Acute Lymphoblastic Leukemia

Epidemiology – most common childhood malignancy

Leukemia most common form of childhood cancer (30%) – ALL is the predominant form of leukemia
Childhood leukemia: ALL – 89%, Acute Myelogenous Leukemia – 15%, Mixed lineage leukemia, undifferentiated leukemia, "juvenile" chronic myelogenous Leukemia – 5%

Genetics

Down’s syndrome: 15-20x more likely to develop ALL, More likely in disorders of DNA repair or increased DNA fragility (Fanconei anemia, dyskeratosis Congenita, Bloom’s syndrome, Ataxia telangiectasia)

Genes involved with: cellular regulatory activities, DNA transcription, and signal transduction: Chromosome 21

Pathogenesis

ALL encompasses a group of neoplasms compoosed of immature, precursor B (pre-B) or T (pre-T) lymphocytes referred to as lymphoblasts

Pre-B cell tumors – Majority (85%) typically present as childhood acute leukemias
Pre T-Cell – presen in adolescent males as lymphomas with thymic involvement

Terminal deoxytransferase (TdT): positive > 95% of pre-B and pre-T lymphoblasts, disappears with maturity

Generally, leukemia cells are of the same lineage and at the same stage of maturity

Clonal Pathogenesis: Develops from a single cell which undergoes malignant transformation

ALL is a systemic disorder of clonal proliferation of immature lymphoid precursors
Precursors: serve no useful function and rapidly occupy more space in the bone marrow. Eventually normal cells an their precursors are inhibited (crowded out) as marrow replacement occurs.
Rapidly proliferating normal lymphoid precursors are at "higher risk" for development of spontaneous mutations because of the "regulated" mutagenic activity which normally occurs during gene rearrangement
90% of patients have numerical or structural changes in the chromosomes of the leukemia cells: hyperdiploidy (> 50 chromsomes)

Better Prognosis: hyperdiploidy (chromosomal replication) is associated with a BETTER prognosis but NOT in adults
Poorer prognosis: t(9;22), t(8;14), t(4;11)

2 events necessary for malignant transformation:

(1) Initiating event: mutation which occurred during embryonic life
(2) "promotional" event: considered to be the "cause" of the overt leukemia. Occurs in the clone of cells that has been expanded from the cell which had been subjected to the first event
Support: cytogenetic studies of leukemia karyotypes

Clinical Presentation Onset is abrupt, patients present within days to weeks

Symptoms:

CNS manifestations: Fever, headaches, severe headaches, mental status changes, stroke, seizures.
Bleeding: Bruising, petechiae
Fatigue, irritability , need for more sleep: related to depression of normal marrow function
Bone pain, joint pain, limp: occurs as a result of bony infiltration and/or marow expansion

Signs

Lymphadenopathy, hepatosplenomegaly: neoplastic infiltration
"T-cell" disease: hilar adenopathy - represents as "mediastinal mass" on CXR
Ocular manifestations: direct leukemic infiltrate (usually asymptomatic)
Less common findings: Testicular involvement, Skin infiltrates, bone necrosis, breast infiltration, pleural infiltration

Diagnosis:

Complete Blood Count: anemia, neutropenia, thrombocytopenia

Accumulation of neoplastic blast cells in bone marrow that suppress normal hematopoiesis by physical crowding

Peripheral blood smear: immature leukemia cells NOT always noted
Bone marrow aspiration:

L1: cells with large nuclei, scant cytoplasm, few nucleoli, smooth nuclear border – subtype most commonly seen
L2: cells are larger, have more prominent nucleoli, more cytoplasm – usually seen in adults
L3: characteristic of "Burkitt’s leukemiea" Very large, irregular nuclei, some nucleoli, vacuoles: cells found in Burkitt’s lymphoma

Risk Groups

Risk factor	"Average" risk	"High" risk
Age in years	>2 and < 10	Infants < 6mths and older teenagers
WBC at diagnosis	< 10,000	> 50,000
Subtype	"Pre B-cell"	Mature B or T cell
DNA Content	Hyperdiploid
Cytogenetics	?	T(9;22) t(8;14) t(4;11)
CNS disease at diagnosis	No	Yews
Result of Bone marrow 7 days after treatment has begun	< 5% leukemia cells	> 5% leukemia cells

Treatment

Patients are treated with a 5-phase approach. Goal: reduce the leukemic burden. Not "every last leukemia cell" is killed

More than 95% of children and majority of adults will achieve remission by day 28 of therapy.

Remission: defined as recovery of normal marrow elements, absence of leukemia, platelet count>100,000 and absolute neutrophil count rising about 1,000.

Good prognosis: achieve remission by Day 14 and who have < 5% blasts on Day 7
Poor Prognosis: fail to achieve remission by Day 28

Intrathecal chemotherapy: chemo given directly into the spinal fluid is necessary to prevent CNS relapse. Blood brain barrier is effective in keeping out chemotherapy

Side effects: 75% of young children have a 75% chance of developing structural changes in CNS. Result: lower IQ’s, learning problems, memorydeficits, personality disordersm Growth retardation, Pituitary dysfunction, hypothyroidism, infertility, cardiac toxicity (from anthracycline)