Indian J Pediatr (September 2015) 82(9):817824
DOI 10.1007/s12098-015-1695-5
REVIEW ARTICLE
Guest Editor: Bhim S. Pandhi
Leukemias in Children
Rachna Seth & Amitabh Singh
Received: 6 June 2014 / Accepted: 7 January 2015 / Published online: 15 February 2015
# Dr. K C Chaudhuri Foundation 2015
Abstract Childhood cancers are rare but an important cause of
morbidity and mortality in children younger than 15y of age.
Common childhood malignancies include leukemias
(commonest, 3040%), brain tumors (20%) and lymphoma
(12%) followed by neuroblastoma, retinoblastoma and tumors
arising from soft tissues, bones and gonads. Leukemias, the
commonest childhood cancer, arise from clonal proliferation
of abnormal hematopoietic cells leading to disruption of normal
marrow function and marrow failure. The various clinical man-
ifestations of leukemia result from unregulated proliferation of
the malignant clone and bone marrow failure. There are two
main subtypes, the commoner, acute lymphoblastic leukemia
(ALL) and acute myeloid leukemia (AML). A small proportion
may have chronic myeloid leukemia (CML) and juvenile
myelomonocytic leukemia (JMML). A systematic approach is
necessary for diagnosis. Treatment should be initiated as early
as possible to avoid complications. A timely referral to a cancer
center must be done if facilities for diagnosis/treatment, man-
agement of complications and provision for supportive care are
not available at the treating center.
Keywords Leukemia . Children
Introduction
Leukemia is the most common cancer in children. It is a ma-
lignancy that arises from proliferation of hematopoietic cells
leading to disruption of normal marrow function and marrow
failure. The clinical manifestations of leukemia are result of
R. Seth (*) : A. Singh
Division of Oncology, Department of Pediatrics, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi 110029, India
e-mail: drrachnaseth@yahoo.co.in
the unregulated proliferation of the malignant clone and bone
marrow failure.
There are two main subtypes of acute leukemias in chil-
dren; the commoner acute lymphoblastic leukemia (ALL) and
acute myeloid leukemia (AML). Acute leukemia constitutes
about 40% of all childhood cancers. Chronic leukemias are
more common in adults than in children. They tend to grow
more slowly than acute leukemias and are harder to treat.
Chronic leukemias are divided into two main types: chronic
myelogenous leukemia (CML) and chronic lymphocytic leu-
kemia (CLL). CML is rare in children and is treatable as in
adults. CLL on the other hand is extremely rare in children.
Juvenile myelomonocytic leukemia (JMML) is a form of leu-
kemia that is neither chronic nor acute and occurs most often
in children under the age of four. JMML begins from myeloid
cells, but is not as fast-growing as AML or as slow as CML.
Acute Lymphoblastic Leukemia (ALL)
ALL is the most common childhood malignancy accounting
for one-fourth of all childhood cancers and three-fourths of all
newly diagnosed patients with acute leukemia [1]. Its inci-
dence is approximately 34 cases per 100,000 children below
15y of age in USA. In India, leukemia is the most common
childhood cancer (2540%) with higher proportion of T cells
(2050%) compared to west (1020%) [2]. Boys have higher
rates than girls, especially in adolescents with T-cell ALL [3].
The etiology of ALL remains unknown in a majority of cases.
However, several genetic syndromes like Down syndrome have
been associated with an increased risk of leukemia [1, 4, 5].
Morphology
The classification of ALL is based on morphology, cytochem-
istry, immunephenotyping, karyotyping and molecular
818 Indian J Pediatr (September 2015) 82(9):817824

biology techniques. ALL cells can be classified using the Table 1 Co-relation of ALL subtypes with surface markers
French-American-British (FAB) criteria into morphologic Pro B/Early Pre B CD34+/CD19+
subtypes. L1 morphology lymphoblasts are the most common
subtype (8085%), and are associated with a better prognosis. Pre B cell CD79a, CD10+, Presence of CD10
L2 subtype accounts for 15% cases. Only 12% patients with CD18+,CD19+, (common ALL
CD20+,CD21+, antigen-CALLA)
ALL show L3 morphology. The lymphoblast has high HLADR+ represents a
nuclear/cytoplasmic (N/C) ratio, clumped chromatin com- favorable prognosis
pared to the myeloblast which has low N/C ratio and a spongy Absence of CD10 is
nuclear chromatin. Myeloperoxidase positivity is characteris- associated with MLL
translocations, particularly
tic of myeloblast (Fig. 1). t(4;11) and a poor
outcome.
Immunophenotype Mature B cell CD19+,CD20+, Correlates with L3
CD21+,sIg+ leukemia -Burkitts
leukemia, needs
Immunophenotype classification describes ALL as either B
intensified regime
cell derived or T cell derived. 8085% ALL are progenitor B
Pre T cell CD 2+/CD5+/CD8+
cell derived, 15% are derived from T cells and 12% from
T cell CD3+,CD5+, Associated with older
mature B cells (Table 1). CD7+,CD2 age, high initial
white cell count,
Cytogenetics mediastinal mass
and risk for CNS
involvement of disease
Genetic abnormalities found in the leukemic clone greatly
impact the therapy and prognosis of ALL. Conventional cy-
togenetics and fluorescence in-situ hybridization (FISH) The most common cytogenetic abnormalities in B cell ALL
should be performed on the bone marrow specimen to look are hyperdiploidy25 %, t(12;21)25%, MLL5 %, hypodip-
for common genetic alterations in ALL. These should be per- loidy15 % and t(9;22)4%.
formed for diagnostic as well as follow-up specimens during Mature B cell ALL has poorer prognosis than earlier B
treatment. The presence of hyperdiploidy (chromosome num- lineage subgroups but distinction between pre B cell and early
ber >50, DNA index >1.16) is associated with good prognosis pre B cell is not relevant from prognosis point of view.
in contrast to the poor prognosis in patients with hypodiploidy
(chromosome number <45 per cell) [6]. Specific chromosom-
al translocations in ALL, including t (8; 14, associated with Prognostic Factors and Risk Assessment
Burkitt leukemia) in B-cell ALL, t(4;11) in infant leukemia
and t(9;22) translocation, that forms the Philadelphia chromo- The improvement in survival in ALL is partly due to recogni-
some, are associated with a poor prognosis. Certain chromo- tion that all cases are not same. Risk adapted therapy of ALL,
somal abnormalities are associated with a favorable prognosis recognizing standard, intermediate and high risk groups has led
like t(12;21) and simultaneous presence of trisomy 4 and 10. to different treatment approaches. Host factors like age, sex,
ethnicity and disease characteristics like initial total white blood
count, immunophenotype, cytogenetic abnormality and treat-
ment response are used to define these three groups. The two
most important prognostic factors include age at diagnosis and
the initial leukocyte count. Children less than 1-y-old have an
unsatisfactory prognosis; infant leukemia is often associated
with t(4;11) translocation and high leukocyte counts. Children
between the ages of 1- and 9-y do well. The presence of leu-
kocyte count more than 50,000/ cu mm at diagnosis is associ-
ated with a bad prognosis. Relapse rates are higher in boys.
Patients showing hyperdiploidy have a good prognosis, while
presence of hypodiploidy is associated with an unsatisfactory
Fig. 1 Bone marrow from a child with acute lymphoblastic leukemia outcome. Philadelphia positive t(9;22) ALL and translocation
shows reduced normal marrow elements which are replaced by t(4;11) which is present in infant leukemia are associated with
lymphoblasts. The neoplastic lymphoblasts are slightly larger than
lymphocytes and have round or convoluted nuclei, fine chromatin,
poor prognosis. Response to treatment with prednisone is con-
often with a smudged appearance, inconspicuous nucleoli and scant, sidered a prognostic factor; patients showing 1000/cu mm
faintly basophilic cytoplasm blasts in peripheral blood following 7d treatment with
Indian J Pediatr (September 2015) 82(9):817824 819

prednisone and an intrathecal dose of methotrexate are likely to
have an adverse outcome [7, 8]. Treatment response is influ-
enced by the drug sensitivity of leukemic cells and host phar-
macodynamics and pharmacogenomics (Table 2).
Clinical Presentation
Central nervous system involvement, diagnosed by CSF
examination is rare (25%) at diagnosis; and may present with
features of raised intracranial pressure. Overt testicular leuke-
mia presenting as firm, painless, unilateral or bilateral swell-
ing may be seen in about 1% of cases. Other rare sites of
extramedullary involvement include heart, lungs, kidneys,
ovaries, skin, eye or the gastrointestinal tract.

The clinical features of ALL are attributed to bone marrow Diagnosis and Differential Diagnosis
infiltration with leukemic cells (bone marrow failure) and
extramedullary involvement. Common features include man- Children may present with pancytopenia or
ifestations of anemia, thrombocytopenia and neutropenia. hyperleukocytosis. The diagnosis is confirmed by peripheral
These include pallor and fatigue, petechiae or purpura and smear examination and/or bone marrow aspirate / biopsy.
infections. Lymphadenopathy, hepatomegaly and splenomeg- Higher white blood cell counts are more common with T-
aly are present in more than 60% patients. Bone or joint pain cell ALL. The bone marrow smear where >25% of bone mar-
and tenderness may occur due to leukemic involvement of the row cells are leukemic lymphoblasts, is diagnostic for ALL.
periosteum of bones or joints. Infants and young children may While morphology of the leukemic blasts can give important
present with a limp or refusal to walk. Tachypnea and respi- clues to the diagnosis, it needs to be confirmed by
ratory distress may be present secondary to severe anemia immunephenotyping of the bone marrow. Immunophenotype
leading to congestive heart failure or secondary to the pres- differentiates the cellular lineages of ALL into pre-B, T cell
ence of mediastinal mass leading to tracheal compression (su- and mature B cell. This distinction has therapeutic implica-
perior mediastinal syndrome). A large mediastinal mass may tions. Evaluation of CSF for presence of leukemic blasts to
sometimes cause superior vena cava syndrome with facial determine CNS involvement is important for staging of leu-
edema and plethora, throbbing headache, conjunctival con- kemia. The first spinal tap must be performed ideally with
gestion and dilated neck veins. Patients with high tumor bur- platelet count close to 100,000/cu mm. Children with CNS
den can occasionally present with very high total white cell leukemia require more intensive CNS directed therapy
count (hyperleukocytosis, TLC >1,00,000/cu mm) or tumor The clinical profile of acute lymphoblastic leukemia
lysis syndrome with decreased urine output and azotemia sec- may mimic many other clinical conditions like infectious
ondary to uric acid nephropathy. The elevated number of leu- mononucleosis, acute infectious lymphocytosis, idiopathic
kemia blast cells in hyperleukocytosis may sludge in the vas- thrombocytopenic purpura, aplastic anemia and viral in-
cular supply to brain, lungs, and liver producing symptoms of fections like cytomegalovirus and others that result in leu-
organ dysfunction. kemoid reactions and pancytopenia. Idiopathic thrombo-
cytopenic purpura (ITP) is the most common cause of
Table 2 Prognostic features in acute lymphoblastic leukemia
acute onset of petechiae and purpura in children.
Feature Standard risk High risk Ordinarily children with ITP have no evidence of anemia
and have normal total and differential leukocyte count.
Age 210 y Less than 1 y Bone marrow smear reveals normal hematopoiesis and
Greater than 10 y
normal or increased number of megakaryocytes. A bone
Sex Female Male
marrow examination is recommended prior to initiation of
Initial white cell count <50,000/cu mm >50,000/cu mm
steroid treatment for presumed ITP, in order to exclude
Hepatosplenomegaly Absent Massive leukemia. ALL must be differentiated from aplastic ane-
Lymphadenopathy Absent Massive mia, juvenile rheumatoid arthritis and other malignancies
Mediastinal mass Absent Present (Neuroblastoma, Non-Hodgkin lymphoma,
Central nervous Absent Present Rhabdomyosarcoma, Ewing sarcoma and
system (CNS) leukemia
Phenotype Pre B (T- cell Mature B - cell Retinoblastoma). Morphologic, cytochemical,
intermediate) immunophenotypic and cytogenetic characteristics of the
Ploidy Hyperdiploidy Hypodiploidy malignant cells should be done. Occasionally, patients
Cytogenetics t(12;21),trisomy t(9;22), with ALL may present with hypereosinophilia or as an
4 and 10 t(4;11),t(8;14) emergency with very high white cell count
Response to treatment Good early response Poor early (hyperleukocytosis, TLC>100,000/cu mm), life threaten-
response
ing infections, hemorrhage, organ dysfunction secondary
Minimal residual disease Negative Positive
(MRD) after first induction
to leukostasis or signs and symptoms of superior vena
cava/superior mediastinal syndrome.
820
Management
Improvement in supportive care and use of combination che-
motherapy has led to survival rate of more than 80% overall
and greater than 95% in children with low risk disease, in
western countries. Treatment is determined by the risk of re-
lapse in each patient.
Risk based approach allows use of modest therapy for chil-
dren who have historically had very good outcome thereby
avoiding the toxic adverse effects of high intensity therapy.
The three most important determinants of this risk are age at
presentation, total WBC count at presentation and response to
initial therapy.
The successful treatment of ALL requires the control of
bone marrow or systemic disease, as well as treatment (or
prevention) of extramedullary disease in sanctuary sites, par-
ticularly the central nervous system (CNS). The cornerstone
of this strategy is systemic combination chemotherapy togeth-
er with CNS prophylaxis. Different centers use different pro-
tocols for childhood ALL. Most European and American pro-
tocols use aggressive chemotherapy regimens with 5y survival
rates above 8085% [9].
The treatment of ALL is divided into 4 stages. (i) Induction
therapy (to attain remission) (ii) CNS prophylaxis or CNS
preventive therapy, (iii) Intensification (consolidation) and
(iv) Maintenance therapy (continuation). The intensification
(consolidation) phase, following induction of remission, may
not be required in low risk patients, though recent studies
suggest benefits in long-term survival with intensification
therapy in both low risk and high risk patients. The average
duration of treatment in ALL ranges between 2 and 2.5 y.
Induction Therapy
The goal of this phase is to eradicate leukemia from the bone
marrow such that at end of this phase there are <5% leukemic
blasts in the bone marrow by morphology. Patients who
achieve rapid early remission (<5% blasts in marrow) by
day 7 or 14 of induction have a better prognosis than slow
responders. Failure to achieve this at end of induction is asso-
ciated with high risk of relapse. Induction therapy generally
consists of 46 wk of therapy and current induction regimens
include vincristine, prednisone, L-asparaginase and an
anthracycline, with remission achieved in 9598% of cases.
Basic two drug regimen of vincristine and steroid achieves
remission in 85% of children and addition of L-asparginase,
an anthracycline or both improves remission induction to
95%. Because of the complications related with
anthracyclines, some protocols use four drug induction for
high risk patients only. Three drug induction i.e., steroid, vin-
cristine and L-asparginase is used for standard risk patients in
these protocols. Some protocols also use seven day predniso-
lone prophase along with intrathecal methotrexate. The rate
Indian J Pediatr (September 2015) 82(9):817824
and magnitude of disappearance of peripheral blasts after pro-
phase is highly predictive of outcome.
CNS Preventive Therapy
The concept of CNS preventive therapy is based on the fact
that most children with leukemia have subclinical CNS in-
volvement at the time of diagnosis and this acts as a sanctuary
site where leukemic cells are protected from systemic chemo-
therapy because of the blood brain barrier. The early institu-
tion of CNS prophylaxis is essential to eradicate leukemic
cells which have passed the blood brain barrier. CNS prophy-
laxis has enabled increased survival rates in leukemia. Most
children in the past received a combination of intrathecal
methotrexate and cranial irradiation. However, there is consid-
erable concern regarding long term neurotoxicity and risk of
development of brain tumors following this therapy. In order
to achieve effective CNS prophylaxis while minimizing neu-
rotoxicity, experts now recommend a lower dose of cranial
irradiation (1800cGy) with intrathecal methotrexate.
Intrathecal methotrexate, given periodically starting from
day 1 of induction, provides good CNS protection and has
good prognosis. Other alternative regimens for CNS prophy-
laxis include the use of triple intrathecal therapy consisting of
methotrexate, hydrocortisone and cytarabine without cranial
irradiation. Others propose that cranial irradiation should be
limited for patients with high risk features at diagnosis, includ-
ing T-cell ALL with leukocyte count >1000,000/cu mm,
Philadelphia chromosome positive and presence of CNS
leukemia.
Intensification (Consolidation) Therapy
This is a period of intensified treatment, administered shortly
after remission induction with administration of new chemo-
therapeutic agents to tackle the problem of drug resistance
[10]. Commonly used agents include high dose methotrexate,
L-asparginase, epipodophyllotoxin, cyclophosphamide and
cytarabine.
Maintenance (Continuing) Therapy
It has been estimated that approximately two to three logs of
leukemic blasts are killed during the induction therapy, leav-
ing a leukemic cell burden in the range of 10 9 10 10 .
Additional therapy is therefore necessary to prevent a relapse.
Once remission is achieved, maintenance therapy is continued
for an additional 22.5 y. The main agents used include 6-
mercaptopurine daily and methotrexate once a week given
orally, with or without pulses of vincristine and prednisone
or other cytostatic drugs. Monthly pulses of vincristine and
prednisolone appear to be beneficial in terms of better event
free survival. For better outcome, methotrexate and 6-
Indian J Pediatr (September 2015) 82(9):817824
mercaptopurine should be given to the limits of tolerance as
determined by absolute neutrophil counts.
Philadelphia chromosome positive (ph+) ALL requires
addition of tyrosine kinase inhibitor (TKI) like imatinib to
chemotherapy regimen. Second generation TKIs, e.g.,
dasatinib and nilotinib, show activity against most of the
bcr-abl tyrosine kinase domain (TKD) mutations involved
in acquired imatinib resistance, but clinical benefit is gen-
erally short-lived. Accordingly, stem cell transplantation
(SCT) in first complete remission (CR) is considered to
be the best curative option.
Stem cell transplantation, also called bone marrow trans-
plantation (BMT), is performed only in patients who have
abnormal cytogenetic, or high-risk ALL features in first or
second remission. Cytogenetics is the most important compo-
nent of deciding whether or not a person should have a bone
marrow transplant for ALL. Patients with the Philadelphia
chromosome positive ALL or young infants with the translo-
cation involving chromosomes 4 and 11(MLL gene rearrange-
ment), are candidates for BMT.
Supportive Care
Because of the potential complications encountered with treat-
ment and the need for aggressive supportive care like blood
component therapy, monitoring and management of tumor
lysis syndrome, detection and management of infections, nu-
tritional and metabolic needs and psychosocial support, these
children should be treated by a specialist in a cancer center or
hospital with all support facilities. These children should be
given cotrimoxazole as prophylaxis against Pneumocystis
carinii pneumonia. They should be vaccinated against hepati-
tis B infection and screened for HIV infection. Oral hygiene
should be taken care of. Facilities for blood component ther-
apy should be available [11]. The survival rates of children
with malignancies are enhanced through access to state-of-
the-art treatment given according to well defined protocols
in specialized centers.
Prognosis
Hypodiploidy, Philadelphia chromosome positivity, T-cell
ALL, MLL rearrangement, IKZF1 gene deletion, age <1y
and >10y, leukocyte count >50,000/cu mm and presence of
CNS disease are poor prognostic features.
Assessment of minimal residual disease (MRD) by PCR
assay using immunoglobulin/ T- cell receptor gene rearrange-
ments or by flow cytometry has been shown to be an impor-
tant determinant of outcome. These methods can detect one
leukemic cell in 10,000 to 100,000 normal cells. Patients with
MRD <0.01% on day 29 of induction are at low risk of relapse
[12].
821
More than 80% of children with ALL are long term
survivors in the developed countries. However, survival
remains poor in the developing nations. Several factors
are responsible for this difference. There is increased
infection related mortality due to lack of adequate sup-
portive care. Malnutrition also increases mortality in
children with ALL. Also, there is higher incidence of
T-cell ALL in India leading to poorer survival.
Treatment after Relapse
Despite the success of modern treatment, 2030% of
children with ALL relapse [13]. The main cause of
treatment failure in leukemia is relapse of the disease.
The most common site of relapse is in the bone marrow
(20%), followed by CNS (5%) and testis (3%). The
prognosis for a child with ALL who relapses depends
on the site and time of relapse. Early bone marrow
relapse before completing maintenance therapy has the
worst prognosis and longtime survival of only 1020%
while late relapses occurring after cessation of mainte-
nance therapy have a better prognosis (3040% surviv-
al). Relapse in extramedullary sites, particularly testes,
is more favorable in terms of survival. The treatment of
relapse must be more aggressive than the first line ther-
apy with use of new drugs to overcome the problem of
drug resistance.
Allogenic bone marrow transplantation offers a better
chance of cure than conventional chemotherapy for chil-
dren with ALL who enter a second remission after he-
matologic relapse. In addition to the treatment related
morbidity and mortality, lack of a suitable matched do-
nor limits widespread application of allergenic transplan-
tation. Facilities for bone marrow transplantation are
available in all major centers in India including
Bombay, Vellore, Chennai and Delhi.
Late Effects of Treatment
Long term effects of treatment, which may take years to
become apparent, are of particular concern. Continued
evaluation of these patients for prolonged periods is
necessary. Patients who have received cranial irradiation
at a younger age are at risk for cognitive and intellec-
tual impairment [14] and development of CNS neo-
plasms. There is a risk of development of secondary
AML after the intensive use of epipodophyllotoxin
(etoposide or teniposide) therapy [15]. Endocrine dys-
function leading to short stature, obesity [16], preco-
cious puberty, osteoporosis, thyroid dysfunction and
growth retardation (growth hormone deficiency) are re-
ported. Patients having received treatment with an
anthracycline are at risk of cardiac toxicity [17, 18].
822
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) or acute non-lymphoblastic
leukemia, the second most common type of leukemia in chil-
dren, accounts for 1520% of leukemia in children. AML
results from clonal proliferation of hematopoietic precursors
of myeloid, erythroid and megakaryocytic lineage. Intensive
myelosuppressive induction and post-remission therapy en-
ables long term survival in 4050% patients only.
Epidemiology
AML can occur at any age but the incidence is more during
adolescence; males are affected as frequently as females.
Congenital leukemia (occurring during first 4wk of life) is
mostly AML. While the etiology of AML is not known, there
is an association following exposure to ionizing radiation.
Down syndrome is the most common genetic predisposing
factor associated with risk of developing AML during the first
three years of life.
Classification
AML can be divided into several subgroups according to the
FAB classification: M0, undifferentiated; M1, acute myelo-
blastic leukemia with minimal maturation; M2, acute myelo-
blastic leukemia with maturation; M3, acute promyelocytic
leukemia; M4, acute myelomonocytic leukemia; M5, acute
monoblastic leukemia; M6, erythroblastic leukemia and M7,
acute megakaryoblastic leukemia (Fig. 2). Several genetic ab-
normalities have been identified in AML.
Clinical Features
The clinical presentation of AML is similar to ALL but it is
more likely to have higher white cell count and incidence of
infections at the time of presentation. Most patients with AML
present with pallor, fatigue, bleeding or fever as manifesta-
tions of underlying anemia, thrombocytopenia and
Fig. 2 Peripheral smear of a 6-y-old child diagnosed with acute myeloid
leukemia (AML-M2) showing a myeloblast containing an Auer rod (pink
colored aggregated lysosome)
Indian J Pediatr (September 2015) 82(9):817824
neutropenia. Unlike ALL, lymphadenopathy and massive
hepatosplenomegaly is not very common in AML. However,
infants and toddlers with AML have more organomegaly, high
leukocyte counts and CNS disease at diagnosis. Disseminated
intravascular coagulation may occur with any subgroup, but is
common in acute promyelocytic leukemia (M3). Chloromas
are localized collections of leukemic cells seen exclusively in
patients with AML. They may occur at any site including
CNS, neck, bones (typically orbit) and skin (Fig. 3).
Gingival hypertrophy may be present (Fig. 4). Patients with
high WBC count may present with signs of leukostasis such as
pulmonary infiltrates causing respiratory distress or stroke.
Central nervous system involvement may occur in up to
15% of patients.
Diagnosis is ascertained as in acute lymphoblastic leuke-
mia by a peripheral smear and bone marrow examination.
Treatment
The long term survival for children with AML has increased
from less than 10% to almost 50% during the past two de-
cades. This is due to intensification of therapy along with
improved supportive care. However compared to ALL, the
cure rate is hampered by a lower remission rate, an increased
relapse rate due to the development of resistance to multiple
chemotherapeutic drugs and a greater risk of death in remis-
sion due to infections and hemorrhage [19]. The main drugs
used for induction therapy are combination of cytosine arabi-
noside and an anthracycline (doxorubicin or daunorubicin)
with or without additional drugs (etoposide, thioguanine).
Post remission therapy (consolidation therapy) includes high
dose chemotherapy including cytosine arabinoside and
etoposide. Risk based approach is also used for treatment of
AML. Various prognostic factors in childhood AML have
been identified: older age, obesity, M0 and M7 subtype of
Fig. 3 A child presenting with proptosis (chloroma) and diagnosed
as AML
Indian J Pediatr (September 2015) 82(9):817824
Fig. 4 A child diagnosed as AML showing gum hypertrophy
AML FAB classification, presence of CNS disease at diagno-
sis, absence of minimal residual disease and cytogenetics
characteristics like Inv16, t(8;21) and t(15;17) and are associ-
ated with a favorable outcome. M3 subtype and AML with
Down syndrome are associated with a favorable outcome.
Patients with unfavorable genetic alterations undergo stem
cell transplantation in 1st remission. Since patients with
AML are at high risk for myelosuppression following chemo-
therapy, they require intensive blood component support in-
cluding platelet transfusions and broad spectrum antibiotics
for control of infection which is one of the reason that not
all centers treat AML.
Acute Promyelocytic Leukemia (APL) Acute promyelocytic
leukemia (M3), accounts for about 1015% of patients of
AML, and are treated differently with all trans retinoic
acid or arsenic and systemic chemotherapy. All trans
retinoic acid (ATRA) significantly improved the outcome
in patients with APL. These patients are treated with
intensive anthracyclines and high dose cytarabine and
ATRA. Arsenic trioxiode is also now used in combination
with ATRA for this disease.
Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML), a myeloproliferative dis-
order, is primarily a disease of middle age; the peak incidence
is in the fourth and fifth decade. However, it may occur at any
age including infants and young children. Two main types of
well differentiated myelogenous leukemia have been recog-
nized. One is clinically and rheumatologically comparable
with the adult form of chronic myeloid leukemia and occurs
in children above the age of 4y. The other presents in infancy
and early childhood usually below the age of 4y, called juve-
nile chronic myelogenous leukemia (JCML) has a much more
rapid course.
823
Adult Variety of Chronic Myeloid Leukemia
Though the adult variety of CML is one of the commonest
leukemias in adults, it is rare in children accounting for 35%
cases. The natural history is divided into chronic, accelerated
and blast phases. In the chronic phase, patient has nonspecific
symptoms such as fever, malaise and weight loss.
Occasionally, patients present with acute symptoms such as
bone or joint pain or priapism. Splenomegaly is the most
common physical finding and is usually massive. Mild hepa-
tomegaly and lymphadenopathy may be present. Symptoms
of leukostasis such as headache, dizziness and visual distur-
bances may occur rarely. Leukocytosis is present in all cases
and 80% patients have leukocyte counts above 100,000/cu mm.
The differential count shows all forms of myeloid cells from
promyelocytic to polymorphonuclear leukocytes; basophilia
is common. Mild anemia and thrombocytosis are common,
but thrombocytopenia is rare. Bone marrow examination
shows extreme hypercellularity. Myeloid blasts and
promyelocytes constitute <20% of cells in the marrow in
chronic phase. Diagnosis is made by detection of
Philadelphia (Ph) chromosome on cytogenetics or by FISH
or RT-PCR. Chronic phase typically progresses to blast crisis
which shows sudden rise in leukocytes and blast count and is
indistinguishable from acute leukemia. Leukocyte alkaline
phosphatase activity is low. Philadelphia chromosome, which
involves a reciprocal translocation between long arms of chro-
mosomes 22 and 9; t(9;22) is present in 90% cases.
Allogeneic transplantation from an HLA matched sibling
donor can cure 80% of patients with CML [20, 21]. The aim of
treatment during chronic phase is to control the increasing
white cell counts. This can usually be achieved by single agent
chemotherapy with either busulfan or hydroxyurea. However,
these agents are being replaced with -interferon and more
recently developed tyrosine kinase inhibitor, imatinib
Fig. 5 A 1-y-old boy presented with fever, rashes, anemia, significant
splenomegaly and hepatomegaly. He was diagnosed as JMML
824
mesylate. Majority of patients achieve complete hematologic
and cytogenetic response with this therapy and the rate of
progression to accelerated or blast crisis is decreased.
Dasatinib, a newer tyrosine kinase inhibitor approved for use
in adults with CML is currently under clinical trials in chil-
dren. The blood counts return to normal or near normal in
almost all patients within 68 wk. Spleen size also decreases.
With the conventional treatment, the average survival is 34 y.
Survival after development of accelerated phase is usually less
than a year and after blast transformation only a few months.
Allogeneic stem cell transplantation is now used for patients
who do not respond to tyrosine kinase inhibitors.
Juvenile Chronic Myeloid Leukemia
JCML, also termed as juvenile myelomonocytic leukemia, is
an uncommon hematological malignancy accounting for less
than 2% leukemias in children. Patients with neurofibromato-
sis are at high risk for development of JCML. Compared to
ACML, JCML, a disease of infancy and early childhood, of-
t e n p r e s e n t s w i t h l y m p h a d e n o p a t h y, a n e m i a ,
hepatosplenomegaly, skin involvement (eczema, xanthoma
and caf-au-lait spots), infection and thrombocytopenia
(Fig. 5).
Peripheral smear shows leukocytosis (usually less than
1000,000/mm3) with the full spectrum of granulocytic
precursors and increased normoblasts; monocytosis is of-
ten striking. Thrombocytopenia and anemia are common.
The leukocyte alkaline phosphatase score is normal or
low and fetal hemoglobin levels are elevated. Bone mar-
row aspirates show an increased cellularity with predom-
inance of granulocytic cells in all stages of maturation;
megakaryocytes are normal or decreased. Most patients
have normal karyotypes or nonspecific chromosomal ab-
normalities. Philadelphia chromosome is negative; mono-
somy 7 is found in 30% patients [22].
JCML has a fulminant and rapidly fatal course.
Management involves supportive care including packed red
cell and platelet transfusions, treatment of infections and allo-
geneic stem cell transplant if a matched sibling donor is pres-
ent. Even with transplant, there is 3050 % event-free survival
rate at 3y. Cis retinoic acid has been tried with some benefit in
JMML.
Contributions RS: Wrote the article; AS: Did literature search, edito-
rial corrections and assisted in revising the manuscript. RS will act as
guarantor for this paper.
Conflict of Interest None.
Source of Funding None.
Indian J Pediatr (September 2015) 82(9):817824
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