisolone, L-asparaginase, and in-
trathecal methotrexate. More recently (after 2000),
patients with high-risk disease and/or those affording
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after January 2001, CNS irradiation was administered
only to patients with CNS disease or with ‘high-risk’
disease. The change in protocol after January 2001
was a move-forward in our endeavor to cure patients
with ALL in keeping with the contemporary proto-
cols. Owing to risk concerns of irradiation, young
children under 3 years of age received intrathecal
triple therapy (methotrexate, cytosine arabinoside
and hydrocortisone) at 12 weekly intervals till they
attained the age of 3 years. The dose of intrathecal
methotrexate was 8, 10, and 12 mg in children under
2, 2–3, and 43 years of age, respectively.
The maintenance therapy included daily oral 6-
mercaptopurine (60–75 mg/m2/day), weekly oral

the drug were administered doxorubicin in addition
to the above drugs during remission induction. All
patients received either an early or an early and
delayed intensification (vincristine, prednisolone or
dexamethasone, daunomycin and thioguanine) in the
form of 5-day blocks.
CNS-directed therapy (weeks 9–12) in patients
with/without CNS disease during the years of accrual
is detailed in Table I. Two hundred fifty-two and 280
patients were treated prior to and after January 2001,
For personal use only.
methotrexate (15–20 mg/m2/week) and 4 weekly
pulses of vincristine with prednisolone (40 mg/m2/
day) or dexamethasone (6 mg/m2/day). The total
duration of therapy was 27 months after attaining
complete remission (CR). Intermediate- or high-
dose systemic methotrexate was not used in this
treatment protocol.
Lumbar puncture

respectively. After January 2001, all patients received LP was performed by an experienced clinician under
14–15 doses of intrathecal methotrexate in contrast to deep sedation after appropriate informed consent in a
6 doses of intrathecal therapy prior to it. Similarly, dedicated area. The patients were kept nil by mouth

Table I. CNS directed therapy in patients with/without CNS involvement at presentation.

Patients January 1990 to December 2000 January 2001 onwards

Patients with Intrathecal methotrexate: six doses [three doses during Intrathecal methotrexate: six doses
CNS disease at induction (weeks 1, 3 and 4); three doses during CNS
presentation directed therapy (weeks 9–12)]
Cranial irradiation: 18 Gray in 10 fractions during weeks Cranial irradiation: 18 Gray in 10 fractions during
9–12 of therapy weeks 9–12 of therapy. Three monthly intrathecal
methotrexate during maintenance phase till end of
therapy (eight to nine doses)
Patients without Intrathecal methotrexate: six doses [three doses during Intrathecal methotrexate: six doses
CNS disease at induction (weeks 1,3 and 4); three doses during CNS
presentation directed therapy (weeks 9–12)]
Cranial irradiation: 18 Gray in 10 fractions during weeks Cranial irradiation: 18 Gray in 10 fractions during
9–12 of therapy weeks 9–12 of therapy to patients with ‘high-risk’
disease. Three monthly intrathecal methotrexate
during maintenance phase till end of therapy
(eight to nine doses)
Traumatic Intrathecal methotrexate: six doses [three doses during Weekly intra-thecal triple (methotrexate, cytosine
lumbar induction (weeks 1,3 and 4); three doses during CNS arabinoside and hydrocortisone) therapy 6 four
puncture directed therapy (weeks 9–12)] doses or till clear CSF
Cranial irradiation: 18 Gray in 10 fractions during weeks Intrathecal methotrexate: three doses (during weeks
9–12 of therapy 9–12 of therapy). Three monthly intrathecal
methotrexate during maintenance phase till end of
therapy (eight to nine doses)
Cranial irradiation: 18 Gray in 10 fractions during
weeks 9–12 of therapy to patients with ‘high-risk’
disease

CNS, central nervous system; CSF, cerebrospinal fluid.

 Central nervous system involvement in childhood leukemia 263

for 3–4 h prior to the procedure. Midazolam
(0.1 mg/kg, repeated as necessary) and/or ketamine
(1 mg/kg, repeated if necessary) were used. LP was
performed with the appropriate size of LP/spinal
needle. Intrathecal chemotherapeutic agents were
diluted to volumes up to 5 ml and administered
slowly over 2–3 min whilst diluting with CSF during
administration. In patients receiving triple intrathecal
chemotherapy, the medications were mixed prior to
administration. Post-procedure, patients were kept in
supine or semiprone position for 30 min to 1 h or till
they were fully awake and observed for headache.
The above protocol was followed during first and
each of the subsequent LPs.
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with and without CNS disease at presentation.
Cumulative risk of different types of relapse after
remission induction was estimated using the Kalb-
fleisch and Prentice test and the functions were
compared with Gray’s test [10,11]. Deaths were
considered as competing events in the estimation of
cumulative incidence for each type of relapse. Cox
multivariate regression analysis was applied to the
predictor variables to identify the factors significantly
associated with inferior survival outcome.
Results
Out of the 747 patients accrued, 31 (4.14%) patients

Based on the time from the initiation of therapy,
relapses were categorized as [10]: (a) very early:
relapse within 18 months of diagnosis, whilst on
chemotherapy, (b) early: relapse after 18 months of
diagnosis and within 6 months of treatment comple-
tion, and (c) late: relapse 46 months after treatment
completion.
Statistical analysis
For personal use only.
had CNS involvement at presentation. There were
13, 12, and 6 patients with CNS2/3 (Group A), overt
CNS leukemia (Group B), and TLP (Group C),
respectively. The rate of TLP was 0.8% (n ¼ 6 out of
747). The mean age at presentation was 69.8 + 15.6
months (range: 12–157 months) while the male:
female ratio was 2.75:1. The salient characteristics of
Groups A, B, and C patients are detailed in
Tables II–IV, respectively. Among patients with
overt CNS leukemia, cases 7, 9, and 10 had overt

The statistical analysis was performed from Decem-
ber 2008 onwards. The percentage, mean, and range
were used to describe continuous and categorical
variables. Qualitative variables in the two groups
were compared using the Chi-square test. Quantita-
tive variables were compared using the Student ‘t’
test. The event free survival (EFS) was calculated by
Kaplan–Meier method. EFS was derived from the
date of commencement of treatment to date of the
last follow-up or occurrence of an event (induction
death, induction failure, remission death, relapse, or
treatment default). Log-rank test was used to
compute ‘p’ value for survival analysis in patients
testicular disease, renal failure, and lytic lesions in
dorso-lumbar vertebrae, respectively at diagnosis.
The mean age, PLC, and platelet count at
presentation in Groups A, B, and C are shown in
Table V. The results of the comparative analysis of
salient clinical and laboratory characteristics in
patients with/without CNS disease at presentation
are enlisted in Table VI. The mean PLC and
incidence of hyperleukocytosis in patients with
CNS disease at presentation were significantly higher
compared to the other patients.
Twenty-eight out of 31 patients opted for therapy.
The outcome was dismal (Tables II–V). At the time of

Table II. CNS2/3 status at presentation.

Age Bulk Mediastinal PLC Platelet count EFS

Case (months) Gender disease adenopathy Hemoglobin (6109/L) (6109/L) Outcome (months)

1 48 Female 7 7 6.0 80.0 74.0 Death 0.2

2 24 Female 7 7 6.1 24.7 58.0 Loss to follow-up (in CCR) 29.0
3 132 Male þ 7 5.0 0.8 31.0 CNS relapse 19.0
4 12 Male þ 7 5.3 64.0 37.0 BM relapse 14.0
5 36 Female 7 7 4.1 120.0 10.0 Treatment default 15.0
6 132 Male 7 þ NA NA NA Death 0.7
7 12 Male þ 7 10.0 90.0 119.0 Death 0.5
8 84 Female þ 7 4.2 160.0 11.0 Death 0.8
9 48 Male þ 7 12.0 10.9 358.0 Treatment default 0.1
10 24 Male 7 þ 14.1 28.7 21.0 Death 22.0
11 108 Male 7 7 6.0 260.0 125.0 BM relapse 12.0
12 24 Female 7 7 12.1 144.0 22.0 BM relapse 9.0
13 84 Male þ 7 13.3 5.8 219.0 BM þ CNS þ ocular relapse 38.0

BM, bone marrow; CNS, central nervous system; CCR, Continuous complete remission; EFS, event free survival; PLC, presenting
leukocyte count; NA, Not available.
 264 R. K. Marwaha et al.

Table III. Patients with Overt CNS leukemia at presentation.

CNS feature at Bulk Platelet

Case Age Gender SDI presentation disease Hemoglobin PLC count Outcome EFS

1 62 Male 90 Right facial palsy No 8.0 14.4 150.0 Isolated ocular relapse 47
2 87 Male 45 Left facial palsy No 11.1 266.8 18.0 BM þ extrame-dullary 5
relapse
3 124 Male 6 Left hemiparesis, Yes 7.6 420.3 41.0 Did not opt for treatment –
left facial palsy, right
oculomotor palsy
4 110 Male 10 Left facial palsy No 10.3 15.5 29.0 Treatment default 0.2
5 39 Male 87 Paraplegia No 8.1 4.2 78.0 Did not opt for treatment –
6 132 Male 45 Paraplegia Yes 5.2 19.0 25.0 Treatment default 0.4
7 36 Male 120 Paraplegia Yes 7.3 11.9 22.0 Treatment default 0.7
8 127 Male 150 Paraplegia Yes 7.0 8.2 829.0 CCR 26
9 63 Male 90 Conus-medullaris syndrome No 4.3 0.8 19.0 Death 2
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10 122 Female 60 Decreased hearing No 11.0 20.0 154.0 Did not opt for treatment –
11 14 Male 7 Altered sensoruim Yes 7.0 223.0 5.0 Death before induction –
12 84 Male 4 Raised intracranial pressure 5.0 356.5 43.0 Treatment default 0.2

BM, bone marrow; CCR, continuous complete remission; CNS, central nervous system; EFS, event free survival; SDI, symptom diagnosis
interval; PLC, presenting leukocyte count.

Table IV. Patients with TLP at diagnosis.

Age Bulk Mediastinal PLC Platelet count EFS

Case (months) Gender disease adenopathy Hemoglobin (6109/L) (6109/L) Outcome (months)
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1 49 Female 7 7 12.0 105.0 43.0 Defaulted therapy 0.6

2 38 Male 7 þ 4.2 20.0 5.0 Isolated testicular relapse 25
3 26 Male þ 7 7.1 17.0 26.0 Defaulted therapy 0.4
4 88 Male þ 7 10.3 2.0 450.0 (In CCR) Lost to follow-up 32.0
5 157 Female þ 7 6.7 115.0 70.0 Death 17.0
6 39 Male þ 7 2.5 210.0 8.0 BM þ CNS relapse 7.0

BM, bone marrow; CNS, central nervous system; CCR, continuous complete remission; EFS, event free survival; PLC, presenting leukocyte
count.

Table V. Comparison of salient characteristics in Groups A, B, and C.

Parameter Group A (n ¼ 13) Group B (n ¼ 12) Group C (n ¼ 6)

Age (mean) 59.1 + 24.3 83.4 + 23.2 66.2 + 40.3

PLC (6109/L) (mean) 82.4 + 45 113.4 + 90.6 78.2 + 65.6
Platelet count (6109/L) (mean) 90.4 + 60.3 117.7 + 132.5 100.3 + 141.3
High risk disease (%) 9 (69.2) 8 (66.7) 5 (83.3)
Death 5 2 1
Relapse 5 2 2
Treatment default 2 4 2

PLC, presenting leukocyte count.

analysis, only three patients with CNS disease were in
continuous CR. Two of them were lost to follow-up
while a solitary patient was nearing completion of
therapy. Death and relapse were documented in eight
(29.6%) and nine (33.3%) patients, respectively
(Table V). There were three isolated bone marrow
(BM) and one each of isolated CNS, isolated
testicular and isolated ocular relapses. Combined
relapse was observed in three patients: one in BM þ
CNS, one in BM þ extramedullary, and one in BM þ
CNS þ ocular. All patients with BM relapse (isolated
or combined) were very early relapsers. Isolated
testicular and isolated CNS relapses were ‘early’
while ocular relapses (isolated or combined) occurred
‘late’. Incidence of CNS relapse was 11.1% (n ¼ 3) in
comparison to 8.3% (42 out of 502 patients who
opted for therapy) in patients without CNS involve-
ment at diagnosis (p ¼ 0.49). Eight patients defaulted
to therapy (Tables IV and V). There was a significant
(p ¼ 0.008) improvement in the CNS relapse rate
 Central nervous system involvement in childhood leukemia 265

Table VI. Comparison of salient clinical characteristics in patients with and without CNS involvement.

Patients with CNS Patients with CNS1 status

Parameter disease at presentation (n ¼ 31) at presentation (n ¼ 716) p value

Age (months) (range) 69.8 + 15.6 (12–157) 67.2 + 1.41 0.9

Male:female ratio 2.75:1 3.18:1 0.526
SDI* (days) 48.6 57.2 0.417
Bulk disease (%) 50 (n ¼ 15) 40.1 (n ¼ 287) 0.195
Mediastinal adenopathy (%) 16.6 (n ¼ 5) 13.0 (n ¼ 93) 0.400
Hemoglobin (g/dL) 7.52 7.08 0.418
PLC (6109/L) (range) 93.9 + 41.9 (0.8–420.3) 45.8 + 6.0 0.021
Leukocyte count 4100 6 109/L (%) 11 (35.4) 109 (14.6) 0.01
Platelet count (6109/L) (range) 103.3 + 62.6 (5.0–829.0) 78.2 + 6.6 0.238

SDI, symptom diagnosis interval; CNS, central nervous system; PLC, presenting leukocyte count.
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after the change of protocol in January 2001 from

11.5% (29 out of 252) to 5.7% (16 out of 280).
In the entire cohort, the cumulative risk of isolated
BM, CNS, and testicular relapse at 5 years follow-
up was 13.6 + 2.1, 6.8 + 1.3, and 4.3 + 0.9%,
respectively while that of combined relapse (BM
and/or CNS and/or testicular) was 7.8 + 1.6%. The
EFS in patients with and without CNS involvement
is depicted in Figure 1. Survival in patients with CNS
For personal use only.

involvement at presentation was significantly ( p ¼

0.03 by log-rank test) inferior as against patients
without CNS disease. Table VII depicts the sig-
nificance and odds ratio of the predictor variables for
survival in 530 patients who opted for therapy
according to Cox model. CNS involvement at
presentation was not significantly associated with
adverse outcome (p ¼ 0.145) while CNS irradiation Figure 1. EFS in patients with and without CNS involvement at
significantly (p ¼ 0.001) improved survival. Further- presentation.
more, high PLC and prolonged symptom diagnosis
interval (SDI) were other significant predictors of Table VII. Results for Cox multivariate regression model to
inferior survival outcome. determine the impact of predictor variables on survival.

95% CI for
Discussion odds ratio

Although cure rates of ALL in developed nations are Parameter p value Odds ratio Lower Upper
approaching 80–90% with contemporary risk-strati-
CNS involvement 0.145 1.551 0.860 2.796
fied protocols, survival outcome in developing at presentation
nations continues to remain modest [12–17]. Gender 0.096 0.760 0.551 1.050
Furthermore, data from resource-strained nations CNS irradiation 0.001 0.114 0.085 0.152
concerning incidence of CNS leukemia at diagnosis, Age 0.236 1.117 0.930 1.340
SDI 0.002 1.664 1.316 2.103
management experience, and impact on outcome are
PLC 0.001 1.360 1.208 1.530
largely unavailable. Moreover, CNS disease at Platelet count 0.083 0.855 0.716 1.021
diagnosis and CNS relapse continue to pose a Bulk 0.238 0.843 0.635 1.119
significant challenge in the endeavor to deliver cure Mediastinal adenopathy 0.09 0.757 0.550 1.102
to children with ALL even in resource-plenty nations
CI, confidence interval; CNS, central nervous system; SDI,
[18,19]. Our study was conducted in an attempt to symptom diagnosis interval; PLC, presenting leukocyte count.
address these concerns.
Authors have reported CNS2 and CNS33 status in
about 15–20 and 3% of children with ALL, 1.3% of the cases [5]. We observed CNS disease in
respectively [13]. On the contrary, in a study from 4.14% of the cases. Facial palsy, other cranial nerve
India, CNS involvement was reported in merely palsies, paraplegia, and deafness have been reported
 266 R. K. Marwaha et al.
as an initial manifestation of ALL in isolated case
reports or very small case series [20–26]. We
observed four cases each of unilateral facial palsy
and paraplegia. In addition, occurrence of conus-
medullaris syndrome and hearing defect in solitary
cases was noteworthy. In view of these varied
manifestations of CNS disease, a diagnostic delay
is likely and a high index of suspicion should be
maintained for prompt diagnosis and management.
Gajjar et al. reported a TLP rate of 16% and a 10%
rate of bloody LP. In comparison, our rates for TLP
were far lower (0.8%) [27]. Small numbers preclude
identification of risk factors although high PLC and
thrombocytopenia and bulk disease seem most likely
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[13,27,28]. Prone positioning after intrathecal che-
motherapy could be helpful [18,19].
Incidence of high-risk disease in patients with CNS
involvement was similar in Groups A, B, and C and
was only marginally higher than the 60–65% in-
cidence of high-risk disease in India [17,29]. How-
ever, these patients with CNS involvement had a
significantly higher mean PLC compared to other
patients with ALL which implicates an added risk. In
a recent study, Lazarus et al., in a study in adults,
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reported that a T-cell phenotype, high PLC, and the
presence of a mediastinal mass were associated with
CNS leukemia at diagnosis [30].
The outcome was dismal in patients with CNS
involvement despite low incidence of CNS disease
and TLP and was significantly inferior in comparison
to other patients with ALL. It is likely that more
patients with CNS disease at presentation belonged
to CNS3 status which could have contributed to the
unfavorable outcome. Larazius et al. have recorded
poor survival in adult patients with CNS disease
despite adequate therapy [30]. A study from South
India observed that CNS disease was independently
associated with inferior survival outcome [31]. In our
cohort, CNS involvement was significantly asso-
ciated with inferior outcome in univariate log-rank
analysis but in multivariate Cox regression analysis
only PLC, SDI, and CNS irradiation were significant
predictors. This implies that with appropriate ther-
apy, added risk due to CNS involvement could be
modified and that in our cohort other parameters
were more significant prognostic determinants. Our
study suggests that, as such, presence of any CNS
disease/involvement at diagnosis should itself
be considered as an indicator of ‘high-risk’ in
addition to the routinely used parameters atleast in
resource-limited settings. Furthermore, there is need
to assess the cytogenetic and molecular data in this
subgroup to better define their risk-categorization
[1,2,32].
Treatment default, loss to follow-up, and a higher
incidence of relapse and death, than in patients
without CNS involvement, were the major challenges
encountered. Sepsis and/or bleed were contributory
to majority of the deaths. In the entire cohort
financial constraints, poor socioeconomic status,
illiteracy, distant locales from a dedicated cancer
treatment facility, faith in alternate systems of
medicine, and insufficient facilities for shared and
acute care were the major hindrances encountered
locally [17]. We observed that even in patients with
CNS involvement, very early BM relapse was the
commonest while CNS relapse was more frequent
than other patients with ALL. These observations
indicate the need of reappraisal of our treatment
protocols with categorization of CNS disease into
CNS1, CNS2, and CNS3 [13,18,19]. Significant
improvement in the rate of CNS relapse after January
2001 suggests that the CNS-directed therapy used
prior to 2001 was probably inadequate although
CNS irradiation was used in all the patients. There is
a clear need to improve systemic control and use
intrathecal therapy more effectively.
Contemporary protocols have demonstrated the
efficacy and advantages of non-radiotherapy techni-
ques for CNS-directed therapy. However, till re-
cently, in resource poor nations, in view of a
multiplicity of factors enumerated above, CNS
irradiation was being advocated as a cheap, easily
available, and effective form of therapy. Our experi-
ence depicts the difficulties faced in managing
patients on an intensive chemotherapy protocol and
in designing remedial measures. The connotations of
sole use of CNS-directed chemotherapy, although
effective and advantageous; in an Indian setting
remain to be elucidated. Improvements in infra-
structural and cancer treatment facilities could
optimize its use. However, the importance of cranial
irradiation cannot be underestimated in a resource-
limited setting, more so, since, prior to 2000, very
scanty outcome data from India were available
[13,33,34]. Hence, although CNS irradiation must
have definitely contributed to the improvement in
cure rates of ALL in India as observed in our cohort,
its effectiveness is offset by substantial rates of
secondary neoplasms, endocrine disorders, growth
impairment, and neurocognitive dysfunction pre-
cluding its routine use [35,36]. With the use of
modified Medical research Council United Kingdom
2003 protocol, our unit has currently adopted the
policy of prophylactic cranial irradiation only to
patients with increased risk of CNS relapse. Further-
more, a recent study from St. Jude Children
Research Hospital proposes to completely omit
CNS irradiation in all childhood patients with ALL
with use of apt systemic therapy without increase in
incidence of CNS relapse or decrement in survival
outcome [37].
 Central nervous system involvement in childhood leukemia
In conclusion, CNS involvement at presentation
should be considered as a high-risk indicator. Appro-
priate methods and precautions to minimize the risk
of TLP and optimize intrathecal therapy should be
advocated. Identifications of risk-factors in Indian
patients with ALL, appropriate risk-stratification, use
of risk-adapted therapy protocols, use of cranial
irradiation only in high-risk patients, and assessment
of response to therapy along with adequate suppor-
tive facilities should definitely improve the overall
survival in ALL and outcome of patients with CNS
disease at initial presentation.
Declaration of interest: The authors report no
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conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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