ChildhoodAcute

LymphocyticLeukemia
W. A. Smithson, M.D.

G. S. Gilchrist,MB., B.Ch.
E. 0. Burgert, Jr., M.D.

Introduction
Cancer is second only to accidents as a
cause of death in childhood. Acute leu
kemia, about 80 percent of which is the
lymphocytic
type (ALL), is the most
common cancer in children, with an in
cidence of 33.6/1,000,000
children under
15 years old.' In the past, ALL was al
ways fatal within a few months. Now,
however, most children respond favor
ably to available treatment, with a po
tential for cure of approximately
50
percent.
Recent reviews2-5 summarize the his
toric development
of the treatment of
thisdisease,
which began in 1948 with
Farber's use of folic acid antagonists. By
the mid-l960s combination drug therapy
and radiation therapy were introduced,
and in the mid-l970s literature from all
over the world3'6-8 reported complete re
Dr. Smithson is Consultant in Pediatric
Hematology-Oncology,
Mayo Clinic and
Mayo Foundation, and Assistant Professor
of Pediatrics, Mayo Medical School, Roch
ester, Minnesota.
Dr. Gilchrist is Vice Chairman of Pediatrics
and Consultant in Pediatric Hematology
Oncology, Mayo Clinic and Mayo Founda
tion, and Professor of Pediatrics, Mayo
Medical School, Rochester, Minnesota.
Dr. Burgert is Consultant in Pediatric
Hematology-Oncology,
Mayo Clinic and
Mayo Foundation, and Professor of Pedia
trics, Mayo Medical School, Rochester,
Minnesota.
158

missionslasting
fiveor more yearsin at
least half of the children (Fig. 1). Many
are probably cured of their disease, al
though it is uncertain if the disease is
always permanently
eradicated.
With success comes new responsibil
ity. Pediatric oncologists feel they have
the means to cure many children with
ALL, but they are disturbed by the ones
who are not cured. Complications
of
treatment,
such as immunosuppression
and CNS damage, may outweigh the
therapeutic benefits in some children. In
arriving at solutions to these problems,
much intense activity will have to be con
centrated in the following areas:

Refining diagnostic criteria so that all

children are treated appropriately.

Discovering
features of ALL blasts
and clinical presentation
associated
with good and poor prognosis.

Refining available therapy for those

with good prognosis,
to eliminateun
necessary toxicity, and developing new
approaches
to the child with a poor
prognosis.

Eliminating associated metabolic and

infectious complications.

Identifying the longterm harmful ef

fects of treatment and finding ways to
deal with them and eliminate them for
future patients.
These questions can only be answered
in the context of large-scale clinical trials,
in conjunctionwith laboratoryadvances
in subclassifying the leukemic blast cell.
CA-A CANCER JOURNAL FOR CLINICIANS

Many of these problems will become ir

relevant as knowledge about etiology is
expanded
or as new, highly effective
treatment is introduced. Until that time,
the empirical use of combination chemo
therapy, building on past experience, will
continue to be the means of improving
the current treatment programs.

callyrevealssheetsof lymphoblastsand
virtual absence of the normal cell lines.
Sometimes the normal marrow is so ex
tensively replaced by blasts (packed
marrow) that aspiration is impossible. A
biopsy and biopsy touch preparation,
such as that obtained with the Jamshidi
needle, is often necessary to obtain an
adequate sample for diagnosis and should
be routinelyincludedas a diagnostic
Diagnosis
procedure.'
Diagnosis is occasionally difficult. A
ALL can occur at any age from infancy
severely hypoplastic marrow without ob
to adolescence and even in adulthood.
vious lymphoblasts may be indistinguish
However, the form that is unique to
able from aplastic anemia; a prompt re
childhood has its peak incidence at ages
sponse to therapy with prednisone sug
three to five. Symptoms are nonspecific
gests ALL, and careful follow-up will
and sometimes are indistinguishable from
eventually lead to the correct diagnosis.
symptoms of viral illness. The child usu
Differentiation
from acute myelomono
ally looks ill but this is not always the
blastic leukemia (AMML)
may prove
case. Malaise, decreased appetite, and
difficult even for experienced hematopa
low-grade fever are common complaints.
staining with
Features relatedto pancytopenia are thologists. Cytochemica!
bleeding,
bruising,
petechiae,
and pallor. peroxidase, esterase, and Sudan black
Fever may be associated
with infectious which are negative in lymphoblastsmay
differentiate between ALL and AMML.'2
complications of neutropenia or with the
Terminal transferase is present in ALL
disease process itself. Bone pain and
but is not, as a rule, found in AMML
arthralgias, due to infiltration with leu
(see p. 164). The usual course in ques
kemic blasts, may at times mimic the
features
ofjuvenile
rheumatoidarthritis,tionable cases is to begin treatment de
signed for ALL, since it is less toxic than
Legg-Perthes disease, or even psychoso
thatforAMML; alsosome children
with
matic illness. Lymph nodes may be mas
morphologicfeatures
ofAMML
respond
sively enlarged or normal, and hepato
favorablyto thislessintensive
form of
sp!enomegaly is also variable, being pres
therapy.
ent in only about half of the patients.
In some instances clinical or labora
tory abnormalities
are found on routine
Classification of ALL
examination.9 Some abnormality of pe
ripheral blood counts is usually detected,
Morphology
although any single parameter may be
normal. The white blood cell count is With Romanovsky's stains (Wright's stain
over 10,0004J in only about 50 percent
is most widely used), lymphoblasts look
of patients; blasts may be absent from the
different
from patient
topatient.
Variable
peripheral blood but are usually found if
featuresincludecellsize;nuclearstruc
the white cell count is over 10,0004d.
ture; number, size, and distinctness of
Anemia and thrombocytopenia
are often,
nucleoli; amount of cytoplasm in relation
but not invariably, present.
to the nucleus; intensity of cytoplasmic
Chest x-ray may reveal a mediastinal
staining; and cytoplasmic inclusions, such
mass and should be obtained early in the
as vacuoles. Many attempts have been
diagnostic
evaluation,
sinceitmay be of made to systematically relate these differ
prognostic importance (Fig. 2).
ences to prognosis. Two recent proposals
Bone marrow examination
provides
are those of Math'3 and the French
American-British
(FAB)
cooperative
the definitive diagnosis in all cases. The
group.'4
aspirate, subjected to Wright's stain, typi
VOL. 30, NO. 3 MAY/JUNE 1980

159

(4)
C
a
U

a
0.

3
4
5
Years from Diagnosis
Published with permission from Denman Hammond, M.D.

Fig. 1 Combined experience of major cooperative groups treating childhood leukemia.

Dates indicate when treatment programs began. Progressive improvement in survival with
time is shown. (Hammond D: from a presentation to the Board of Scientific Counselors of
the Division of Cancer Treatment, National Cancer Institute, Bethesda, MD, March 26-28,
1979.)

Fig. 2 Chest x-ray of a four-year-old boy with 24 percent E-positive lymphoblasts show
ing anterior mediastinal mass often associated with T-ALL.
160

CA-A CANCER JOURNAL FOR CLINICIANS

.@

All systems associate larger cell size,

more cytoplasm,and inore numerous

and more prominent
nucleoli with a
poorer.prognosis.
The small lymphoblast
(lessthan the diameter of two small
lymphocytes) with a rim of cytoplasm and
one or no indistinct
nucleoli
isthemicro
lymphoblast
described by Math and
called Li by the FAB classification. It is
associated with a better prognosis. Even
though no system has been universally
accepted, recent reports of multi-institu
tional studies including central review of
morphology indicate that the FAB sys
tem can be correlated with prognosis. In
the FAB system, the smaller, more uni
form lymphoblasts with scanty cytoplasm
are designated Li. Larger, heterogeneous
blasts with more abundant cytoplasm and
more distinct nucleoli are designated L2.
L3 blasts are large and homogeneous and
are characterized
by abundant,
deeply
basophilic cytoplasm and striking vacu
olation(Table 1) (Fig.3). The Chil
dren's Cancer Study Group has reported
that children with Li (84 percent of the
group) morphology
have significantly
better prognosis than those with L2 (iS
percent) or L3 (one percent) morphol
ogy.15
Efforts to relate prognosis to cell size
alone have not been successful,'6
al
though a semiquantitative
scoring system
based on several variables, including cell
size, has shown promise.'7

.S.
.dmi

J@

()O

________@____

I
Fig. 3

Morphologic

subtypes

of childhood

ALL designated Li, L2, L3 by the FAB clas

sification.'4 (Courtesy R.V. Pierre, M.D.,
Rochester, Minnesota.)

Immunology

Anotherlineofinvestigation
subclassifies
ALL on the basis of cellular characteris
tics related to the thymic (T-cell) and
bursal-equivalent
(B-cell) origins of nor
mal lymphocytes. Blasts with the char
0
.
acteristics of T-cells form rosettes with
sheep erythrocytes
(E) and react with
antisera against T-lymphocytes.
Blasts
Fig. 4 Lymphoblasts from a 13-year-old
with characteristics
of B-cells have de
boy with ALL. The majority of the blasts
monstrable surface immunoglobulin
(Ig).
formed rosettes with sheep erythrocytes and
also had focal acid phosphatase activity in
The absence of such markers indicates
the Golgi region. Rosette formation and this
nullALL, which may be furthersub
type of acid phosphatase activity are
divided as more methods are devised to
strongly correlated. (Courtesy C.Y. Li, M.D.,
demonstrate T- or B-cell differentiation.'8
Rochester, Minnesota.)
VOL.30, NO.3 MAY/JUNE1980

161

162

CA-A CANCER JOURNAL FOR CLINICIANS

Further subdivisions of T, B, and null

groups have been made.18 Leukemia with
predominantly
T-cell characteristics
can
be related to various stages of differentia
tion and to the helper or suppressor func
tional grouping. Leukemia with B-cell
differentiation
can be subdivided into a
pre-B group by demonstration
of intra
cellular immunoglobulin'9
and by ex
pression of other receptors and different
classes of 1g. The null group has been
subdivided most definitively by Chessels'
identification
of an antigen designated
the common ALL antigen. Common
ALL antigen is present on blasts of the
majority of children with null ALL; this
group has a good prognosis compared to
common antigen-negative
patients.20
T-ALL usually accounts for about
22 percent of cases; B-cell for about three
percent; null cell about 15 percent; and
common
ALL for about 60 percent
(Table 2).
T-ALL has been associated with older
age groups, males, high white cell counts
at diagnosis, mediastinal masses, hepato
splenomegaly, and other clinical features
correlated with a poor prognosis. Several
groups have reported shorter remission
and survival in patients with T-cell char
acteristics.2023
Although it is clear that the sheep
erythrocyte receptor test identifies many
children with a relatively poor prognosis,
it has not yet been established as an inde
pendent prognostic factor. E-positivity is
often associated with features that are
considered unfavorable,24 but some chil
dren with E-positive blasts do not have
the clinical features correlated with early
relapse and appear to respond to treat
ment as well as those in the null group.
Standardization
of laboratory
methods
and careful analysis of groups of uni
formly treated patients will help to clarify
this issue. These studies can best be car
ried out in the cooperative groups, who

have access to large numbers of patients.

Acid phosphatase
(ACP)
activity
demonstrated
cytochemically
in a focal
distribution
in the Golgi region of the
leukemic blast has a strong association
with E-positive ALL25 (Fig. 4). How
VOL.30, NO.3 MAY/JUNE1980

ever, we and others have seen cases in

which the acid phosphatase

was positive

and the cells did not form E rosettes.

Thus, ACP determination
will not sub
stitute forbut may supplementthe
E rosette test. With the addition of T
cell antiserum these ACP-positive
cells
may be revealed to be of T-cell origin in
spite of being E rosette-negative.
B-ALL is morphologically
and clini
cally associated with Burkitt's lymphoma
and has a poor prognosis.26 Pre-B-cell
leukemia, on the other hand, has fea
tures associated with good prognosis and
tends to respond favorably.27
Patients with null cell ALL have
a better prognosis than the group with Bor T-cell differentiation.
Within the null
group, however, there is wide variability
of prognosis, and one determinant is the
presence or absence of the common
ALL antigen.20

Cytogenetics
Chromosomal abnormalities can be dem
onstrated
in blasts of about half the
children with ALL. The commonest ab
normality is hyperdiploidy,
followed by
pseudodiploidy
and hypodiploidy.28
Banding studies have shown no con
sistent pattern of abnormality other than
the translocation
between chromosomes
8 and 14 karyotype associated with both
Burkitt's
lymphoma
and B-ALL.26
Karyotypes
are usually normal in re
mission and tend to revert to the original
pattern at relapse, indicating persistence
of a clone of leukemic
cells.29 The
Philadelphia chromosome (Ph'), usually
found in chronic myelogenous leukemia
of adults, has been demonstrated
in a
small percentage of children with ALL,
and most of them have responded poorly

to treatment30 (Fig. 5). A better prog

nosis has recently been reported for pa
tients with hyperdiploidy.31
Previous
studies, most prior to the availability of

current therapies, failed to show differ

ences in prognosis

between patients with

normal and abnormal karyotypes. Fur

ther studies of the relationship of cyto
genetics to other risk factors and response
163

to treatment are clearly needed because

of the emerging prognostic implications.

Terminal Deoxynucleotidyl
Transferase (TdT)
TdT is a DNA-polymerizing
enzyme
normally found in.primitive lymphocytes
in thymus and bone marrow. At diag
nosis and relapse of ALL, high levels
have been found in bone marrow and
peripheral
blood. In general, null cell
ALL has the highest levels, with lower
elevations in the E-positive and B-cell
leukemias.32 TdT is useful in helping to
differentiate
lymphocytic
from myelo
monocytic leukemia, but it has not been
proved to have prognostic implications.
Elevated levels found during clinical re
mission are of unknown significance but
may be evidence of incomplete elimina
tion of the leukemic cell population.33

Potential Biologic Markers

A variety of markers are showing prom
ise in the emerging biologic subclassifica
tions of ALL. Among these are cortico
steroid membrane
receptors,34 5' nu
cleotidase,35 and adenosine deaminase.32
Clinical Features and Prognostic
Factors
Soon afterthe first
largegroups of chil
dren were treated with modern chemo
therapeutic programs, it was possible to
identify factors that predicted, with a
high degree of certainty, which children
were likely to survive.36'37 The most im
portant of these are age and initial white
count.Among childrenbetween theages
of three and seven, 80 percent with an
initial WBC of less than i0,000/@.@.lare
alive four years from diagnosis, whereas
children with white counts over
S0,000/@d have a median survival under
two years. Children under three or over
seven years old with a WBC of less than
l0,0004i1,
and any child with a WBC
between 10,000 and S0,000/pJ, have a
median survival of three years.38
164

Many other factors contribute

to
prognosis.38 In general, a large leukemia
burden augurs shorter survival, but the
situation is complex: higher hemoglobin
is correlated with poorer prognosis. Some
parameters are not independent, but are
associated with more important
prog
nostic indicators,
as illustrated by the
example of mediastinal mass: this find
ing is often associated with a high WBC
at diagnosis and is thus associated with a
poor prognosis. However, when a medi
astinal mass occurs with normal WBC,
prognosisisno worse than for children
without a mass.41 Table 3 lists additional
factors known to influence prognosis.
T-cell leukemia often presents with
many poor prognostic factors (male sex,
high WBC, older age) ,21 but it is not yet
known how important T-cell markers are
iftheyoccur ina patientwith otherwise
good prognostic
factors.
Multivariate analysis applied to data
from large groups of children will be
needed to rank these factors in order of
importance
and to determine which are
independent
variables. Future research
into the biology and treatment
of the
poor-prognosis
groups will be greatly in
fluenced by the findings.
Management

Stabilization
Initial treatment is directed to correcting
metabolic abnormalities,
preventing hy
peruricemia, correcting anemia, treating
thrombocytopenia-related
bleeding, and
controlling infection. This may require
up to 48 hours, but can usuallybe
achieved by 24 hours.
Allopurinol is started at diagnosis to
decrease the formation of relatively insol
uble uric acid from catabolic products of
leukemia cells. Hyperuricemia,
caused by
theturnoverofblastcells,
may occurprior
to antileukemic treatment and occasion
ally may be severe enough to produce re
nal failure before therapy can be started.
Alkalinization and high urine flow should
be established, and hyperuricemia
and
azotemia substantially
corrected before
CA-ACANCERJOURNALFORCLINICIANS

AcuteLymphocytic
Leukemia
60,XXY,-19,+4,+5,+6,+8,
+8,+13,+20,+20,+21,t(9@22)(q34iq11
),+5mars

81111
@

111)1
,@i
I;' U aui

@44
@*@S
@

13

14

15

16

20

18
/

Ml M2 M3

19

17

21

22 Y

Fig. 5 Karyotype of a bone marrow specimen from a 9-year-old boy with ALL in relapse.
The cells are aneuploid and have structural abnormalities, including a Philadelphia chromo
some t(9;22) (q34;qii). The patient never attained complete remission despite aggressive
chemotherapy. (Courtesy Gordon DeWald, Ph.D., Rochester, Minnesota.)

cytotoxic therapy is initiated.

Anemia should be corrected, espe
cially if the hemoglobin
is below 7.0
gm/dl or if symptomatic. Caution is re
quired if the leukocyte count is greater
than l00,000/pJ,
since there is evidence
that rapid expansion of intravascular
blood volume may precipitate cerebral
hemorrhage.42 Frozen or leukocyte-poor
red cells are preferred if the child is a
potential candidate
for bone marrow
transplantation.
Frozen red cells are least
contaminated
with platelets and leuko
cytes and are less likely to sensitize the
child against transplantation
antigens.
Packed red cells rendered leukocyte-poor
by other methods are a good alternative
if frozen cells are not available.
Bleeding
is usually the result of
thrombocytopenia,
although deficiencies
VOL. 30, NO. 3 MAY/JUNE 1980

of other coagulation
factors must be
ruled out. Symptomatic intravascular co
agulation is uncommon except with sep
ticemia. One unit of platelets will raise
the count about 12,000 platelets pJ/m2
body surface area. Reaching a level be
tween 50-100,000
per
@1will usually
control bleeding.
Infection occurs less often in diag
nosis than at other stages of the illness
when a similar degree of neutropenia is
present. The most common organism
found at diagnosis is Streptococcus pyog
enes, which is distinctly different from
the organisms usually found at other
stages of the illness, when gram-negative
organisms predominate.43 Infection,
which rarely occurs after induction treat
ment is started, is effectively managed
with antibiotics.
165

166

CA-ACANCERJOURNALFORCLINICIANS

Many children have fever without an

identifiable
infection.
In this circum
stance, if granulocytes
are below 500
cells/p.l, blood and urine cultures should
be taken and antibiotics started if the
fever pattern or general clinical condition
suggests sepsis. If the granulocytes
are
greater than 500 cells/p.!, cultures should
be taken but antibiotics may be withheld
pending results, unless sepsis is strongly
suspected. Initially, we use gentamicin
and oxacillin intraveneously.
Intramus
cular antibiotics are contraindicated
be
cause of thrombocytopenia
and the dan
ger of causing a hematoma. If cultures
remain negative, antibiotics can be dis
continued,
according to clinical judg
ment, after two to three days. If cultures
are positive, the appropriate
antibiotic
is administered.
If the fever is due to
leukemia, it will decrease rapidly once
antileukemic therapy (particularly corti
costeroids) is started.
A special situation exists when the
child presents in blast crisis, with a white
count of over 100,000 cells/p.1. Leuko
stasis and vascular rupture occur in cere
bral vessels, sometimes resulting in sud
den, fatal cerebral hemorrhage. As soon
as possible after the diagnosis is estab
lished, cranial radiation should be given;
in our experience,
this has prevented
cerebral hemorrhage in these patients.@
Others have successfully
reduced the
white blood count by using leukopher
esis.45
Other metabolic
complications
of
leukemia include hyper- and hypocal
cemia, hyperphosphatemia,
and hyper
kalemia. Discussion
of their manage
ment, as well as other problems of the
stabilization period, is contained in two
recent texts.@'47

Induction of Remission
The first goal of therapy is to reduce
the leukemic cell burden to a clinically
undetectable level. At the same time, the
physicalexam and bone marrow func
tion will return to normal. Many drugs
and administration
schedules can induce
remission. Vincristine,
prednisone,
and
VOL.30, NO.3 MAY/JUNE1980

L-asparaginase are common to most reg

imens, producing an 85 to 93 percent
complete remission rate. 2,6,8,48,49 Add
ing other agents, such as daunorubicin
and cyclophosphamide,
has not im
proved the remission rate50 and may
even be detrimental.49
If a child fails
to enter remission, continuing vincristine
and prednisone and adding doxorubicin
or daunomycin are standard approaches.
Recently, the combination
of cytosine
arabinoside
and VM-26 was reported
as effective for those in whom standard
therapy fails to induce remission.51
The induction period lasts for four
weeks. During this time, anemia, neutro
penia, and thrombocytopenia
are pres
ent to a variable degree. Most patients
do not require transfusions
other than
packed red cells, so it is usually pos
sible to discharge the child a few days
after treatment is initiated. Indications
for continued
hospitalization
are in
fection, unresolved metabolic abnormal
ities, or bleeding; cytopenias alone are
rarely, if ever, reason for keeping the
child in the hospital. Returning the child
to the home decreases costs and restores
the family's
regular routines,
which
seems to help them adjust to their new
situation.
Hospitalization
should not be too
brief, however. Most families need a
few days to absorb the diagnosis, while
having easy access to members of the
medical
care team. Questions
occur
throughout the day and can be answered
by nurses, social workers, and physi
cianswho will be available at all times
so
that more can be accomplished than
if all questions have to be saved for an
outpatient visit. Hospitalization
also pro
vides an opportunity
for the parents to
be together, away from the sick child.
After a few days to a week, most fam
ilies begin to cope with the realities of
the situation; if all medical problems are
stabilized, the child can return home.
Sometimes longer hospitalization
is re
quired before the family is emotionally
able to cope with the situation at home;
however, in our experience this is un
usual.
167

A frequently-asked
question
is
whether or not the child should returnto
school. Certainly when the child is in re
mission he should be in a classroom.
Prior to remission induction, the decision
is highly individualized.
We are guided
by the fact that serious bacterial infec
tions associated with neutropenia are not
communicable,
but originate from the
resident flora of the patient's skin and
gastrointestinal
tract.38 Bleeding from
thrombocytopenia
is not a greater risk in
a classroom than at home, although re
strictions on physical activity may have
to be imposed. We ask patients to avoid
activities such as contact sports, which
can result in serious injury when they are
thrombocytopenic.
Younger children and
those with platelet counts under 20,000/
m3 should probably remain under paren
tal supervision until the improvement
is
documented.

Psychosocial Care
The keys to helping families cope with
leukemia are communication
and avail
ability. A complete explanation of ALL,
its treatment, complications,
and prog
nosis must be given to the parents at the
time of diagnosis. The child is often in
cluded in these discussions, to the extent
thathisorherdevelopmentallevelmakes
it reasonable. Time must be available for
questions, and additional sessions are of
ten required before parents have enough
information assimilated to begin to make
decisions. It is often wise to include
grandparents in formal discussions, since
they often have as many questions and
concerns as the parents. Both parents
should be included in all conversations,
if possible. The word leukemia
is used,
to desensitize the parents to it, and the
possibility of death is made clear. The
child, however, is not told that he might
die. If a child asks questions, they must
be answered honestlybut with emphasis
on hopefulness. Prognostic factors, dis
cussed above, influence what parents are
told about their child's chances of cure.
An honest, open discussion between
patient, parents, nurses, social workers,
168

hospital staff, and the responsible phy

sician is crucial to successfully coping
with a diagnosis of leukemia. Written
material is often useful to patients and
their families as an adjunct to such dis
cussions.
We have extensively
used
Baker's You and Leukemia.52 A social
worker should be introduced to the fam
ily at the time of diagnosis, so that he
or she is clearly identified as a member
of the medical care team. The social
worker should also be fully informed of
the treatment plan. Contact with agen
cies that might provide financial help
should be made within a few days of
diagnosis.
Central Nervous System Treatment
The CNS is a sanctuary for leukemic
cells during
systemic
chemotherapy.
About 50 percent of children will de
velop symptomatic CNS leukemia while
still in bone marrow remission if specific
preventive
measures
are not taken.
Twenty-four hundred rads of cranial ra
diation, with six doses of intrathecal
methotrexate,
reduces CNS relapse to
less than 10 percent.53 Recently, a dose
of 1800 rads of cranial radiation with
intrathecal
methotrexate
was shown to
be as effective as the higher dose.54 Cra
niospinal radiation is also effective, al
though it is more myelosuppressive,55
and intrathecal
methotrexate
alone is
being investigated as CNS prophylaxis in
low-risk patients.
CNS therapy is usually begun, during
the induction
period, with intrathecal
methotrexate.
The possibility of early
CNS relapse requires this early interven
tion, but cranial radiation is usually not
given until after bone marrow remission
is achieved.
Complications
of CNS
therapy includealopecia,arachnoiditis,
and toxic encephalopathy.S6@Sea Somno
lence may develop, several weeks after
radiation
and may lastup to two weeks.
It may cause great concern but it is with
out sequelae, as far as is known.56,56a
Longterm effects on intelligence and in
tegrated CNS function are a major con
cern, but in a systematic study of our
CA-ACANCERJOURNALFORCLINICIANS

patients treated with both cranial radia

tion and intrathecal methotrexate we did
not find clear evidence of treatment
related dysfunction.57
Other
approaches to the treatment of
preclinical
CNS leukemiaincludeinter
mediate-dose
methotrexate
by 24-hour
i.v. infusion with intrathecal methotrex
ate,58 administration of intrathecal meth
otrexate at intervals during remission,59
and use of an Ommaya reservoir
forad
ministration
of methotrexate.59a
All are
investigational
and must be evaluated
both for effective prevention of CNS re
lapse and for psychoneurologic
toxicity.

larger group studies.63 At present, im

munotherapy
has no established role in
ALL; however, Mathand his group con
tinue to report promising results with
immunotherapy,
and further trials may
establish its role.M

Bone Marrow Transplantation*

Some longterm
survivals
have been
achieved using bone marrow transplan
tation in leukemic children refractory to
all other treatment. But the exact role of
this procedure is still unclear, and many
problems remain because the high-dose
chemotherapy
and radiation
given in
preparation
for transplant leave the re
Maintenance Therapy
cipient susceptible to opportunistic
in
After induction of remission, a large
fections and graft-versus-host
disease.
number of leukemic cells remain and
Relapse of leukemia occurs in spite of
additional chemotherapy
is required to
the ablative therapy and, in addition,
reduce this population to a level at which
many children lack the necessary HLA
cure can be achieved. It is thought that
identical,
mixed lymphocyte culture
human leukemia followsthe cellkill nonreactive donor.65 However, promis
kineticsdemonstrated in animals by
ing results in patients transplanted
in
Skipper.6
second remission encourage further ex
Daily 6-mercaptopurine
and weekly
ploration in this group,66'67 and the tech
methotrexate,
administered
orally pro
nique will continue to be investigated in
vide the basis for most maintenance pro
patients refractory to chemotherapy
and
grams. Vincristine
and prednisone,
particularly
in high-risk patients in re
administeredon a periodicbasis,add mission. Patient selection for this pro
significantly
toremissionduration.6'
cedure is difficult and is best done in con
Addition of other agents may be nec
junction with centers active in this area
essary in some patients, particularly those
or as part of well-designed prospective
at increased risk, but this will also in
studies.
crease the risk of infection and other
Duration of Treatment
complications
of the maintenance
peri
od62 and is investigational at present.
How long maintenance
therapy should
be continuedisan unsettled
questionand
there will probably be a different optimal
time for each major change in a treat
An immunologic response to leukemia
ment program. Investigators at St. Jude
associated
antigenscan be demonstrated Children's
Research
Hospital
studied
in both animals and humans, and it is
278 patients whose therapy was stopped
possible to immunize
animals against
after two-and-one-half
years. About 20
leukemia and to treat established disease
percent relapsed, and none relapsed after
with both antigen-specific
and antigen
four years. The relapse rate was about
nonspecificimmunostimulation.These twice as high in boys as in girls, but
results led naturally to clinical trials of
except for this, other prognostic factors
immunotherapy.63
Early promising results using BCG
*See also Fefer A: Bone Marrow Trans
and allogeneic leukemia cells to maintain
plants in Leukemia Patients in Remission.
remission have not been confirmed by
Ca 30:45-52, 1980.
Immunotherapy

VOL.30, NO.3 MAY/JUNE1980

169

170

CA-ACANCERJOURNALFORCLINICIANS

Treatment of Relapse
so
important in predicting relapse prior
to two-and-one-half
yearsdid not pre
Bone Marrow
dict relapse after cessation of therapy.68
Reinduction with vincristine, prednisone,
An obvious question is whether or
will produce second
not continuingtreatmentwould prevent and L-asparaginase
remissions in approximately
70 percent
relapse. In a randomized
study con
of patients who relapse while on ther
ducted
by Children's
Cancer
Study
apy.71 Use of Erwinia L-asparaginase
Group, 101 children in remission either
will decrease the risk of allergic reactions
had therapy stopped after three years or
in children previously treated with, and
had therapy continued three more years.
sensitized
to, E. coli L-asparaginase.
Relapses were significantly fewer in the
Duration of remission in those who re
group who continued
treatment,
and
lapse on therapy is usually brjef, so that
males had significantly
more relapses
devising effective maintenance
is the
than females. Pretreatment
risk factors
major objective at present, and this con
other than sex did not predict those at
tinues to be actively investigated.
higher risk. Many of these children were
Children who relapse while off treat
treated prior to the development of cur
ment have a better experience with re
rently accepted chemotherapy,
so the
induction and maintenance, and an effec
results cannot be applied directly to chil
tive program has been reported from St.
dren now undergoing
therapy.69 In a
Jude.72 It employed vincristine, predni
Cancer and Leukemia Group B study,
sone, and Adriamycin for induction, with
children were randomized
to continue
randomized
cytosine arabinoside/L-as
therapy for seven years or stop at five
paraginase
intensification
and standard
years and so far, no difference has ap
6-mercaptopurine,
methotrexate
main
peared in the number of relapses.70
tenance. Bone marrow transplantation
Thus, with currently available treat
may emerge in the near future as the best
ment, continuing therapy past five years
chance for longterm control in the re
does not seem to be advantageous to the
lapsed patient who has a suitable donor.67
group as a whole, although continuing
past three years may be advisable, at
least in males.69 Means of identifying the
Central Nervous System Relapse
patient who will benefit from further
therapy are needed; one such method
CNS relapse presents most frequently
already in wide use is testicular biopsy,
with signs and symptoms of increased
intracranial
pressure: headache, vomit
which identifies the male at high risk for
ing, and papilledema
(Fig. 6). Cranial
testicular relapse and possibly relapse at
nerve
involvement,
focal neurologic
other sites.69
signs, or seizures may be present. Rapid
Optimal length of treatment will be
weight gain may be the only sign of
clarified with longer follow-up, but will
CNS leukemia and is thought to be due
probably prove to be dependent not only
to hypothalamic
involvement.73 Diagno
on time but on the type and intensity of
sis is usually established
by finding
therapy. Decisions regarding individual
lymphoblasts
in CSF examined in cyto
children must take these background re
spin preparations.74 Protein may be ele
sults into account in relation to the in
vated in about one-third
of patients.
tensity and toxicity of the maintenance
When lymphoblasts are not found in the
therapy being administered.
We have
CSF of a patient with leukemia-related
stopped treatment
after five years of
neurologic deficits, the diagnosis must be
continuous,
complete remission in chil
established on clinical grounds.
dren who were not part of prospective
Treatment with weekly intrathecal
studies and were receiving a standard
methotrexate until the spinal fluid is
maintenance
program of daily 6-mer
clear, followed by periodic intrathecal
captopurine,
weekly oral methotrexate,
methotrexate as maintenance, is an ef
and periodic vincristine with prednisone.
VOL.30, NO.3 MAY/JUNE1980

171

fective, well-tolerated
program. Cranial
radiation should always be used if the
patient has not already received it for
prophylaxis.75
A second courseof com
bined cranial and spinal radiation with
intrathecal
methotrexate
may be more
effective in longterm control of leukemia
and is being investigated
in controlled
trials. No child considered a potential
candidate for bone marrow transplant
shouldreceivea secondcourseof cranial
radiation,
sincethewhole-bodyradiation
requiredfor transplant
willthen exceed
braintissue
tolerance.
Both bone marrow relapse and recur
rence of CNS disease frequently follow
the first episode of CNS leukemia. How
ever, even with present methods it is
possible to achieve longterm remission
and even cessation of therapy in some
childrenwith CNS leukemia.Thus, an
aggressive and positive approach to man
aging CNS leukemia is justified.53
Testicular Relapse

Fig. 6 CT scans of the head at approxi

mately the same level taken before and
after onset of headache and papilledema in
a child with ALL. Ventricular dilatation sec
ondary to increased intracranial pressure is
shown. Spinal fluid was under increased
pressure and contained lymphoblasts.
(Courtesy

OW.

Houser,

M.D.,

Rochester,

Minnesota.)

Fig. 7 Photograph of a boy with ALL show

ing bilateral testicular enlargement, which
was painless and was first noted on physical
examination. Biopsy revealed leukemic in
filtration.
172

Leukemic infiltration of the testicle pre

sents as a painless enlargement
of the
testicle; often, it is first noticed on phys
ical examination (Fig. 7), and it is always
confirmed by biopsy. Radiation in a dose
of 1200 to 2400 radsisdelivered
toboth
testicles,
since both are usually
in
volved.76 This dose controls leukemia
locally. Sterilization results, but andro
genic function remains intact.
Testicular relapse is usually followed
by bone marrow relapse. Whether the
testicle is a sanctuary for leukemic cells
or is simply the first site of relapse in
some patients whose leukemic cells have
become drug-resistant is unknown. Con
sequently, prophylactic
radiation to the
testicle and the use of drugs known to
affect testicular
function
(e.g., cyclo
phosphamide)
are being studied.77'78

Treatment of Patients with

Poor Prognosis
Patients with characteristics that indicate
highriskforrelapse(e.g.,
age,whitecell
count, and blast characteristics)
fail to
CA-ACANCERJOURNALFORCLINICIANS

..

41
I

9,

-@

A
-@@

a..

@.

a-

a'
4.

.
S

.4

41

41,

..

..

c
S..

@.,
@

F A

8 Photograph of a boy with ALL in remission. He had severe varicella with hemor
rhagic skin lesions and pneumonitis. He survived and made a complete recovery.

achieve longterm remissionswith the

vincristine,
prednisone,
L-asparaginase,
CNS prophylaxis,
6-mercaptopurine,
and oral methotrexateprogram, which
has become standardtherapy.By defini
tion, new treatment
approaches
are
needed.Sincein high-risk
patients
pres
ent standard therapy does result in remis
sion, with relapse occurring
early in
maintenance
therapy, additional
treat
ment during the maintenance period has
been the usual approach. Since morbidity
from increased toxicity may outweigh
the antileukemic effect, these new treat
ment approaches should be carried out
in controlled
trials. Thus far, reports
have not established the benefit of using
more intense treatment. Burgert reported
that administration
of daunomycin dur
ing induction and the first year of main
tenance has not enhanced relapse-free
survival in a high-risk group of pa
tients.50 The Southwest Oncology Group
has reported encouraging
results using
an even more intensive approach for the
high-risk patient,79 and the Children's
Cancer Study Group is conducting
a
similar trial.
VOL.30, NO.3 MAY/JUNE1980

Psychosocial Support
of the Family
The child in remission is healthy-looking,
active, and competitive
in school and
play. Several of our patients participate
in interscholastic
sports and are encour
aged to do so. Deviation from normal
behavior and underachieving
in school
are not expected complications
of anti
leukemia treatment and should therefore
be handled just as they would in any
child.
Usually, during remission, the only
visible sign of the leukemia is alopecia.
It varies in degree but may be present
throughout the maintenance
period and
isinevitable
duringthe first
few months
of treatmenta side effect of weekly yin
cristine and cranial radiation. Alopecia
is reversible after treatment has ended,
but copingwith itmay be a major prob
lem for some patients, particularly teen
agers. We encourage an individualized
approach. Some choose a wig, some pre
fer a stylish kerchief or an NFL football
cap. The concept that bald
is beautiful
suits some who opt for the Kojak look.
173

174

CA-A CANCER JOURNAL FOR CLINICIANS

essential for proper coordination

and
Parents are encouraged to have con
utilization
of all available
resources
ferences with teachers and school nurses
(Table 5).
about the facts of leukemia and the ac
companying alopecia, with emphasis on
the expected normal activities. If the
Medical Care During Remission
classmates receive an explanation about
the situation,
including necessary ab
The schedule of clinic visits will depend
sences and physical changes, things seem
on the particular maintenance
program
to go more smoothly. The physician, so
the child is following. White cell count,
cial worker, or nurse should be available
hemoglobin
level, and platelet counts
to communicate with school personnel if
with differential white cell counts and
problems arise. Social workers and on
examination of the blood smear are per
cologic nurses visit with the family fre
formed every four to six weeks at mini
quently, providing
emotional
support,
mum. Bone marrow is examined every
and they are often the first to learn of
three to four months and SGOT, bili
problems requiring investigation or in
rubin, alkaline phosphatase,
and creati
tervention.
nine are determined
periodically
to
The responsible physician must be
monitor toxic effects of treatment.
available during clinic visits, to anticipate
and answer questionsand to participate
in the psychologicalsupport of the Infection
family.
Most febrile illnesses in children are self
A major function of a medical cen
limited viral infections and the same is
ter caring for children with leukemia is
true of children with leukemia in remis
to provide information
and access to
sion. Most viral infections are well tol
sources of financial assistance. In our
erated by the child, without discontinua
state the Minnesota Services for Children
tion of chemotherapy.
However, it is
with Handicaps is a major source of aid,
necessary to carefully evaluate infectious
and all states have such an agency; many,
butnotall,
covertreatmentforchildhood episodes, using the history, physical ex
amination, and peripheral blood counts.
leukemia within the limits of financial
Bacterial infections rarely occur dur
eligibility. One of the key requirements
of such agenciesisthattheybe informed ing remission, but blood cultures should
of a new patient
promptlyafterdiagnosis. be taken routinely when significant fever
occurs and the absolute
granulocyte
Nonmedical
costs are considerable
count falls below SOO/p.l.
and are borne by the familyunlessas
Influenza may be prolonged in the
sistance from private sources is avail
child with ALL, but is not usually com
able.80 A major innovation in this area
plicated by specific organ involvement or
is the creation of houses near major
bacterial infection.8' Immunization
with
pediatric medical centers where families
split virus vaccines is effective in children
from out of town can live when extended
on chemotherapy,
provided the appro
periods of treatment are required. The
priate dose and schedule are used.82
McDonald Corporation has been a major
Herpes zoster and herpes simplex
sponsor of this philanthropy.
The Leu
usually follow a self-limited, localized
kemia Society of America and the Amer
course, similar to that in the child with
ican Cancer Society may also provide
out ALL.8' We discontinue all chemo
some help with nonmedical costs. Can
dlelighters is a national organization with
therapy during herpes infections, until
resolution has clearly begun.
local chapters. Its members are parents
of children with cancer and it provides
Chickenpox may be quite severe or
group support for parents, as well as
even fatal (Fig. 8). When a child is ex
information
about childhood leukemia
posed, through contact with a family
and cancer. A trained social worker is
member or close playmate, zoster im
VOL. 30, NO. 3 MAY/JUNE 1980

175

curred.M Without this protection, 32 per

tent of a group with clinical
varicella
at

St. Jude had systemic disease and seven

percent died.85 If varicella develops, all
drugs are stopped and the child is treated
supportively.
Pneumonitis,
encephalitis,
hepatitis, or disseminated
hemorrhagic
skin lesions can develop; bacterial sepsis
occurs in about one-third of children not
given passive protection.
Adenine ara
binoside (Ara-A), recently approved for
herpes simplex encephalitis,
has been
used successfully in children with sys
temic varicella,86 but it has not yet been
approved for this use by the FDA. Inter
feron is also being investigated as a pos
sible treatment for varicella in this popu
lation.87
Measles is another childhood
ill
ness that has an atypical and more severe
clinical course in leukemic
children.
Fig. 9 Chest x-ray of a girl with ALL show
ing diffuse, bilateral pulmonary infiltrates. Pneumonia88 and encephalopathy,89
oc
Lung biopsy revealed Pneumocystis carinhi. cur with increased
frequency
in
this
She recovered after treatment with pentami
population,
and can be fatal.
The unim
dine.
munized child should receive gamma
globulin if there is a definite exposure.
Immunization
with live virus vaccines is
contraindicated
because of the danger of
mune globulin(ZIG) * shouldbe given dissemination
of the attenuated virus.
within 96 hours. Any scheduled rein
Interstitial pneumonia is another seri
forcement treatment, e.g., vincristine and
ous problem for the child in remission.
prednisone,
is postponed,
but we con
Viruses have been incriminated
in some
tinue 6-mercaptopurine
and methotrex
cases,90 but the most important, and most
ate during the incubation period. Zoster
lethal,
agentisPneumocystiscarinii;
un
immune globulinis said to preventor treated, it is often fatal. Cough, fever,
ameliorate
varicella in 96 percent of
and tachypnea usually warrant a chest
x-ray in children with ALL, since the
those exposed.83 In a group of 102 leu
infiltrates
of Pneumocystis
kemic childrenin remissionwho were interstitial
may be silentto auscultation
(Fig.9).
treated with zoster immune
globulin
The presence of infiltrates, with respira
prior to the onset of clinical varicella, no
tory distress and cyanosis, is usually an
deaths and six cases of pneumonia
oc
indication for lung biopsy to establish the
diagnosis. Since serologic testing and cul
tures are not available for clinical use,
*Zoster immune globulin is available
microscopic demonstration
of the silver
through J. A. Zaia, M.D., Boston, Massa
methenamine-stained
organism
is re
chusetts, (617 732-3121 or 617 237-6649),
quired for diagnosis. Trimethoprim
sulfa
and should be requested within 72 hours of
given orally or pentamidine
given intra
exposure.
Varicella-zoster
immune globulin
muscularly are highly effective. The pro
(VZIG), obtained from banked blood, is
phylactic use of trimethoprim
sulfa, in
more plentiful
and may replace
ZIG, which centers with a high incidence of Pneumo
is obtainedfrom patientswith clinical
cystis, is successful in lowering the in
herpes zoster infection. VZIG may soon
cidence of the disease.91
become commercially available.85a
176

CA-ACANCERJOURNALFORCLINICIANS

cyclophosphamide
or treated after pu
berty may have impaired reproductive
As mentioned,vaccinescontaininglive function.96'97
virus should not be used for the child on
Hepatic, pulmonary, and bone toxicity
treatment. Several months should elapse
of longterm methotrexate has been docu
between stopping treatment and employ
mented,98 but in our experience has not
ing such vaccines.
been a factor that limits duration of
Tetanus and diphtheria toxoids can
treatment.
be used according to current recommen
Second cancers, although a signifi
dations. Immunizing
leukemic children
cant problem following Hodgkin's dis
against influenza has been advocated, but
ease, have been only a theoretic concern
further trials are needed before they can
following childhood leukemia. A recent
be routinely recommended.82
report of rhabdomyosarcoma
arising dur
ing treatment for ALL@ illustrates the
need to evaluate the risk of second
Longterm Sequelae
tumors in assessing
the longtermeffects
of treatment for ALL.
Prolonged survival of significant num
bers of children with ALL means that
longterm consequences
of the disease
Summary
and itstreatmentmust be carefully
as
sessed.We hope to see well-adjusted At present, significant numbers of chil
dren with ALL enjoy prolonged survival
adults, normal in their interpersonal
re
without serious sequelae. All children
lationships, intellectual ability, physical
should be given the benefit of treatment
activities, economic self-support, and re
under the supervision of physicians ex
production. A pilot study92 suggests that
perienced in childhood cancer. Risk fac
the psychologic makeup of longterm sur
tors
should be properly assessed and
vivors, though colored by the experience
of a potentially
fatalillness,
is largely children at high risk placed in innovative
programs.
Longterm
follow-up of pa
normal. Likewise, neurologic,
electro
tients is essential to detect, as early as
encephalographic,
computerized tomo
possible, potentially prohibitive toxicity.
graphic, and psychometric examinations
have revealed
a functionally
normal
group of children treated with cranial
radiation
with or without intrathecal
Secretarial support of Mrs. Jean Lambert is
methotrexate one-half to eight years pre
gratefully acknowledged.
viously.57 Some disturbing CT scan evi
dence of neurologic
damage has ap
peared in children treated with more in
tensive CNS regimens, so that continued
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Supported in part by the USPHS grant

CA04646 from the NC!.

NOTES OF A BIOLOGY-WATCHER
It is hard for us to imagine anything taking place in the brain of an insect that bears
any resemblance to the events in our own heads. We take it for granted that insects

are little whirring machines, programmed by their genes to do this or that insect-like
thing, but we recoil from the notion that the bug is a conscious,
We do this partly because we feel superior, and partly because

thinking creature.
we know that we

could never do so reproducibly what beetles do.

It could be that simple animals

possess the same kind of awareness

as ours, but

that they are conscious of fewer items...

From: Lewis Thomas, M.D.: Notes of a biology-watcher:
I Med 302:507, 1980.
VOL.30, NO.3 MAY/JUNE1980

on artificial intelligence. N Engi

181