REVIEW OF RELATED LITERATURE

Acute lymphoblastic leukemia is the most common malignancy of children

and adolescents. The evolution of treatment with combination chemotherapy,

CNS treatment, and intensified therapy for high-risk categories has led to cure

rates of nearly 8 0% in children. Favourable factors are age 5-10 years,

hyperdiploidy (best, 54-62 with trisomy 4, 10, and/0r 17), t(12;21) and normal

or low WBC. Poor risk factors include age younger than 1 year, t(9;22) and

t(4;11). Among adults, only 30%-40% are cured, in part because of higher

frequency of adverse genetic abnormalities. Adult incidence increases in middle

to older age. (Pui, 2004)

Acute lymphoblastic leukemia is a heterogenous group of disease with

varied clinical outcomes, depending on molecular, cytogenic, and clinical

characterization. There have been significant advances in our understanding of

the molecular pathogenesis of this disease, which should translate into

effective targeted therapies and better patient outcomes. Given the rarity of this

disease, it is strongly recommended that patients are preferred to centers of

expertise, and it is crucial that patients be enrolled in clinical trials designed to

evaluate subset-specific therapies to improve survival

According to Hematology Basic Principles and Practice (Hoffman, et al.,)

Acute lymphoblastic leukemia (ALL) is a heterogenous group of diseases

characterized by clonal proliferation of lymphoid progenitors (Lymphoblasts). A

small minority of ALL cases (<5%) associated with predisposing inherited

syndromes such as Down syndrome, Blood syndrome, ataxia telangiectasia, and

Nijmegen breakage syndrome. However, the underlying etiology is not known in

most cases. Although parental tobacco or alcohol use, exposure to pesticides or

solvents, and cigarette smoking have all been implicated, only ionizing radiation

has been significantly linked to increased risk of developing ALL. A group of

investigators hypothesized that overt leukemia evolves as a consequence of an

abnormal lymphoid proliferation that occurs in response to exposure to an as

yet unidentified infectious agents(s). Supporting this hypothesis are data suggest

that day care attendance associated with a lower incidence of ALL. Similarly,

industrialization associated with improved socioeconomic status and exposure

to common infectious agents later in life has been postulated to result in

abnormal and excessive lymphoid proliferation and leukemic transformation.

(Hoffman, et al., 2013)

Acute leukemias are mainly due to accumulation of blasts that were not

able to differentiate resulting from an interference in the maturation process.

These blasts may accumulate in the bone marrow and other organs leading to

clinical feature such as bone marrow failure and tissue invasion. Acute leukemia

may involve myeloid precursors (acute myeloid leukemia) and also cells of

lymphoid lineage (acute lymphoblastic leukemia). Myeloblast or promyelocyte

maturation arrest is observed in acute myeloid leukemia while maturation arrest

of lymphoblasts is seen in acute lymphoblastic leukemia.

Cell morphology can be described as having a small size with scant

cytoplasm, nucleoli varying by subtype with the absence of auer rods. Patients

with ALL have positive periodic acid Schiff (PAS) test and terminal
deoxynucleotide transferase (TdT). Flow cytometry results are: CD19, CD20,

surface or cytoplasmic IgG, and CALLA antigens.

Majority of the cases of acute leukemia is of unknown etiology. However,

some causes and risk factors are known. These include ionizing radiation,

chemical agents, viruses, genetic disorders, acquired disorders, and secondary

leukemia. Common clinical features are also worth noting. These ineffective

hematopoiesis caused by the infiltration of bone marrow with blast cells.

Ineffective hematopoiesis may involve anemia which may lead to fatigue and

shortness of breath, thrombocytopenia which increases the risk for bleeding and

may also cause bruising, and neutropenia which can make the patient

susceptible to infection. Another clinical feature is the infiltration of other organs

and soft tissues which may cause hepatomegaly, splenomegaly,

lymphadenopathy, and even testicular involvement. (Abraham & Monahan,

2001)

Acute lymphoblastic leukemia (ALL) is primarily a disease of childhood and

adolescence, accounting for 25% of childhood cancers and up to 75% of

childhood leukemia. The peak incidence of ALL in children is between 2 and 5

years of age. Although ALL is rare in adults, risk increases with age; most adult

patients are older than 50 years of age. The subtype of ALL is important

prognostic indicator for survival. Adults have a poorer outlook: 80%-90%

experience complete remission, but the cure rate is less than 40%.

According to Acute Leukemia (Foon & Casciato, 2000) eighty percent of

cases of acute lymphoblastic leukemia (ALL) occur in children. It is a rare

condition after 40 years of age and shows a male predilection only in very young

and elderly patients.

Majority of adults with acute lymphoblastic leukemia is at high risk for

recurrence which may be due to the high occurrence (20-30% of cases) of

Philadelphia chromosome rearrangement. Other indicators of poor prognosis

include high WBC count at the time of diagnosis, age older than 35 years,

Philadelphia chromosome, t(9:22) rearrangement, prolonged achievement of

remission (>4 weeks upon treatment initiation), and leukemic cell

immunophenotype. T cell ALL has a favorable prognosis while Pre B cell ALL has

intermediate prognosis while Mature B cell (Burkitt’s) has poor prognosis with

standard all treatment regimens and requires a specialized chemotherapy and

CNS therapy approach. (Abraham & Monahan, 2001)

Precursor B cell ALL (B-ALL) is more common in children than in adults.

Typical clinical presentation include anemia, petechiae and ecchymosis due to

thrombocytopenia, bone pain due to bone marrow involvement,

hepatosplenomegaly, and lymphadenopathy. CBC often reveals pancytopenia

observed with lymphoblasts on the blood smear. B-ALL can be subclassified into

three: early precursor B-ALL, common B-ALL, and pre-B-ALL.

T cell ALL occurs more commonly in older children and adolescents than

B-ALL and more commonly in males. Frequent clinical features are: anterior

mediastinal mass which can lead to superior vena cava or mediastinal syndrome

if bulky; with cough, dyspnea, dysphagia, stridor, cyanosis, and facial edema.
Marrow involvement in T-ALL is less likely to be associated with pancytopenia.

T-ALL is composed of CD7+, cCD3+, TdT+ lymphoblasts. (Hudnall, 2012)

Specific clinical features for acute lymphoblastic leukemia include

hepatosplenomegaly, lymphadenopathy, mediastinal masses in T-cell subtypes,

abdominal nodes in B-cell subtypes, and possible central nervous system

involvement. (Abraham & Monahan, 2001)

Generalized lymphadenopathy, splenomegaly, and hepatomegaly are

common findings. Because leukemic cells infiltrate many tissues of the body,

other symptoms may occur. Leg pain can be associated with periosteal

infiltrates, as well as headache, nausea, and vomiting with meningeal leukemia.

Rapid onset of unconsciousness may indicate subarachnoid haemorrhage.

Patients with B cell ALL typically present with fatigue (caused by anemia),

fever (caused by neutropenia and infection), and mucocutaneous bleeding

(caused by thrombocytopenia). Lymphadenopathy, including enlargement, is

often a symptom. Enlargement of the spleen (splenomegaly) and of the liver

(hepatomegaly) may be seen. Bone pain often results from intramedullary growth

of leukemic cells. Eventual infiltration of malignant cells into the meninges,

testes, or ovaries occurs frequently, and lymphoblasts can be found in the

cerebrospinal fluid

The typical symptoms, that is correlate with the degree of Bone marrow

involvement and the resultant cytopenias, as well as the leukemic cell burden,

includes fatigue, anorexia, night sweats, pallor, shortness of breath, bone pain,

fever, and bleeding diathesis. Involvement of extramedullary sites may present

with lymphadenopathy, hepatomegaly, or splenomegaly. Less commonly, ALL

can involve the CNS, leading to headache, vomiting, lethargy, and cranial nerve

palsies. (Hoffman, et al., 2013)

Regardless of the type of lymphoid malignancy, the initial evaluation of the

patient should include performance of a careful history and physical

examination. These will help confirm the diagnosis, identify those manifestations

of the disease that might require prompt attention, and aid in the selection of

further studies to optimally characterize the patient’s status to allow the best of

choice of therapy. It is difficult to overemphasize the importance of a carefully

done history and physical examination. They might provide observations that

lead to reconsidering the diagnosis, provide hints at etiology, clarify the stage,

and allow the physician to establish rapport with the patient that will make it

possible to develop and carry out a therapeutic plan.

For patients with ALL, evaluation is usually completed after a complete

blood count, chemistry studies reflecting major organ function, a bone marrow

biopsy with genetic and immunologic studies, and a lumbar puncture. The latter

is necessary to rule out occult CNS involvement. At this point, most patients

would be ready to begin therapy. In ALL, prognosis is dependent upon the genetic

characteristics of tumor, the patient’s age, the white cell count, and the patient’s

overall clinical status and major organ function. (Fauci, et al., 2008)

Some laboratory tests to establish diagnosis for leukemias include history

and physical examination, complete blood count with WBC differential,

peripheral blood smear examination, coagulation studies, chemistry tests for

serum electrolytes, uric acid, calcium and phosphorus, serological tests for

Hepatits B and C, HSV, CMV, varicella, and HIV, CT scan of the chest and

abdomen, and bone marrow aspirate examination for morphology,

cytochemistry, cytogenetics, and flow cytometry. Bone marrow biopsy may also

be performed for the cellularity percentage and dysplastic feature evaluation.

(Abraham & Monahan, 2001)

Initial evaluation of a Patient with Acute Lymphoblastic Leukemia is

composed of Complete history (including family history), physical examination,

CBC with differential, Comprehensive metabolic profile, including LFTs, LDH,

Uric Acid, Coagulation profile, Bone marrow aspiration and biopsy, HLA typing

of the patient, lumbar puncture, and chest radiography or CT imaging of the

chest. (Hoffman, et al., 2013)

Initial laboratory evaluation starts with a complete blood count (CBC) and

morphologic evaluation of a Giemsa-stained peripheral blood smear. An

abnormality of at least one of the CBC parameters is detected in more than 90%

of ALL patients at the time of diagnosis. Anemia and thrombocytopenia are

common. The anemia is usually a normochromic, normocytic anemia

accompanied by reticulocytopenia. The hemoglobin levels range from 30 to 174

g/L, and almost 50% of the patients have hemoglobin levels below 100 g/L.

Although the total white blood cell (WBC) count may be low, normal or elevated,

neutropenia is commonly present. In a Cancer and Leukemia Group B (CALGB)

study, the median WBC count as presentation was 19.3 x 109/L. Almost one-

third of the patients are likely to present with WBC count greater than 30 x
109/L. Several metabolic abnormalities are present at the time of diagnosis and

frequently reflect tumor burden. For example, lactate dehydrogenase (LDH) levels

are frequently elevated together with an elevated serum levels of calcium,

potassium, and phosphorous that is noted. Most importantly, elevated serum

uric acid levels are frequently present and reflect tumor burden.

Romanowsky-based stains such as Wright’s Giemsa and Giemsa provide

the greatest cytoplasmic detail for evaluation of cytomorphology of cells in the

peripheral blood smear, bone marrow (BM) aspirate smear, and touch imprints.

B lymphoblasts are morphologically indistinguishable from T lymphoblasts, and

this distinction relies on immunophenotyping. The nuclei is usually round, with

uniformly dispersed “smudgy” chromatin and inconspicuous nucleoli. (Hoffman,

et al., 2013)

Although morphology is the first tool used to distinguish ALL from AML,

immunophenotyping and genetic analysis are the most reliable indicators of a

cell’s origin. Because both B and T cells are derived from lymphoid progenitors,

both usually express CD34, terminal deoxyribonucleotidyl transferase (TdT), and

HLA-DR.

Molecular diagnosis is currently of limited utility in the management of

adult ALL. In marked contrast, the molecular diagnostic evaluation of pediatric

ALL is of substantial value in the stratification of patients to “risk-adapted”

treatment strategies. Early treatment response and tumor genetics were led by

the concept or tailoring therapy to defined subsets of patients based on a

combination of presenting clinical and biologic features. (Pui, 2004; O’Leary,

2008)

The diagnosis of acute leukemia is established by bone marrow

examination. Blasts must account for more than 30% of the nucleated cells to

establish the diagnosis. Cytochemistry should be word in all cases of acute

leukemia. Immunologic cell-surface markers should be evaluated in all cases

suspected of being ALL. 90% of patients have a normocytic, normochromatic

anemia. Reticulocytes are nearly always decreased. The white blood cell (WBC)

count is elevated in 60% of cases, normal in 15%, and decreased in 25%.Blasts

account for most of the circulating cells in patients with elevated. WBC Counts.

A staging system for acute leukemia does not exist. Complete remission

(CR) is the paramount prognostic factor in all forms of acute leukemia. A CR is

defined as a bone marrow contains less than 5% blasts or an Erythrocyte,

granulocyte, and platelet counts are normal. Or Organomegaly is resolved, and

performance status has returned to normal. (Foon & Casciato, 2000)

The prognosis for ALL depends on age at the time of diagnosis,

lymphoblast load (tumor burden), immunophenotype, and genetic

abnormalities.

Poor prognosis may be associated with several genetic defects such as

hypoploidy (< 45 chromosomes), BCR-ABL fusion t(9;22). ETA-PBX1 fusion

t(1;19), and MLL-AF4 fusion t(4;11). (Hudnall, 2012)

The goal of maintenance treatment is to prevent disease relapse by

elimination of leukemia clones by long-term exposure to cytotoxic drugs. One of

the commonly used regimens uses daily 6-mercaptopurine and weekly oral

methotrexate with monthly vincristine and prednisone (POMP) regimen). Some

groups replaced prednisone with dexamethasone. The duration of maintenance

treatment is usually 2 to 3 years (2 years for women and 3 years for men).

Treatment for ALL consists of remission induction, consolidation, CNS

prophylaxis, late intensification. An example of a specific regimen for ALL

treatment is the “Hoelzer (Berlin-Frankfurt-Munster; “BFM”) Regimen”, there two

inductions phases, one phase of CNS prophylaxis, two reinduction phases and

final of phase maintenance treatement.

Treatment may also have special considerations for B cell ALL (L3) which

expresses surface immunoglobulin and cytogenetic abnormalities such as

t(8;14), t(2;8), and t(8;22) so it is not usally treated with typical ALL treatment

regimens. Higher cure rates have been observed in aggressive

cyclophosphamide-containing regimens similar to those used in high-grade non-

Hodgkin’s lymphoma (NHL). Therapy will require an aggressive CNS phase (IT

therapy, high-dose methotrexate; e.g., Hoelzer regimen and Magrath regimen).

Also, no maintenance therapy needed.

Allogeneic stem cell transplantation in acute lymphoblastic leukemia has

a treatment-related mortality of 20-40%. ALL patients with Ph+ will benefit from

an allogeneic stem cell transplantation in first remission due to their poor

prognosis with standard therapy. Otherwise, allogeneic bone marrow

transplantation is the choice for patients in second remission. (Abraham &

Monahan, 2001)
 Combination chemotherapy is the cornerstone of ALL management. The

Berlin-Frankfurt-Muenster (BFM) group in the 1980’s conducted pioneering

studies and showed that an intensive multidrug induction and consolidation

chemotherapy followed by delayed intensification led to improvement in survival

in the majority of children. Only a few of these drugs have been tested

individually in randomized clinical trials in adults with ALL. The therapy for ALL

is typically divided into three phases: (1) the remission induction phase, (2)

remission consolidation or intensification, and (3) the maintenance (or

continuous) phase. The remission induction and consolidation phases typically

involve blocks of monthly treatment for 6-8 months followed by long-term

maintenance, which is given for up to 3 years; thus, the treatment of ALL is long

and challenging and requires tremendous attention to detail, compliance, and

support. (Hoffman, et al., 2013)

Treatment of ALL consists of combination therapy with transfusion for

management of life-threatening cytopenias, hydration, and allopurinol or

rasburicase (recombinant urate oxidase) for control of tumor lysis syndrome, and

aggressive antibiotic treatment of infections. To prevent relapse in the CNS,

patients also receive intrathecal chemotherapy. Allogeneic bone marrow

transplantation is often limited to patients with ALL in relapse. (Hudnall, 2012)