Leukemia Research Vol. 13, No. 10, pp. 899-906, 1989. 0145-2126/89 $3.00 + .

00
Printed in Great Britain. Pergamon Press plc

L E U K A E M I A AND NUTRITION I: MALNUTRITION IS AN

A D V E R S E PROGNOSTIC FACTOR IN THE OUTCOME OF
T R E A T M E N T OF PATIENTS WITH STANDARD-RISK ACUTE
LYMPHOBLASTIC LEUKAEMIA*

EDUARDO LOBATO-MENDIZ,~BAL,* GUILLERMO J. RUIZ-ARG(JELLESt and ANTONIO MARIN-

LOPEZt
*tCentro de Hematologia y Medicina Interna de Puebla; tLaboratorios Clinicos de Puebla and
*Hospital Universitario de Puebla, Puebla, Pue, Mexico

(Received 9 February 1989. Revision accepted 13 May 1989)

Ahstract--A group of 43 pediatric patients with standard-risk ALL were studied. Thirty-seven per
cent of them presented with malnutrition at diagnosis. Malnourished children had a significantly worse
outcome than well-nourished children. Five-year DFS was 83% for well-nourished children (WNC)
and 26% for under-nourished children (UNC) (p < 0.001). Relapses presented more frequently in
the bone marrow in UNC than in WNC (56% vs 7%, p < 0.0001). The doses of maintenance
chemotherapy had to be reduced in 68% of UNC and 11% of WNC (p < 0.005); the doses of
maintenance myelosuppressive chemotherapy (6-MP, oral MTX and hydroxyldaunorubicin) received
by UNC were approximately 50% of those received by WNC (p < 0.01). The correlation between
malnutrition and compromised treatment was 0.92. Malnutrition might be included as an adverse
prognostic factor in acute lymphoblastic leukaemia (ALL).

Key words: Leukaemia, acute leukaemia, lymphoblastic, treatment, malnutrition.

INTRODUCTION
CHILDHOOD acute lymphoblastic leukaemia ( A L L ) is
a curable malignant disease. The factors predicting
the outcome to treatment of children with A L L have
been recognized [1-5], and include: age [6]; sex [6-
8]; race [9]; liver a n d / o r spleen enlargement [10, 11];
morphology (French-American-British Cooperative
Group (FAB)) of the blast-cells [12-14]; immuno-
logic phenotype of the blast-cells [3, 4, 15-17], white
* This work was supported in part by the Consejo Estatal
de Ciencia y Tecnologia de Puebla, M6xico.
Abbreviations: AL, acute leukaemia; ALL, acute
lymphoblastic leukaemia; AML, acute myeloblastic leu-
kaemia; HOP, hydroxyldaunorubicin, vincristine and
prednisone; MTX, methotrexate; 6-MP, 6-mercaptopu-
rine; CNS, central nervous system; UNC, under-nourished
children; WNC, well-nourished children; WBC, white
blood cell count; m 2, meter square of body surface; DFS,
disease free survival; FAB, French-American-British
Cooperative Group; PAS, Peryodic acid Schiff; AGC,
absolute granulocyte count; PC, platelet count; CR, com-
plete remission; HUP, Hospital Universitario de Puebla;
HMI, Centro de Hematologia y Medicina Interna de
Puebla; CALLA, common acute lymphoblastic leukaemia
(CD10) antigen; i. v., intravenous; bid, every twelve hours.
Correspondence to: Dr Guillermo J. Ruiz-Argiielles,
Consultant in Haematology, Laboratorios Clinicos de
Puebla, Diaz Ordaz 808, 72530 Puebla, Pue, Mrxico.
899
blood cell count (BC) at diagnosis [3, 11, 18]; plate-
let count at diagnosis [19]; central nervous system
(CNS) leukaemic infiltration at diagnosis [11, 20];
glucocorticoid receptors in the blast-cells [21];
Peryodic acid shift (PAS) reactivity of the blast cells
[1]; time to achieve complete remission [22,23];
chromosomal abnormalities [24], number of blast-
cells in D N A synthesis phase [25], etc.
Haematologists in Mexico involved in the treat-
ment of patients with acute leukaemia have observed
that the outcome of treatment of such patients is
worse than that observed in other developed
countries. The reasons seem to be various. We have
previously shown that in Mexico, morphology alone
leads to an erroneous classification of acute leu-
kaemia in about 20% of the cases [26-29]. Even in
groups of haematologists where the immunologic
classification of acute leukaemia (AL) is done on a
regular basis, Mexican haematologists obtain less
favourable results in the treatment of patients with
AL. These observations have been made in patients
studied and treated in city hospitals, where chemo-
therapy doses have to be reduced quite frequently.
Similar observations have been done in other devel-
oping countries such as Argentina (Pavlovsky, S.,
personal communication), Venezuela (Arends, T.,
90(1 E. LOBATO-MENDIZABAL et al.

personal communication), Brasil (De Carvalho, R.
I., personal communication), G u a t e m a l a (Moscoso,
C., personal communication), and even in some parts
of the United States (Coltman, C., personal com-
munication), where the site of treatment (private
practice or University hospital) has been considered
as a prognostic factor in the outcome to treatment
of adult patients with acute myeloblastic leukaemia
(AML); i.e. patients treated by physicians in private
practice do better than those treated by physicians in
University hospitals.
In this study we have analyzed the outcome to
treatment of a h o m o g e n e o u s group of patients with
standard-risk A L L . We examined 10 presenting fea-
tures: age; sex; W B C at diagnosis; FAB morphology;
immunologic profile of the blast cells; lymph node
enlargement; liver enlargement; spleen enlargement;
site of treatment (city hospital vs private practice)
and nutritional status. The first eight showed little
variation since they were used in part to place patients
in the standard-risk group. The last two, site of
treatment and malnutrition, were independent of
classification by risk category, and therefore more
heterogeneous. Only malnourishment had a signifi-
cant prognostic value: under-nourished children
(UNC) (n = 16) had a significantly worse outcome
to treatment than well-nourished children (WNC)
(n = 27). The poor outcome to treatment of UNC
was related to bone marrow relapses due to a poor
tolerance to maintenance myelosuppressive chemo-
therapy. Malnutrition was found to be an adverse
prognostic factor in the outcome to treatment of
patients with A L L .
MATERIALS AND METHODS
Patients
All pediatric (less or equal to age 15 years) patients
with ALL, studied and treated at either the Centro de
Hematologia Medicina Interna de Puebla (HMI) (private
practice) or at the Hospital Universitario de Puebla (HUP)
(city hospital) were prospectively entered in this study. In
order to select homogeneous group of patients, we chose
only those with standard-risk ALL, using a score system
modified from that of Palmer et al. [1], considering different
prognostic factors (age, sex, WBC at diagnosis, CNS infil-
tration at diagnosis, morphology of the blast cells, immune
phenotype of the blast cells, lymph-node, liver and spleen
enlargement) (Table 1). All patients with three or more
points were excluded from the study because their malig-
nancy was classified as high-risk ALL.
Treatment
All patients were treated with the same protocol; in
order to make the treatment absolutely homogeneous, the
drugs were supplied by the Asociaci6n Poblana de Apoyo
a Personas con Problemas Onco-Hematol6gicos A.C., a
non-profit organization devoted to support the treatment
of patients with haematoiogical malignancies, irrespective
of their social/economical status. The treatment used is
summarized in Table 2. The doses of doxorubicin, 6-mer-
captopurine (6-MP) and methotrexate MTX were dim-
inished according to the following: if the absolute
granulocyte count (AGC) was between 500 and 1000 and/
or the PC between 25,000 and 50,000, 50% of the doses
were delivered; if the AGC was lower than 500 and/or the
platelet count (PC) lower than 25,000, the drugs were

TABLE 1. SCORE TO DEFINE THE RISK OF PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL)
Variable Points Variable Points

(1) Age (years): (5) Liver enlargement (cm):

<2 2 <5 0
2-10 0 5-10 1
>10 2 >10 2
(2) WBC at diagnosis (//A): (6) Lymph-node enlargement (cm):
<25,000 0 >3 1
25,000-50,000 1 (7) Leukaemic infiltration at diagnosis:
50,000-100,000 2 Testis 3
> 100,000 3 Mediastinal 3
(3) FAB morphology: Central nervous system 3
L1 0 Kidney 3
L2 1
L3 3
(4) Immunologic phenotype:
CALLA/CDIO (+) 0
Null 1
T, B, pre B 3

Two or less points define standard-risk ALL; high-risk ALL is diagnosed with three or more points.
Modified from Palmer et al. [1].
WBC = white blood cell count.
 Lymphoblastic leukaemia and malnutrition 901

TABLE 2. SALIENT FEATURES OF THE TREATMENT EMPLOYED IN EVERY PATIENT

Dose
Drug (mg/m 2) Route Frequency, Duration

(A) Induction to remission, (HOP):

Hydroxyldaunorubicin* 25 i.v. every week ×6
Vincristine 1.4 i.v. every week ×6
Prednisone 60 p.o. daily for 6 weeks
(B) Consolidation of remission, ( H A T ) :
Hydroxyldaunorubicin 25 i.v. daily for 3 days
Cytosine arabinoside 100 i.v. daily for 5 days
Thioguanine 100 p.o. daily for 5 days
(C) Central nervous system prophylaxis:
Methotrexate 12 i.t. twice weekly ×5
Cranial irradiation 2400 cGy in twelve fractions
(D) Maintenance and periodic reinductions:
6-Mercaptopurine 50 p.o. daily for 30 months
Methotrexate 20 p.o. weekly for 30 months
H O P (Same as above, but only 3 doses) every 3 months for 30 months
Methotrexate 12 i.t. every 3 months for 30 months

m 2, meter square of the body surface; p.o., orally; i.t., intrathecal.

* Maximum accumulative dose: 500 mg/m 2

avoided. Vincristine, prednisone and consolidation of
remission dosages were not changed; 6-MP and oral MTX
doses were escalated to achieve a WBC of 3000-4000/mm 2.
Intrathecal MTX doses were not changed; the maximum
intrathecal MTX dose was 15 mg. Platelets and packed-red
cells were used as appropriate. No granulocyte transfusions
were given. Oral trimethoprim-sulfamethoxazole and keto-
conazole (both every 12 h) were used along the 5-week
period of induction.
Assessment o f the nutritional status
The tables constructed by Ramos-Galv~in, Cravioto and
G6mez et al. [30, 31] for normal values of weight and
height for Mexican children were used; malnutrition was
considered when the weight was at least 10% below than
the minimum ideal for age and sex minus 1 S.D., and
definite signs of malnourishment were present (failure to
thrive, hair loss, edema, cutaneous abnormalcies) [32, 33].
Studies in the leukaemic cells
In addition to morphological classification of the acute
leukaemias according to the FAB criteria [34, 35], the
immunologic phenotype of the blast-cells was also studied,
using a panel of immunologic reagents, previously shown
to be useful in the classification of acute leukaemia [26--
29], which included: E-rosetting; surface and cytoplasmic
immunoglobulin investigation and reactivity of the blast
cells with the following monoclonal reagents: Anti-com-

TABLE 3. FIVE YEAR DISEASE-FREE-SURVIVALWAS ANALYZED AND GROUPS OF

PATIENTS COMPARED

Feature Comparison of groups p value

Age <10 vs >10 years NS*

Sex male vs female NS
F A B morphology L1 vs L2 NS
WBC at diagnosis <20,000 vs >20,000 NS
Neutrophils at diagnosis <1,000 vs >1,000 NS
Immunophenotype C A L L A / C D 1 0 ( + ) vs ( - ) NS
Adenomegaly <3 cm vs >3 cm NS
Splenomegaly present vs absent NS
Hepatomegaly present vs absent NS
Site of treatment city hospital vs private NS
Nutritional status well vs under-nourished <0.01

The only significant difference was found between well-nourished and under-
nourished children using the log-rank X 2 method [36, 37].
F A B , French-American-British cooperative group; WBC, white blood cell
count; C A L L A , Common acute lymphoblastic leukemia (CD10) antigen.
* Not significant.
902 E. LOBATO-MENDIZ,&BALet al.
TABLE 4. OVERALL FEATURES AND RESULTS OF ALL THE PATIENTS ENTERED IN THE
STUDY
Number of patients
Sex: Male
Female
Age range (years)
WBC range, (x 109/1)
Neutrophils range (x 10/1)
FAB classification: Ll(%)
L2(%)
Immunophenotype: CALLA/CD10 (+) (%)
Null, non-T, non-B (%)
Site of treatment: City hospital (%)
Private practice (%)
Nourishment status: Malnourished (%)
Well nourished (%)
Complete remission achievement (%)
Five year disease-free survival (%)
Relapses (%)
Off-therapy (%)
WBC, white blood cell count at diagnosis; CALLA, common acute lymphoblastic
leukaemia (CD10) antigen.
mon acute lymphoblastic leukaemia antigen (CALLA)/
CD10; anti-CD15; anti-CDwl4; anti-coagulation factor
VIII; Von Willebrand factor; anti-plasma cell antigen and
anti-transferrin-receptor antigen. Cytochemistry was used
when the morphological and immunologic studies were not
enough to classify the leukaemias.
Statistical analysis
Survival plots were constructed according to Kaplan and
Meier [36]. Differences in survival were assessed by means
of the log-rank %2 method [36]. Intergroup comparisons
were assessed by means of the Fisher's exact and Student's
t-test [37]. The variables depicted in Table 3 were analyzed
in their impact on survival.
RESULTS
Patients
Between March 1983 and April 1988, 52 patients,
less than 15 years of age, with A L L were studied and
treated. Nine patients were excluded from the study
on the basis of high-risk ALL: two patients with pre-
B ALL, one patient with B-ALL, two with T - A L L
and four with more than three points in the score
described. Forty-three patients were included in the
study.
Total group
Table 4 summarizes the overall features of the
group of patients studied.
Analysis of prognostic factors
As expected, not all the homogeneous variables had
a significant impact on the survival of the patients
43
21
22
2-15, median 5
1.4-99.0, median 4.9
0.0-12.6, median 2.1
72
28
95
5
53
47
37
63
95.3
67
41.4
27
(Table 3). Of the two heterogeneous variables (site of
treatment and nutritional status), only malnutrition
was found to be associated with a significantly worse
outcome. Even though 5-year disease-free survival
(DFS) is 72% for patients treated at the private prac-
tice and 44% for those treated at the city hospital, the
difference is not significant.
Table 5 shows the response to treatment, survival,
relapses and chemotherapy doses of the patients div-
ided into two groups: under-nourished and well-nou-
rished. In order to have more information on the
cause of significantly more frequent bone marrow
relapses in UNC, after having achieved complete
remission (CR), we analyzed the amount of main-
tenance myelosuppressive drugs (oral 6-MP, oral
MTX and i.v. adriamycin). Neutropenia and
thrombocytopenia, as described above, were the only
reasons for reducing the amount of chemotherapy;
in some cases they were presented together with data
of mucositis. We found that chemotherapy had to be
reduced significantly more frequently in UNC than
in WNC; in addition, the total amount of myelo-
suppressive chemotherapy was significantly lower in
UNC than in WNC (Table 5). The correlation
between malnutrition and compromised treatment
was 0.92; UNC with compromised treatment (n =
12) had a 5-year DFS of 9%, whereas WNC with
optimal treatment (n = 24) had a 5-year DFS of 92%
(p < 0.001). Irrespective of the nutritional status, the
5-year survival of the children treated with compro-
mised treatment was 7%, whereas that for children
with optimal doses was 65% (p < 0.001). One out of
 Lymphoblastic leukaemia and malnutrition 903

TABLE 5. OUTCOME OF TREATMENT, SURVIVAL, RELAPSES AND DOSES OF CHEMOTHERAPY OF THE PATIENTS DIVIDED INTO
TWO GROUPS: WELL-NOURISHED AND UNDER-NOURISHED

Feature Well-nourished Under-nourished p value

Complete remission achievement (%) 98 94 NS*

Five year disease-free survival (%) 83 26 <0.001
Deaths in complete remission (%) 7 6 NS
Deaths in relapse (%) 4 63 <0.001
Relapses, total (%) 18 75 <0.0005
Isolated CNS relapses (%) 11 19 NS
Bone marrow relapses (%) 7 56 <0.0001
Reduction of chemotherapy doses, due
to granulocytopenia or
thrombocytopenia (%) 11 68 <0.005
Daily 6-MP received, median (ideal = 50) (mg/m 2) 48 22 <0.01
Weekly MTX received, median (ideal = 20) (mg/m 2) 19 10 <0.01
Hydroxyldaunorubicin per dose, median (ideal = 25) (mg/m 2) 24 11.7 <0.01
Hydroxyldaunorubicin cumulative dose, median (mg/m 2) 428 228 <0.01

The differences have been analyzed using both the log-rank and the Fisher's exact test [36, 37].
CNS, central nervous system; 6-MP, six mercaptopurine; MTX, methotrexate.
* Not significant

I00 adverse prognostic factor in patients with A L L . In

developing countries, where the number of mal-
80 nourished patients is high, this observation may be
critical. In our group of pediatric patients, 37% of
so them were malnourished at the time of diagnosis.
Iz: Even though we do not know the prevalence of
It) I I p<O.O01
ae 40_
malnutrition in children with A L in developed

l,
UNDER NOURISHEDCHILDREN (n=16)
I= ALIVE IN COMPLETE R E M I S S I O N
' I~0 ' 2~0 ' 5no ' 4'0 ' 5~0
TIME IN M O N T H S
FIG. 1. Survival of the two groups of children (well-
nourished and under-nourished) according to Kaplan and
Meier [36]. Differences are significant according to the log-
rank X2 test [37].
24 WNC became malnourished during the treatment;
that patient had a survival of only 6 months. On the
other hand 62.5 % of UNC improved their nutritional
status during treatment; their median DFS was 22
months vs 7 months for those who did not improve
their nutritional status.
DISCUSSION
This study shows that malnutrition is related to the
prognosis of patients with standard-risk ALL: under-
nourished children had a worse outcome to treatment
as compared with well-nourished children. Mal-
nutrition had not been previously identified as an
countries, we feel that it may be lower than that we
have found in this study.
Malnutrition was associated with a shorter survival
of patients due to bone marrow-related relapses. The
~ 6'0
reason for these relapses was apparently insufficient
myelosuppressive chemotherapy during the main-
tenance phase of the anti-leukaemic treatment;
myelosuppressive drugs could not be delivered in the
proper doses because UNC did not tolerate treatment
as well as WNC; thus the amount of maintenance
chemotherapy received by UNC was approximately
50% of the optimal dose, which was very close to
that received by WNC. The difference was found to
be significant at the 0.01 level (Table 5).
Malnutrition had been previously identified as an
adverse prognostic factor in patients with solid
tumors [38-40]. Dewys et al. have shown shortened
survival of low-weight patients with different types
of malignant diseases that included some cases of
non-Hodgkin's lymphoma and non-lymphoblastic
leukaemias [40]. In patients with cancer, the anti-
neoplastic treatment turns malnutrition into an
adverse prognostic factor because of increased hae-
mopoietic alterations [39]. It has been shown that
under-nourished individuals have impaired haemo-
poietic and immune functions [41, 42]. Diminished
904 E. LOBATO-MENDIZ,~BALet al.
growth of haemopoietic colonies (CFU-S) has been
shown in animals with protein-calorie malnutrition
[43]. In humans, under-nourishment leads to abnor-
mal mucopolysaccharide deposition in the bone
marrow, anaemia, decreased number of myeloid pre-
cursors and decreased granulocytic reserve [44--51].
Thymic atrophy associated with zinc deficiency has
been described in UNC and related to impaired
immunity and an infection-prone state [52]. All these
data support the hypothesis that the bone marrow
of UNC is less able to recover from the effects of
chemotherapy than normal bone marrow. This fact
could explain why UNC patients tolerate poorly
myelosuppressive chemotherapy during the main-
tenance phase and why UNC more frequently relapse
in the bone marrow. Myelosuppressive chemo-
therapy had to be reduced in 68% of UNC and 10%
of WNC (p < 0.005); the reductions in chemotherapy
were useful to avoid severe myelotoxicity in both
groups. Only two WNC (7%) and one UNC (6%)
died during CR, because of myelosuppression-associ-
ated mortality or morbidity (p > 0.5).
Inasmuch as the remission-induction treatment of
patients with A L L is not based on ablative chemo-
therapy, but on the exquisite sensitivity of the blast-
cells to the non-myelosuppressive agents vincristine
and prednisone, it seems logical that UNC did not
have a poorer outcome to remission induction treat-
ment as compared with WNC. The number of iso-
lated CNS relapses was not significantly higher in the
group of UNC than in WNC.
Children treated at the city hospital were more
frequently malnourished than those treated at the
private practice (52% vs 20%, p < 0.05). The dif-
ferences in outcome observed between these two
groups, both in long-term survival and bone-marrow
related relapses, are secondary to malnutrition,
which itself was the single independent isolated vari-
able with significant impact in the outcome to treat-
ment. It must be mentioned that compromised
treatment, i.e. sub-optimal doses of maintenance
chemotherapy, was also a variable, dependent on
malnutrition and associated with a bad prognosis.
The 5-year survival of children given compromised
treatment was 7%, whereas that for children receiv-
ing optimal treatment was 65%, p = 0.001. Compro-
mised treatment had to be delivered in 68% of UNC
and only in 11% of WNC (p < 0.005). The doses of
6-MP, oral MTX and hydroxyldaunorubicin were
significantly lower in the group of UNC. The cor-
relation between malnutrition and compromised
treatment was 0.92. It was therefore clear that mal-
nutrition was the reason for delivering sub-optimal
doses of chemotherapy to the patients.
Our data, together with those previously
published, suggest that UNC with A L L do have a
worse prognosis than WNC and that this difference
is related to a poor tolerance of the bone marrow to
myelosuppressive agents. Other alternative expla-
nations may be offered for the differences observed:
inasmuch as the immune surveillance in UNC is
defective, it is also possible that bone marrow
relapses occur more frequently due to defective clear-
ance of residual leukaemic cells. Altogether, these
data may explain in part why the treatment of patients
with A L L is less favourable in developing countries,
where malnourishment is rather frequent. Mal-
nutrition might be included as an adverse prognostic
factor in the outcome to treatment of patients with
ALL. In countries where malnourishment is a fre-
quent health problem, this observation may be
critical, perhaps in such places anti-leukaemic
chemotherapy has to be delivered together with a
nourishment schedule.
Acknowledgements--The authors are most grateful to
Dr Charles A. Coltman Jr for his helpful and careful
criticism of this paper. Drs Alvin M. Mauer, Jestls F. San-
Miguel, Alejandro Ruiz-Argiielles, Sergio Ponce-de-Le6n,
Joaquin Cravioto and Alejandro Cravioto are also
acknowledged for their comments. The drugs used to treat
the patients were kindly supplied by FUNDALEU and the
Asociaci6n Poblana de Apoyo a Personas con Problemas
Onco-Hematol6gicos A.C.
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