LEUKEMIA

Defintion: Leukemias are diseases in which localised or generalised proliferation or

accumulation of neoplastic leucocytes /hematopoietic cells with or without
involvement of peripheral blood.

 Leukemias are malignant neoplasms arising from the uncontrolled proliferation

and loss of differentiation of hematopoietic stem cells.
 Genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal
proliferation of cells. The progeny of these cells have a growth advantage over
normal cellular elements, because of their increased rate of proliferation and a
decreased rate of spontaneous apoptosis. The result is a disruption of normal
marrow function and, ultimately, marrow failure.
Epidemiology:
 The leukemias are the most common malignant neoplasms in childhood,
accounting for approximately 30% of all malignancies that occur in children
younger than 15 yr of age.
 Incidence 1:25,000 (<15 years)

Classification:
 Lymphoid/myeloid leukemia: Depending on the lineage of the progenitor stem
cell involved, they are classified as lymphoid or myeloid.
 Acute/chronic leukemia:
 Depending on the natural history of the leukemia, they are classified as acute
or chronic.
 They were classified on the basis of their natural history in the prechemotherapy era.
 Leukemia is classified in the FAB system as acute when more than 25% of the BM
consists of blast cells.
 Acute Lymphoblastic Leukemia (ALL) – 75%
 Acute Myeloid Leukemia (AML) – 20%
 Chronic Myeloid Leukemia (CML) - 5%
 Juvenile myelomonocytic leukemia (JMML)
 ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Questions:
 Describe management of acute lymphoblastic leukemia. Add a note on side
effects related to the treatment.
 A 6 yr old child is brought with history of fever, pallor and bone pain for 7 days.
How will you investigate and manage this child?
 FAB classification of ALL
 Immediate and long term complications of ALL

 ALL refers to a group of lymphoid disordes, resulting from monoclonal

proliferation and expansion of lymphoid blasts in the bonemarrow, blood and
other organs.
(The malignant lymphoblasts of each patient with ALL are all descendants of a
single abnormal cell and as such comprise a clone)
 Childhood ALL was the first disseminated cancer shown to be curable

Epidemiology:
 ALL is the most common childhood malignancy accounting for one-fourth of all
childhood cancers and 3/4th of all newly diagnosed patients with acute leukemia.
 Incidence: 3-4 cases per 1,00,000 children < 15 yr of age.
 Age group: Commonly presents in young children aged 2–6yrs.(peak incidence at
2-3 yrs of age)
 Sex: more in boys than in girls at all ages (1.2:1)
Etiology:
o The cause is unknown and is probably multifactorial
o Genetics and environmental factors may play a role.
o Genetic conditions:
 Identical twin: (20% risk) Among identical twins, the risk to the second twin if
1 twin develops leukemia is greater than that in the general population.
 Genetic conditions predisposing to leukemia:
 Down syndrome 
Neurofibromatosis type 1
 Fanconi anemia 
Ataxia-telangiectasia
 Bloom syndrome 
Severe combined immune
 Diamond-Blackfan anemia deficiency
 Shwachman-Diamond syndrome  Paroxysmal nocturnal
 Kostmann syndrome hemoglobinuria
 Li-Fraumeni syndrome
(Down syndrome- 14 fold increase in the overall rate of leukemia)
o Environmental factors:
 Ionizing radiation
 Chemicals: Benzene exposure
 Alkylating agents: cyclophosphamide, ifosfamide, carboplatin, procarbazine
 Epipodophyllotoxins: etoposide, tenoposide
 Nitrosourea
 Parental smoking
 Viral infections
(Chromosomal translocations that occur in utero during fetal
hematopoiesis have been suggested as the primary cause of Pediatric ALL
and postnatal genetic events have been suggested as secondary
contributors.)
Cellular classification:
 Morphologic (Cytologic) classification: FAB classification for ALL
ALL cells can be classified using the FAB criteria into morphologic subtypes as
L1, L2 and L3
Cytologic Feature L1 Type L2 Type L3 Type
Prevalence 80-85% 15% 1-2%
Cell size Small; homogenous Large; heterogenous Large; homogenous
Cytoplasm Scanty Variable Abundant
Nucleoli Small; inconspicuous One or more; often large one or more; prominent
Nuclear chromatin Homogenous Variable; heterogenous Stippled; homogenous
Nuclear Shape Regular; Irregular clefts; Regular; oval to round
occasional clefts indentation
Cytoplasmic Variable Variable Intensely basophilic
Basophilia
Cytoplasmic Variable Variable prominent
Vacuolation
 Immunophenotype classification of ALL:
 Immunophenotype classification describes ALL as either B cell derived or
T cell derived on the basis of the surface markers.
(Phenotypically, surface markers show that Approximately 85% of cases of
ALL are classified as B lymphoblastic leukemia (previously termed precursor
B-ALL or pre–B-ALL), approximately 15% are T-lymphoblastic leukemia, and
approximately 1% are derived from mature B cells.
The rare leukemia of mature B cells is termed Burkitt leukemia.)

ALL subtype Surface markers Significance

B lymphoblastic leukemia CD10+, CD19+, The most common subtype with
CD20+, CD21+, good prognosis
(=pre B ALL)
HLA-DR+
Mature B cell CD19+, CD20+, Burkitt’s leukemia,
CD21+, sIg+ correlates with L3 leukemia,
good prognosis with short duration
intensive chemotherapy
T cell CD3+, CD5+, CD7+ Common in older children, associated
with high WBC counts, mediastinal
mass and CNS involvement

(Note: Lineage specific markers:

1. Myeloid:CD 13,33
2. T lymohoid:CD 3,5,7
3. B lymphoid:CD 10,19,20)
Cytogenetics:
 Cytogenetic analysis further characterizes leukemia on the basis of chromosomal
aberrations that are known to influence outcomes.
 Chromosomal abnormalities are used to subclassify ALL into prognostic groups
 Conventional cytogenetics and FISH should be performed on the bone marrow
specimen to look for common genetic alterations in ALL
 Hyperdiplody (> 50 chromosomes, DNA index >1.16) associated with good
prognosis
 Hypodiploidy(<44 chromosomes)  associated with poor prognosis
 Chromosomal translocations associated with poor prognosis in ALL:
 Mature B-cell leukemia (Burkitt leukemia): t(8;14)
 Infantile ALL(pre B): t(4;11)
 Philadelphia chromosome (pre B): t(9;22)
 Chromosomal abnormalities associated with favorable prognosis in ALL:
 Philadelphia chromosome positive ALL(pre B): t(9;22)
 Simultaneous presence of trisomy 4 and 10 (pre B)
 t(12;21) (pre B)

Prognostic factors and risk assessment:

Clinical presentation:
 Duration of symptoms: may vary from days to weeks and in some cases few
months.
 Gen systemic effects: Fever, lassitude, anorexia, irritability
 Bone marrow invasion:
 Anemiapallor, fatigue, exercise intolerance, shortness of breath
 Thrombocytopenia petechiae, ecchymosis or gum bleeds
 Infection due to neutropenia fever, pneumonia, otitis, skin, soft tissue and
perianal infections
 R E system infiltration
 Lymphadenopathy- can be generalized and sometimes massive
 Hepatosplenomegaly
 Bone or Joint pain: due to leukemic involvement of periosteum of bones or joints
 CNS invasion :  ICT, headache, deficits, hemorrhage, seizures
 Respiratory distressusually due to anemia but can occur due to mediastinal
mass
 Superior mediastinal syndrome resulting from compression of the trachea leads
to cough, breathlessness and air hunger
 SVC syndrome: caused by mediastinal adenopathy compressing the SVCfacial
edema & plethora, throbbing headache, conjuctival congestion & dilated neck
veins.
 Testesfirm, painless enlargement of one or both testes
 Renal Children with large tumor burden may sometimes develop spontaneous
tumor lysis syndrome leading to acute renal failure, secondary to uric acid
nephropathy
 Other rare sites of extramedullary involvement
o Heart o Kidneys
o Lungs o Ovaries
o GIT o Eye
o Skin
(Testes and CNS are common extramedullary sites for ALL)
Lab Diagnosis
 CBC:
 Anemia
 thrombocytopenia,
 TC and DC:
 WBC count is low or normal
 Hyperleukocytosis (WBC count > 100,000/mm3)
 Neutropenia
 PS:
 may or may not reveal blast cells.
 Often, they may be reported as atypical lymphocytes or immature cells when
ALL present with total leukocyte counts of <10,000/μL
 Bone marrowexamination:
 The presence of 25% blast cells confirms the diagnosis of ALL
(Special stains –PAS, Sudan black, Myeloperoxidase)
 Morphology of the leukemic blasts:(FAB):L1, L2, L3
 Immunophenotyping (CD markers) of ALL blasts by flow cytometry
Early pre B, Pre B, B cell, T cell ALL
 Histochemical stains specific for myeloblastic and monoblastic leukemias
(myeloperoxidase and nonspecific esterase) distinguish ALL from AML
 Cytogenetics: Diploidy, translocation
 FISH or PCR for specific translocations
 molecular studies
 CXR for mediastinal mass, more often, in T-cell ALL
 Serum biochemistry: Uric acid & LDHoften elevated at diagnosis as a result of
cell breakdown
 CSF:
 diagnostic and to administer the first intrathecal dose of methotrexate
 If lymphoblasts are found and the CSF leukocyte count is elevated, overt CNS
or meningeal leukemia is present.
 Serology for HIV, HBS Ag, Anti-HCV
 USG abdomenHepatosplenomegaly and kidney enlargement
 RFT- In severe cases, renal function may be compromised with elevation of
blood urea nitrogen (BUN) and creatinine.
 LFT- Elevated transaminases and hyperbilirubinemia may occasionally be
present in cases of extensive liver involvement
 Serum electrolytes: serum sodium, potassium, chloride, calcium, phosphorus,
magnesium
 ECG,ECHO
 Basal cultures.
 Blood Grouping
 Coagulation profile-PT, aPTT may be deranged
(Tumor lysis syndrome is characterized by elevated potassium, phosphorus, uric
acid and depressed calcium.)
DDs:
o Chronic infections by EBV and CMV causing lymphadenopathy,
hepatosplenomegaly, fevers, and anemia.
o ITPProminent petechiae and purpura
o Significant pallor could be caused by transient erythroblastopenia of childhood,
autoimmune hemolytic anemias, or aplastic anemia.
o When only pancytopenia is present, aplastic anemia (congenital or acquired) and
myelofibrosis should be considered
o JRAFevers and joint pains, with or without hepatosplenomegaly and
lymphadenopathy, suggest juvenile rheumatoid arthritis (JRA).
 The diagnosis of leukemia usually becomes straightforward once the CBC
reveals multiple cytopenias and leukemic blasts.
 Serum LDH levels may help distinguish JRA from leukemia, as the LDH is
usually normal in JRA.
o An elevated WBC count with lymphocytosis is typical of pertussis; however, in
pertussis the lymphocytes are mature, and neutropenia is rarely associated.
o ALL should be distinguished from other malignancies—neuroblastoma, NHL,
rhabdomyosarcoma, Ewing sarcoma and retinoblastoma.
Treatment: supportive and specific
Supportive treatment:
o Transfusions- blood components-PRBC and platelet transfusion
o Treatment of infection-broad spectrum antibiotics & antifungals (in febrile
neutropenia)
o Prophylaxis against pneumocystis jiroveci pneumonia cotrimoxazole
o Management of emergencies
 Obstructive conditions--like the superior vena cava syndrome and the superior
mediastinal syndrome
 Metabolic conditions like tumor lysis syndrome
 Hematological conditions like severe anemia and bleeding.
o Metabolic support ―Tumour lysis syndrome‖
 Hyperkalemia,
 Hyperuricemia
  Hydration, alkalinisation, Allopurinol, Rasburicase (to prevent or treat renal
failure)
 Hyperphosphatemia / hypocalcaemia
o Treatment of hyper viscosity (?therapeutic plasma exchange)
o Nutritional support
o Vaccination against Hep B
o Maintenance of oral hygiene (chlorhexidine/betadine mouth wash) & perianal
hygiene (Sitz bath) reduces the risk of infections
o Psychosocial support
o Bone marrow transplantation-is indicated for very high-risk patients, those who
fail induction therapy and those who have early relapse while still on therapy

(Allopurinol, a xanthine oxidase inhibitor, helps to prevent the formation of uric acid.
Rasburicase, a urate oxidase helps in degrading uric acid converting it into the
water soluble allantoin, which is easily excreted by the kidneys.)
Specific treatment: Anti Leukemic therapy
o Risk-directed therapy has become the standard of current ALL treatment
o Protocols
 MCP 841(NCI 841)
(MCP-Multicenter protocol) (NCI-National cancer institute)
 ALL BFM 86 (BFM-Berlin-Frankfurt-Munster)
 UK ALL
o Treatment for ALL consists of four phases:
1. Induction therapy (to attain remission)
2. CNS prophylaxis or CNS preventive therapy
3. Intensification(Consolidation) therapy
4. Maintenance therapy
 Remission induction: – 4-6 weeks
 Vincristine, Prednisolone, Daunomycin, L Asparginase
 Designed to eradicate the leukemic cells from the bone marrow.
 Remission- defined by <5% blasts in the marrow and a return of neutrophil
and platelet counts to near-normal levels after 4-5 wk of treatment.
 About 90–95% patients achieve a remission at the end of induction
chemotherapy.
 CNS directed therapy:
 Aimed at eliminating the leukemic cells from within the CNS, which are usually
shielded from systemic chemotherapy by the blood brain barrier.
 Components:
 Cranial irradiation only for CNS +ve cases
 Intra thecal methotrexate (IT MTX)
 high-dose systemic chemotherapy
 CNS prophylaxis reduces the rate of CNS relapse from 60% 5%.
 Reinduction: in MCP 841 protocol
Consolidation phase: 16–20 weeks of intensive chemotherapy
 Administered shortly after remission induction
 to reduce tumour burden further and reduce risk of relapse and development
of drug-resistant cells
 Commonly used agents- high dose methotrexate, L-asparaginase,
epipodophyllotoxin, cyclophosphamide, vincristine & cytarabine
Maintenance phase:
o for 24–30 months after completion of intensive chemotherapy
o necessary to clear the marrow of residual leukemic cells.
 Methotrexate (weekly) (orally)
 6-mercaptopurine (6 MP) (daily)(orally)
 With periodic intensification-vincristine & prednisone or other cytostatic drugs

Prognosis:
 Overall survival is approximately 80% with current treatment.
 Adverse prognostic factors include:
• Male gender.
• Age < 2yrs or >10yrs.
• Hb > 10 gm%
• WBC count <10,000 or High WBC count (>50,000/cmm) at diagnosis.
• Presence of CNS disease
• Cell type L2, L3
• T cell ALL
• Mediastinal mass
 • Hepatosplenomegaly, lymphadenopathy
• Unfavourable cytogenetics: Hypodiploidy, Philadelphia chromosome—t(9;22);
MLL gene rearrangements (e.g. t(4;11) in infants); AML1 amplification;
• Poor response to induction and failure to remit by day 28.
• High level of minimal residual disease (MRD) at 28 days.
• BM relapse occurring within 18 months
 Good prognosis factors:
• Age 2-10 yrs • No CNS disease
• Girl child • Mild or absent organomegaly
• Hb <10g% • Hyperdiploidy(>50)
• Lower WBC • Early pre B
• Prednisone response • No translocations
• Cell type L1

Treatment of Relapse:
o Despite success of modern treatment, 20-30% of children with ALL relapse.
 1st year -10%
 2nd year -5%
 3rd year -1%
 5th year -<1%
o Common sites of relapse:
 BM (20%)
 CNS (5%)
 Testis (3%)
o Extramedullary relapse (mainly CNS, testes) may present without bone marrow
disease.
o Treatment is stratified according to risk factors, which include:
 Time from first diagnosis (risk reduces with time).
 Extramedullary relapse (lower risk, particularly if isolated).
 Minimal residual disease (MRD) status after re-induction (–ve status reduces
risk).
Treatment:
o Intensive re-induction and consolidation for all risk groups.
o Low risk: 2yrs of continuing conventional chemotherapy.
o High risk: BMT allograft.
o Intermediate risk: the role of BMT in this group is unclear; it may be based on
minimal residual disease and/or availability of matched donor.
o Radiotherapy for extramedullary disease: given as a boost for those receiving
total body irradiation (TBI) for BMT.
Late effects of Treatment:
 Children with high risk disease treated with intensive therapy are at risk for
longterm complications
 Neurocognitive deficits
 Obesity
 Cardiomyopathy
 Avascular necrosis
 Secondary leukemia (secondary AML with etoposide, teniposide)
 Osteoporosis
 Children treated with cranial radiation:
 Cognitive & intellectual impairment
 GH deficiency
 CNS neoplasms