Eur J Haematoll997: 58: 26-31 Copyright 0 Munksgaard 1997

Printed in UK - all rights reserved EUROPEAN

JOURNAL OF HAEMATOLOGY
ISSN 0902-4441

High-dose methylprednisolone for children

with acute lymphoblastic leukemia and
unfavorable presenting features
Hiponmez G, Giimriik F, Zamani PV, Tuncer MA, Yetgin S, Gurgey A, G. Hiqsonmez', F. Giimriik',
Atahan L, Ozsoylu S. High-dose methylprednisolone for children with acute P.V. Zamani', M. A. Tuncer',
lymphoblastic leukemia and unfavorable presenting features. S. Yetgin', A. Giirgey', 1.Atahan'
Eur J Haematol 1997: 58: 26-31. 0 Munksgaard 1997. and S. Ozsoylu'
'Department of Pediatric Hematology, lhsan
Dogramaci Children's Hospital; *Department of
Radiation Oncology, Hacettepe University, Ankara,
Abstract: In an attempt to improve treatment outcome high-dose Turkey
methylprednisolone (HDMP, 20-30 mg/kg, once a day orally) was used
instead of a conventional dose of steroid (2 mg/kg/d, in 3 divided doses) in
children with acute lymphoblastic leukemia (ALL) with increased risk
factors. HDMP combined with cytotoxic agents (vincristine and .
L-asparaginase) resulted in an improved complete remission rate (94%) in
48 newly diagnosed children with ALL compared to 81% in 86 historical
controls receiving standard dose steroid combined with the same treatment
regimen. The bone marrow relapse rate was lower in patients who received
HDMP (31%) than in controls (56%). Treatment was discontinued in 56%
of 48 patients receiving HDMP and in 35% of 86 controls. The difference
was significant (p < 0.05). The 5-yr continuous complete remission rate was
significantly greater in patients received HDMP compared with the control
patients (60% vs. 43%, p < 0.05). HDMP treatment was well tolerated Key words: high-dose methylprednisolone - acute
without significant adverse effects. Moreover, during induction therapy the lymphoblastic leukemia -children
duration of leukopenia (< 2 x 109/L)was shorter in patients receiving HDMP. Correspondence: G. HiGsonmez, Department of
We conclude that HDMP combined with other antileukemic agents Pediatric Hematology, Children's Hospital, Hacettepe
increased the CR rate and prolonged the duration of remission in children University 06100, Ankara, Turkey
with ALL who had increased risk factors. However, the optimal dosage of Tel: 90-312-3241681
HDMP and its role in maintenance therapy should be determined in future, Fax: 90-312-3241681
I randomized studies. Accepted for publication 5 August 1996

Introduction
Glucocorticoids (GC) have been used successfully
in the treatment of acute lymphoblastic leukemia
(ALL) for almost 5 decades. In an effort to enhance
the effectiveness of GCs in ALL, massive doses
have been used, mostly before 1960 (1-5). The
clinical efficacy of high-dose GC therapy was
shown in ALL (1-4), even in patients who failed
to respond to standard-dose steroids (5). Although
increasing the doses of chemotherapeutic agents
has been shown to enhance the treatment response,
higher doses of other antileukemic agents were
included in the treatment protocols but steroids at
high doses were not. Recently, we have demon-
strated remarkable antileukemic effects of high-
dose methylprednisolone (HDMP, 20-30 mg/kg/day)
treatment (6) by inducing terminal differentiation
of leukemic cells in children with acute promyelo-
cytic leukemia and other subtypes of acute myelo-
blastic leukemia (AML) (7-9). Patients with AML
receiving HDMP-containing regimens have experi-
enced high remission rates and prolongation of the
duration of remission (10). In addition we have
obtained favorable results with HDMP as a single
agent in children with ALL refractory to initial
conventional chemotherapy and in relapsed atients
(11).Successful results with HDMP (1 g/m2P) alone
in the treatment of central nervous system (CNS)
infiltration, bone marrow and testicular relapse of
children with ALL were also reported by Ryalls
et al. (12).
Despite significant progress in the treatment of
ALL the prognosis in high-risk ALL patients
remains unfavorable. Therefore, the aim of the
present study was to evaluate the effect of HDMP

26
 High-dose methylprednisolonein ALL

containing regimens in an attempt to improve the Table 1 , Patient characteristics

outcome for children who had increased risk fea-
Patients received Historical
tures.
HDMP" controls

Patients and methods Number of patients 52 90

Malelfemale 28/24 59/31
Between 1 January 1990 and 1 January 1991, 52 Age (yr) <2 7 9
Age (yr) > I 0 12 28
(28 males, 24 females) children with previously WBC > 50 x 109/1 14 19
untreated ALL diagnosed according to FAB criteria Median 21.2 15
(13) entered the study if they had one of the Range 3.7-537 1.7-400
following increased risk features: white blood cell Liver 2 5 cm 18 37
(WBC) count greater than 50x 109/L,extramedul- Spleen > 5 crn 16 35
EMI""
lary infiltration (EMI), liver and/or spleen enlarge- Mediastinal 12
ment greater than 5 cm below the costal margins CNS 3
or age less than 2 yr or greater than 10 yr. Their Bone
median age was 5 yr (range 7 months to 15 yr). _______ ~ ~

Characteristics of the patients are summarized in * High-dose methylprednisolone, ** extramedullary infiltration

Table 1.
Informed consent was obtained from all patients
before treatment was started. The outline of the
treatment protocol is summarized in Table 2.
Initial chemotherapy consisted of methylprednisolone
(Prednol-L, 30-20 mg/kg/d), vincristine (VCR) and
L-asparaginase. Intravenous preparation of meth-
ylprednisolone was administered orally once a day.
CNS prophylaxis consisted of intrathecal (IT)
methotrexate plus prednisolone on d 1, 7, 21, 50,
90 and 130, and then every 3 months for the first
2 yr of continuation therapy. All patients received
cranial irradiation with 24 Gy. Consolidation therapy
consisted of VCR, adriamycin and cyclophospha-
mide weekly for 2 wk. Maintenance therapy con-
sisted of daily oral 6-mercaptopurine and weekly
methotrexate and cyclophosphamide to complete
a total therapy duration of 36 months. During the
continuation phase, patients received reinforcement
therapy every 3 months consisting of VCR and
adriamycin as well as cytosine arabinoside for
2 wk and methylprednisolone (20 mg/kg/d) for 7 d.
Patients with lytic bone infiltration did not receive
irradiation for bone. The patients were generally
followed in the outpatient clinic. Results in patients
receiving HDMP-containing regimens were com-
pared with 86 of 90 (because of early death of 4
patients) historical controls treated from 1January
1988 to 1 January 1990. These 86 patients had the
same eligibility criteria as the patients who received
HDMP (Table 1).They were treated with the same
treatment protocol but they received conventional
dose of prednisolone (2 mg/kg in 3 divided doses)
instead of HDMP. During reinforcement therapy,
they received prednisolone for 5 d.
Response criteria
Patients were considered to be in complete remis-
sion (CR) if the blast cells were found less than 5%
in the bone marrow with normal peripheral blood
and no evidence of leukemic infiltration of other
sites. Relapse was defined as the presence of more
than 5% bone marrow blasts or any extramedullary
microscopically documented leukemia. CNS leuke-
mia was assumed when there were >5 nucleated
cells/mm3 with the presence of blasts in the cyto-
centrifuged sediment of the cerebrospinal fluid.
None of the patients in either group received
prophylactic antibiotics or antifungal agents and
supportive care was not standardized in the proto-
col. In the study group the initial cytoreductive
response to induction therapy was evaluated on
bone marrow aspirates on d 7 and 15, and it was
repeated prior to consolidation therapy. The dura-
tion of remission was measured from the date of
achieving CR to that of relapse. Refractory disease
was defined as failure to achieve CR after comple-
tion of induction chemotherapy. Continuous com-
plete remission (CCR) analysis was based on patients
achieving CR. It was computed on the total group
of protocol patients by the method of Kaplan &
Meier. Toxicity was graded according to the World
Health Organization (WHO) criteria. This prelimi-
nary evaluation reports on 48 patients assessed as
of February, 1996.
Results of treatment
The overall results are presented in Table 3. Three
of the 52 patients developed fatal cerebral hemor-
rhage, and 1 died of infection before the onset of
therapy; thus these patients were not included in
the evaluation. One patient of the remaining 48
died with septicemia 2wk after the initiation of
induction therapy. Two children (1 presented with
lytic bone infiltration) did not respond to treat-
ment.

27
Hiqsonmez et al.

Table 2 Outline of therapy (81%) of the 86 evaluable historical controls. Bone

marrow aspirates could be obtained on d 7 and 15
Induction therapy in 31 of the 48 patients. Marrow aspirate contained
Methylprednisolone 30 mg/kg/d p.0 d 1-7 a median of 9% blasts (range 0-77%) and 2%
20 mg/kg/d p o d 8-15 blasts (range 0-56%) on d 7 and 15, respectively.
20 mg/kg/d p.0 d 17, 19, 21. 23, Blast cells were less than 5% in 10 (32%) of 31
25. 27, 29
Vincristine 0.05 mg/kg i.v d 1. 8, 15. 22
patients on d 7 and in 71% of patients on d 15.
t-Asparaginase 200 U/kg i.m d 3-5, 10-12. Since the bone marrow aspirates were not
17-19 obtained on d 7 and 15, the initial cytoreductive
CNS prophylaxis response could not be evaluated in the control
Methotrexate 0 5 mg/kg IT
IT
group. During induction therapy the median dura-
Prednisolone 0.5 mg/kg
Cranial irradiation 2400 Rad tion of leukopenia ( < 2 x 109/1) was 9.8 f5.6 d
(range 3-23 d) and 11.3k6.0 d (range 3-21 d) in
Consolidation therapy
patients who received high-dose or conventional
Vincristine 0 05 mg/kg i.v. d 29, 36 doses of steroid, respectively. The difference in the
Adriamycin 1 mg/kg i.v. d 29. 36
duration of leukopenia between the 2 groups was
Maintenance therapy significant ( p < 0.05).
6-Mercaptopurine 1.5 mg/kg/d p.0. Four of the 45 children in the study group died
Methotrexate 1 mg/kg p.0. once a week within 1yr after achieving remission due to pulmo-
Cyclophosphamide 3-5 mg/kg p.0. once a week nary infection in 3 and varicella in 1. Treatment
Methotrexate + Prednisolone i.t. every 3 months
for 2 yr
was discontinued in 27 (56%) (including 5 patients
who developed isolated CNS infiltration) of the 48
Reinforcement (Every 3 months)
patients received HDMP compared to 30 (35%)
Vincristine 0.05 mg/kg i.v. d 1, 8 (including 6 patients who developed isolated CNS
Adriamycin 1 mg/kg i.v. d 1. 8
i.m. d 1-3, 8-10
or testicular infiltration) of the 86 historical con-
Cytarabine 3 mdkg
Methylprednisolone 20 mglkg P.O. d 1-7
trols, which was statistically significant ( p < 0.005).
Following the isolated CNS or testicular relapse,
patients in both groups have remained in CCR for
more than 5 yr. Of the 45 patients 27 (60%) were
Table 3. Overall results of treatment
in CCR with a median of 63 months (range 50-71
HDMP" + Pred"" + months). However, of the 70 historical control
chemotherapy chemotherapy patients who achieved remission, 30(43 YO) still
remain in CCR with a median of 84 months (range
Number of patients 52 90
55-94 months). The Kaplan-Meier analysis for
Death before chemotherapy 4 4
Patients evaluable 48 86 5-yr CCR rate of patients who received HDMP
Death during induction 1 compared with 70 historical controls is shown in
Nonresponder 2(4%) 16(190/,) Fig. 1. Since the outcome for patients related to
CR 45(94%) 70(81%) sex at diagnosis is an important factor, we evalu-
Death in CR 4 1
Relapse
ated its effect in our patients. In the study group,
Bone marrow 14131%) 39(56%) after 36 months of CCR, treatment could be
Testis - 3(4%) stopped in 50% of the male children (13 of 26
CNS 5(11%) 3(4%) males) compared with 22% of the historical control
Off therapy""" 27/48( 56%) 30/86(35%)
males (12 of 55 males) (p<O.O5). It was discon-
CR: complete remission.
tinued in 54.5% and 41% of females in the study
*: High-dose methylprednisole (20-30 mg/kg); **: prednisolone (2 mg/kg); and historical control group, respectively. Treat-
*I*: including patients who developed isolated CNS or testicular relapse. ment was stopped in 67% of children over 10 yr of
age (8 of 12 patients) received HDMP compared
with 18% (5 of 28 patients) of the historical
CR was achieved in 45 of the 48 (94%) patients. controls (p<0.05). Fourteen (31%) of the 45
With the exception of 4 patients who had lytic bone patients who received HDMP had bone marrow
infiltration, CR was achieved after a median of relapse after a median time of 14 months (range
3 wk (range 1-8 wk). Radiological findings of bone 2-14 months). It occurred in 39 (56%) of the
infiltration in 4 responding patients were found 70 patients who received conventional doses of
normal between 2 and 4 months after the initiation steroids after a median time of 13.5 months (range
of treatment. The overall CR rate (94%) of 2-36 months).
patients treated with HDMP containing regimens In the study group 5 patients presented with
was considerably higher than that obtained in 70 lytic bone infiltration at diagnosis. The localization

28
 High-dose methylprednisolone in ALL

and outcome of these patients are shown in %

._
Table 4. CR was achieved in 4 patients; 3 are 100

still in CCR. Mediastinal infiltration was present 80

n:45
at diagnosis in 8 of the 48 and 12 of the 86 chil- 60
dren in the study and the historical controls, respec-
tively, and the remission rate was almost the same -- -1 n:70
(71% vs. 72%). However, treatment was able to be
0
-Historical Control
-
J
- ~~

stopped at 36 months in 2 (25%) of the 8 patients 1 2 3 4 5

who received HDMP and in 2 (16%) of the Years after complete remission
12 patients who received standard-dose steroid.
Patients in both groups who initially had CNS Fig. 1. Continuous complete remission rate in ALL children
with increased risk factors with high-dose methylprednisolone
infiltration developed bone marrow relapse. As of and cytotoxic chemotherapy compared with historical controls
February 1996 none of the patients had developed (p i0.05).
relapse in the study group; however, 1 patient in
the historical controls developed bone marrow
relapse 44 months after the cessation of chemo- Table 4 Outcome in patients who had l v i c bone infiltration at diagnosis
therapy.
The major toxicity seen during the induction Localization of
therapy was infection, not exceeding WHO grade Patient's bone infiltration
ageW
2, with the exception of 1 patient who died with gender Vertebra Tibia Humerus CR Outcome
Gram negative septicemia 2 wk after the initiation
of induction therapy. HDMP administration was 1 15/F - - + + In remission
well tolerated without significant side effects. +
(61 )x
Five patients developed a mild cushingoid appear- 2 5/F - + - + In remission (68+)

ance, and mild hypertension was observed in

4 patients. Hyperglycemia occurred in 1 patient,
and 4 patients developed abdominal pain which
resolved after stopping HDMP treatment. No one
developed myopathy or other side effects of
steroids.
Discussion
In this report the therapeutic efficacy of the addi-
tion of HDMP to cytotoxic chemotherapy was
demonsrated in previously untreated ALL children
with unfavorable presenting features. The com-
plete response rate was 94% in patients treated
with HDMP combined with chemotherapy, com-
pared with 81% for historical controls receiving
conventional doses of steroid with the same treat-
ment protocol. In addition, the bone marrow
relapse rate was markedly lower in HDMP-treated
patients (31%) compared with historical controls
(56%). Duration of CCR in all responding patients
was improved. The overall 5-yr CCR rate was
significantly higher in HDMP receiving patients
(60%) than in patients receiving conventional
doses of steroid (43%), (p<0.05) (Fig. 1).These
results corroborate our previous results obtained
with HDMP combined chemotherapy in newly
diagnosed AML children (10). Improved survival
for patients with high-risk ALL has been reported
by using intensive chemotherapy protocols (14,15).
Because of different eligibility criteria it is difficult
to compare the results of the present study with
previously published studies. However, we believe
3 5/M + - - + In remission (64+)
4 6/M - - + + E M relapse (20)
5 3/F - - + NR
*: Numbers in parentheses indicate the duration of remission in months.
that the addition of HDMP to more intensified
chemotherapy protocols than used in the present
study will improve the outcome of these patients
more significantly.
Since gender is an important factor influencing
prognosis (16), the improved outcome in patients
treated with HDMP compared to historical con-
trols in the present study might appear to be
related to the relatively higher number of females
in the HDMP receiving group than in the his-
torical controls. However, the addition of HDMP
to the treatment protocol increased the 3-yr CCR
rate for both males (50% vs. 22%) and females
(54.5% vs. 41%), indicating the effect of treatment.
The outcome of patients over 10 years of age also
improved significantly by the addition of HDMP
( p < 0.05).
Although other cytotoxic agents at high doses
are not without risk of significant toxicity, steroids
at high doses have not been used in the treatment
of ALL because of the fear of risks and compli-
cations. However HDMP, usually at doses of
15-30 mg/kg/d (6-12, 17-23) and even in much
higher doses (2, 5, 19) has been used in various
hematologic and nonhematologic conditions (24-
26) without major adverse effects. It is worth
noting that when high-dose steroids have been

29
Higsonmez et al.
administered in a single dose, as used in the present
study, a lower rate of serious side effects were
observed (6-12, 17-23, 27), possibly due to rapid
clearance of steroids (28).
The pharmacological manipulation of apoptosis
(programmed cell death) has been reported to be
a promising approach for the treatment of leuke-
mia (29, 30). GCs have been shown to induce cell
death in lymphoblastoid cells by apoptosis (31).
Recently apoptosis has been shown to be a possible
way of destruction of lymphoblasts after predni-
solone treatment in children with ALL, without
indicating the dose (32). An increase in the apop-
totic cell death would be expected in leukemic cells
by increasing the dosage of steroid, as demon-
strated in the human lymphoid cell line in vitro
(33).
We have recently shown morphological evidence
of apoptosis in children with AML treated with
HDMP (34). A dramatic reduction in the size of
EM1 (35) in children with AML (8-10) and myelo-
dysplastic syndrome (36) might be explained by
HDMP induced apoptosis. In the present study,
HDMP-induced apoptosis may play a role in the
outcome of ALL children who initially had EMI.
Although the number of patients is small, the
outcome for patients presenting with lytic bone
lesions and mediastinal infiltrations treated with
HDMP is promising. Interestingly, in contrast to
control patients none of the patients who received
HDMP developed testicular relapse. Ryalls et al.
have also reported successful results in ALL chil-
dren with extramedullary disease with HDMP-
only treatment (12). A striking effect of high-dose
corticosteroid treatment has also been shown in
patients with Hodgkin’s disease and lymphoma
when conventional therapy and radiation were
ineffective (37).
Previously short-course (3-5 d) HDMP treat-
ment has been shown by us to shorten the duration
of chemotherapy induced leukopenia (< 2 x 109/1)
in children with ALL (38). In contrast to other
antileukemic agents, HDMP has been used suc-
cessfully in ALL and AML children who had
leukopenia at diagnosis (11, 39). In this study,
during the induction phase the leukopenic period
was significantly shorter in patients treated with
HDMP than that of historical controls, as observed
in our previous study (38, 40). Our clinical results
supported the results obtained by Kriegler et al.,
who showed the protective effect of dexametha-
sone on murine bone marrow during cytotoxic chem-
otherapy (41). Glucocorticoid-inducedleukocytosis
is a well-known phenomenon and leukocyte recov-
ery has been observed in patients with aplastic
anemia and myelofibrosis by HDMP treatment (17,
22). More recently we have shown that HDMP
30
treatment increases the hematopoietic CD34-posi-
tive progenitor cells in both bone marrow (40) and
peripheral blood (42) in children with acute leuke-
mia, possibly by increasing GM-CSF (43) and G-
CSF (44). The stimulation of normal myelopoiesis
by HDMP treatment could be an additional advan-
tage for patients with ALL.
In conclusion, the addition of HDMP instead of
standard-dose steroids to conventional antileukemic
agents increased the CR rate and prolonged the
duration of remission in ALL children who had
increased risk features. In further studies the opti-
mal dosage of HDMP and its role in maintenance
therapy should be determined in larger randomized
series.
Acknowledgements
The authors would like to express their appreciation to the
Department of Infectious Diseases and the Blood Bank for
their support of our patients and to all the doctors and nurses
who cared for these patients. We are especially grateful to our
nurses Miss Fatma Savas and Miss Miizeyyen Tetik for their
generous and enthusiastic help to these patients.
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