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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:
Discovering
features of ALL blasts
and clinical presentation
associated
with good and poor prognosis.
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. 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
.@
.S.
.dmi
J@
()O
________@____
I
Fig. 3
Morphologic
subtypes
of childhood
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
was positive
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
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
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.)
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
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
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
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
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
OW.
Houser,
M.D.,
Rochester,
Minnesota.)
..
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.
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
175
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
References
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CA-ACANCERJOURNALFORCLINICIANS
RH, Pereira F:
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
as ours, but
181