This document discusses acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It describes the epidemiology, pathogenesis, classification, clinical presentation, diagnosis, prognostic factors, management and outcomes of both ALL and AML in children. ALL is more common and has a better prognosis than AML. Prognostic factors for ALL include age, white blood cell count, specific genetic mutations and response to initial treatment. Treatment involves induction, consolidation, central nervous system prophylaxis and maintenance therapy over 2-3 years.
2. Leukemia is a malignancy that arises from clonal
proliferation of abnormal hematopoietic cells leading to
disruption of normal marrow function leading to marrow
failure. The clinical manifestations of leukemia are the
result of the unregulated proliferation of the malignant
clone and bone marrow failure. Leukemia is the most
common cancer in children. There are two main subtypes,
the commoner acute lymphoblastic leukemia (ALL)
and
acute myeloid leukemia (AML).
3. 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. Its
incidence is approximately 3-4 cases per 100,000 children
below 15 yr of age. There is a peak in the incidence of
childhood ALL, between the ages of 2 and 5 yr, due to
ALL associated with a pre-B lineage (referred to as
common
ALL). Boys have higher rates than girls, especially in
adolescents with T cell ALL.
4. The etiology of ALL remains unknown in a majority of
cases. However, several genetic syndromes have been
associated with an increased risk of leukemia. In
particular,
there is a 10-20 fold increased risk of leukemia (ALL
and AML) in children with Down syndrome. Other genetic
syndromes associated with leukemia include Bloom
syndrome, Fanconi anemia, neurofibromatosis, Klinefelter
syndrome, immunodeficiency and ataxia-telangiectasia.
Exposure to ionizing radiation, certain pesticides and
parental smoking are associated with a higher incidence
of ALL.
5. Morphology
L1 morphology
lymphoblasts, are the most common subtype of childhood
ALL (80-85%), have scant cytoplasm and inconspicuous
nucleoli; these are associated with a better prognosis.
Patients in the L2 category, accounting for 15% cases, show
large, pleomorphic blasts with abundant cytoplasm and
prominent nucleoli. Only 1-2% patients with ALL show
L3 morphology in which cells are large, have deep
cytoplasmic basophilia and prominent vacuolation; these
cells show surface imrnunoglobulin and should be treated
as Burkitt lymphoma.
7. Cytogenetics
Genetic abnormalities found in the leukemic clone greatly
impact the therapy and prognosis of ALL. Conventional
cytogenetics and fluorescence in situ hybridization should
be performed on the bone marrow specimen to look for
common genetic alterations in ALL. The presence of
hyperdiploidy (chromosome number
>50, DNA index >1.16) is associated with good prognosis
in contrast to the poor prognosis in patients with
hypodiploidy.
8. Specific chromosomal translocations in ALL, including
t(8;14, associated with Burkitt leukemia) in B
cell ALL, t(4;11) in infant leukemia and t(9;22)
translocation,
that forms the Philadelphia chromosome, are
associated with a poor prognosis.
9. Prognostic Factors
The two most important prognostic factors include age at
diagnosis and the initial leukocyte count. Children less
than 1-yr-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 yr do well. The presence of leukocyte count more
than 50,000/mm3 at diagnosis is associated with a bad
prognosis. The presence
of T cell leukemia is not a poor prognostic factor unless
associated with other risk factors, including high leukocyte
count, mediastinal mass or disease affecting the central
nervous system at diagnosis.
10. Patients showing hyperdiploid
y have a good prognosis, while presence of
hypodiploidy is associated with an unsatisfactory
outcome. Philadelphia positive t(9;22) ALL and
translocation
t(4;11) which is present in infant leukemia are
associated with poor prognosis. A lack of response to
treatment with prednisone is considered a
prognosticfactor; patients showing :?:1,000/mm3 blasts
in peripheral
blood following 7 days treatment with prednisone and
an intrathecal dose of methotrexate are likely to have an
adverse outcome.
11. Clinical Presentation
The duration of symptoms in a child with ALL may
vary
from days to weeks and in some cases few months. The
clinical features of ALL are attributed to bone marrow
infiltration with leukemic cells (bone marrow failure)
and
extramedullary involvement.
12. Common features include
pallor and fatigue, petechiae or purpura and infections.
Lyrnphadenopathy, hepatomegaly and splenomegaly are
present in more than 60% patients. Bone or joint pain and
tenderness may occur due to leukemic involvement of the
periosteum of bones or joints. Infants and young children
may present with a limp or refusal to walk. Tachypnea
and respiratory distress may be present secondary to
severe anemia leading to congestive heart failure or
secondary to the presence of mediastinal mass leading to
tracheal compression.
13. A
large mediastinal mass may sometimes cause superior
vena cava syndrome with facial edema and plethora,
throbbing headache, conjunctiva! congestion and dilated
neck veins. Patients with high tumor burden can
occasionally present with very high total white cell count
(hyperleukocytosis,TLC >1,00,000/mm3) or tumor lysis
syndrome with decreased urine output and azotemia
secondary to uric acid nephropathy.
14. Few patients (2-5%) show central nervous system
involvement at diagnosis; most are asymptomatic but
some have features of raised intracranial pressure. The
diagnosis of CNS leukemia is made on examination of the
cerebrospinal fluid. Overt testicular leukemia may be seen
in about 1 % of cases. It presents with firm, painless,
unilateral or bilateral swelling of the testes; the diagnosis
is confirmed by testicular biopsy. Other rare sites of
extramedullary involvement include heart, lungs, kidneys,
ovaries, skin, eye or the gastrointestinal tract.
15. Diagnosis and Differential Diagnosis
Clinical presentation and peripheral blood counts and
morphology are indicative of the diagnosis of ALL.
Children may present with pancytopenia or
hyperleukocytosis.
The diagnosis is confirmed by peripheral
smear examination and or bone marrow aspirate and
biopsy. It is important to do both an aspirate as well as
biopsy at time of initial diagnosis. Very rarely leukemic
cells may be seen only in the biopsy specimen and not in
the aspirate. Higher white blood cell counts are more
common with T cell ALL.
16. Bone marrow showing >25%
lymphoblasts is diagnostic for ALL. The clinical profile of acute
lymphoblastic leukemia may
mimic many other clinical conditions like infectious
mononucleosis, acute infectious lymphocytosis, idiopathic
thrombocytopenic purpura, aplastic anemia and viral
infections like cytomegalovirus that result in leukemoid
reactions and pancytopenia. Idiopathic thrombocytopenic
purpura is the most common cause of acute onset of
petechiae and purpura in children. Children with ITP have
no evidence of anemia and have normal total and differential
leukocyte count. Bone marrow smear reveals normal
hematopoiesis and normal or increased number of
megakaryocytes. ALL must be differentiated from a plastic
anemia, which may present with pancytopenia.
17. Bone marrow from a child with acute lymphoblastic
leukemia shows reduced marrow elements and replacement by
lymphoblasts. Neoplastic lymphoblasts are slightly larger than
lymphocytes and have scant, faintly basophilic cytoplasm and round
or convoluted nuclei with inconspicuous nucleoli and fine chromatin,
often in a smudged appearance
18. ALL should be
distinguished from other malignancies (neuroblastoma,
non-Hodgkin lymphoma, rhabdomyosarcoma, Ewing
sarcoma and retinoblastoma) that present with bone marrow
involvement. Morphologic, cytochemical, immunophenotypic
and cytogenetic characteristics of the malignant
cells should be done. Occasionally, patient with ALL may
present with hypereosinophilia or as an emergency with
very high white cell count (hyperleukocytosis, TLC
> 1,00,000 I mm3), life-threatening infections, hemorrhage,
organ dysfunction secondary to leukostasis or signs and
symptoms of superior vena cava or superior mediastinal
syndrome.
19. Management
The management of acute leukemia needs the combined
effort of a number of health professionals. Improvement
in survival from ALL with modern therapy is one of the
greatest successes in the field of pediatric oncology.
Improvement in supportive care and use of combination
chemotherapy has led to a survival more than 80% overall
and greater than 95% in children with low risk ALL.
Treatment is determined by the risk of relapse in each
patient.
20. The treatment on 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
average duration of treatment in ALL
ranges between 2 and 2.5 yr; there is no advantage of
treatment exceeding 3 yr
21. 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 bone the bone marrow by morphology.
Patients who achieve rapid early remission ( <5% blasts in
bone marrow) by day 7 or 14 of induction have a better
prognosis than slow responders. The drug regimen combining
vincristine and prednisone
induces remission in 80-95% patients with ALL. Since the
remission rate and duration are improved by the addition
of a third and fourth drug (L-asparaginase and/ or anthracycline),
current induction regimens include vincristine,
prednisone, L-asparaginase and an anthracycline, with
remission achieved in 95-98% of cases. The induction
therapy lasts for 4-6 weeks.
22. CNS Preventive Therapy
Most children with leukemia have subclinical CNS involvement
at the time of diagnosis and this acts as a sanctuary
site where leukemic cells are protected from systemic
chemotherapy because of the blood brain barrier. The early
institution of CNS prophylaxis is essential to eradicate
leukemic cells which have passed the blood brain barrier.
CNS prophylaxis has enabled increased survival rates in
leukemia. Most children in the past received a combination
of intrathecal methotrexate and cranial irradiation. However,
there is considerable concern regarding longterm
neurotoxicity and risk of development of brain tumors
following this therapy. In order to achieve effective CNS
prophylaxis while minimizing neurotoxicity, experts now
recommend a lower dose of cranial irradiation with
intrathecal methotrexate.
23. Intensification (Consolidation) Therapy
This is a period of intensified treatment administered
shortly after remission induction with administration of
new chemotherapeutic agents to tackle the problem of
drug resistance. There is clear evidence that intensification
has improved the longterm survival in patients with ALL,
especially those with high-risk disease. Commonly used
agents for intensification therapy include high dose
methotrexate, L-asparaginase, epipodophyllotoxin,
cyclophosphamide and cytarabine.
24. Maintenance (Continuation) Therapy
It has been estimated that approximately two to three logs
of leukemic blasts are killed during the induction therapy,
.
Additional therapy is therefore necessary to prevent a
relapse. Once remission is achieved, maintenance therapy is
continued for an additional 2-2.5 yr. Without such therapy,
patients of ALL relapse within the next 2-4 months. A
number of drug combination and schedules are used, some
based on periodic reinduction, others on continued delivery
of effective drugs. 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.
25. Infant ALL
Outcome of ALL remains poor in this group of patients
even with very intense therapy including stem cell
transplant.
Only 30-40% of children with MLL t(4;11) gene
rearrangement are cured. Role of transplantation
remains
controversial. Therapy usually includes high dose
cytarabine
and methotrexate in addition to standard ALL
therapy.
26. Philadelphia chromosome positive ALL
The 3 yr survival for Philadelphia chromosome positive
ALL has improved to 80% with use of imatinib
Other high-risk groups
Hypodiploidy (<44 chromosomes), t(17;19), remission
induction failure and presence of minimal residual disease
> 1 % at end of induction is associated with poor prognosis.
Most such patients undergo stem cell transplantation.
27. Supportive Care
Because of the complications encountered with treatment
and the need for aggressive supportive care like blood
component therapy, detection and management of
infections, nutritional and metabolic needs and psychosocial
support, these children should be treated at centerswith
appropriate facilities. These children should be given
cotrimoxazole as prophylaxis against Pneumocystis jiroveci
pneumonia. They should be vaccinated against hepatitis
B infection and screened for HIV infection. Oral hygiene
should be taken care of. Facilities for blood component
therapy should be available
28. Prognosis
Hypodiploidy, Philadelphia chromosome positivity, T cell
ALL, MLL rearrangement, IKZFl gene deletion, age <1 yr
and > 10 yr, leukocyte count >50,000 / cu mm and
presence
of CNS disease are poor prognostic features. More that
80% of children with ALL are longterm
survivors in the developed countries. However, survival
remains poor in the developing nations, chiefly due to
infection related mortality.
29. Down Syndrome and Acute Leukemia
Children with trisomy 21 have a 15-20 fold higher risk
of
acute leukemia as compared to general population
with a
cumulative risk of developing leukemia of
approximately
2.1%. The ratio of ALL to AML in Down syndrome is as
for childhood acute leukemia.
30. ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML) also termed as acute
nonlymphoblastic
leukemia, accounts for 15-20% of leukemia
in children. AML is a more complex and resistant
disease
than ALL and results from clonal proliferation of
hematopoeitic precursors of myeloid, erythroid and
megakaryocytic lineage.
31. 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 4 weeks 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. Other
predisposing factors are Fanconi anemia, Blooms
syndrome, Kostmann syndrome and Diamond Blackfan
anemia. Medications associated with risk of AML include
alkylating agents and epipodophyllotoxins.
32. Pathogenesis
Genetic aberrations in AML suggest alterations that
regulate self renewal and differentiation cooperate in the
pathogenesis of AML. Several genetic mutations have
been identified in AMLThese include
mutations in FLT3, PTPN11, oncogenic Ras, BC R/ABL
and
TEL/PDGFR. Mutations and translocation fusion
products that impair differentiation and apoptosis (class
II mutations) include PML/RARa fusion from t(15;17),
AML-1/ETO fusion from t(8;21), CEBPa mutations
andMLL rearrangements.
33. Classification
AML is divided into several subgroups according to the
FAB classification: MO undifferentiated, Ml acute myeloblastic
leukemia with minimal maturation, M2 acute
myeloblastic leukemia with maturation, M3 acute promyelocytic
leukemia, M4 acute myelomonocytic leukemia,
MS acute monoblastic leukemia, M6 erythroblastic
leukemia, M7 acute megakaryoblastic leukemia. About
30-40% patients with AML are Ml and M2 and about same
percentage is M4 and MS. M3 type of AML constitutes
about 50-10% and M7 is strongly associated with Down
syndrome.
34. Clinical Features
Clinical presentation is similar to ALL but more likely to
have higher white cell count at presentation and have
higher incidence of infections at time of presentation.
Most
patients with AML present with pallor, fatigue, bleeding
or fever as manifestations of underlying anemia,
thrombocytopenia and neutropenia. Unlike
ALL, lymphadenopathy and massive hepatosplenomegaly
is not common. However, infants and toddlers
with AML have more organomegaly, high leukocyte
counts and CNS disease at diagnosis.
35. Diagnosis is ascertained as in ALL by a peripheral
smear
and bone marrow examination; the morphologic,
cytochemical,
immunophenotypic and genetic characteristics
of blast cells should be determined
36. A 5-yr-old boy presented with fever, epistaxis and petechiae; (A) Note bilateral subconjunctival
bleeding; (B) peripheral
smear showed myeloblasts. The arrow points to an Auer rod within a myeloblast, representing
pink colored aggregated lysosomes. A diagnosis
of acute myeloid leukemia of M2 type was made
37. Treatment
The main
drugs used for induction therapy are combination of
cytosine arabinoside and an anthracycline (daunorubicin).
The induction regimen most commonly used is cytosine
arabinoside (100 mg/ m2 / day given as continuous
infusion
for 7 days) plus daunorubicin (45 mg/m2 / day for 3 days)
with or without additional drugs (etoposide, thioguanine).
With the current regimen, remission is induced in about
70-80% patients.
38. 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, MO and M7 subtype of
AML FAB classification, presence of CNS disease at
diagnosis,
absence of minimal residual disease and cytogenetics
characteristics like Inv 16, t(8;21) and t(15;17) are
associated
with a favorable outcome.
39. M3 subtype and AML with
Down syndrome are associated with a favorable
outcome.
Patients with favorable genetic features or with normal
cytogenetics are treated with chemotherapy alone.
Patients
with unfavorable genetic alterations undergo stem cell
transplantation in first remission.
40. CHRONIC MYELOID LEUKEMIA
Chronic myeloid or myelogenous leukemia (CML) is a
myeloproliferative disorder. CML 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 recognized.
One is clinically and hematologically comparable with the
adult form of CML and occurs in children above the ageof 4
yr. The other presents earlier in infancy and early
childhood usually below the age of 4 yr, called juvenile
CML.
41. A 6-yr-old boy presented with fever, pallor and progressive
abdominal distension for 6 months. Significant splenomegaly and
hepatomegaly was noted. A diagnosis of chronic myeloid leukemia
was made
42. Adult Variety of CML
Though the adult variety of CML is one of the commonest
leukemias in adults, it is rare in children accounting for
3-5% 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.
Splenomegal
y is the most common physical finding and is
usually massive. Mild hepatomegaly and
lymphadenopathy may be present. Symptoms of leukostasis
such as headache, dizziness and visual disturbances
may occur rarely.
43. Leukocytosis is present in all cases and
80% patients have leukocyte counts above l,OO,OOO/mm3•
The differential count shows all forms of myeloid cells
from promyelocytes 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
bone marrow in chronic phase. Chronic phase typically
progresses to blast crisis which shows sudden rise in
leukocytes and blast count and is indistinguishable from
acute leukemia.
44. Philadelphia chromosome, which involves a
reciprocal translocation between long arms of chromosomes
22 and 9; t(9;22) is present in 90% cases. 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 P-interferon and tyrosine kinase inhibitor,
imatinib 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.
45. The blood counts return to normal or near
normal in almost all patients within 6-8 weeks. Spleen
size also decreases. With conventional treatment, the
average survival is 3-4 yr. 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.
46. Juvenile Chronic Myeloid Leukemia
JCML, also termed as juvenile myelomonocytic leukemia,
is an uncommon malignancy accounting for less than 2%
leukemias in children. Patients with neurofibromatosis are
at high risk for this condition. JCML is a disease of infancy
and early childhood below the age of 5 yr, has a more
acute and severe course with frequent lymphadenopathy,
anemia, hepatosplenomegaly, skin involvement (eczema,
xanthoma and cafe au lait spots), infection and
thrombocytopenia.
47. Peripheral smear shows leukocytosis (usually less than
1,00,0000/mm3) with the full spectrum of granulocytic
precursors and increased normoblasts; monocytosis is
often striking. Thrombocytopenia and anemia are
common. Leukocyte alkaline phosphatase score is normal
or low and fetal hemoglobin levels are elevated. Bone
marrow aspirates show an increased cellularity with
predominance of granulocytic cells in all stages of
maturation; megakaryocytes are normal or decreased.
48. JCML has a fulrninant and rapidly fatal course.
Management
involves supportive care including packed red cell
and platelet transfusions, treatment of infections and
allogeneic stem cell transplant if a matched sibling
donor
is present. Even with transplant, there is 30-50%
eventfree
survival rate at 3 yr. Cis-retinoic acid has been tried
with some benefit.
49. A 1-yr-old boy presented with fever, rashes, anemia and
massive splenomegaly and hepatomegaly. He was diagnosed with
juvenile myelomonocytic leukemia
