Acute Lymphoblastic Leukemia (ALL)

ALL is the most common form of cancer in children, constituting 30% of all pediatric malignancies. There are between 2500 and 3500 new cases of ALL diagnosed in children each year in the United States. The peak incidence occurs between ages 2-5 years. ALL is more common in boys than girls and twice as common in whites than Afro-Americans. Other known risk factors for ALL include Down syndrome, NF-1, and immunodeficiency and ataxia telangiectasia.

Clinical presentation:

• Fever (67%) — due to inflammatory response, or infection secondary to decreased immune function.
• Bleeding (50%) can occur secondary to thrombocytopenia — can also present as petechiae and purpura.
• Lymphadenopathy (50%) — indicates extramedullary spread of leukemic cells.
• Musculoskeletal pain (25%) — while relatively nonspecific, persistent bone pain, particularly nocturnal, should prompt further investigation
• Headache (<5%) — though rare, this can indicate CNS involvement
• Testicular enlargement — rare, but painless, unilateral enlargement is cause for concern and further work-up.
• Mediastinal mass

Diagnosis:

• Labs:
• CBC with manual differential and smear will abnormal reveal abnormal white cells, anemia and/or thrombocytopenia. WBC counts can be both normal, high, or low, but peripheral smear and differential will show blasts.
• Indications for bone marrow biopsy:
• Atypical cells in peripheral smear
• Unexplained depression of >1 peripheral blood element
• Unexplained lymphadenopathy, hepatosplenomegaly, and cytopenia
• Bone marrow biopsy will confirm the diagnosis, showing increased cellularity and leukemic infiltrates.
• Other labs sent before initiating treatment and to treat any complications:
• PT/PTT
• BMP including renal function
• LFTs
• Uric acid
• Baseline viral titers: CMV, EBV, VZV, HIV, Hep B
• LP with CNS sent for cytology

Classification: 

ALL has multiple sub-types. Each one of them may portend different treatment plans and prognoses.  Essentially, while two patients may each have ALL, they may have significantly different disease courses based on differing sub-types.

There are different ways to classify ALL:

1) Morphology            2) Immnophenotype                        3) Cytogenetics

Morphology: Bone marrow pathology (i.e looking at cells under a slide)

Three Main Morphological Classes:

-L1 Lymphoblasts: Most common morphological type of ALL                                        -L2 Lymphoblasts: second most common type                                                                -L3 lymphoblasts: Least common with worse prognosis

The morphologic classification has fallen by the wayside given that it is a less accurate way to predict prognosis. Also, given it is a pathological classification, there is a subjectivity component that makes it hard to standardize.  Now classification of ALL is predominantly a combination of immunophenotyping and cytogenetic analysis.

Immunophenotype: Cluster of differentiation (CD) markers (i.e. cell surface markers)

Four Main Sub-classes

-B-precursor ALL: Most common type (CD10, 19, 20, 22, 24)

-B-precursor with myeloid features (CD11, 13, 14, 15, 33, 34, 41, 42)

-Mature B cell: (CD10, 19, 20, 22, 25)

-T-cell: (CD2, 3, 4, 7, 8)

Cytogenetics:

Two Main Divisions:

·      ‘Ploidy: Number of chromosomes

-Hyperdiploidy: ALL cells that have too many chromosomes.  Often times with 54-58 chromosomes.  These patients have a more favorable outcome. 

-Extreme hyperploidy (near triploidy, etc…): More than 58 chromosomes.  Poorer outcomes than hyperdipoidy.

-Hypodiploidy: Less than 45 chromosomes.  Also with poor outcomes

·      Translocations: Aberrations of chromosomes that mix them up with each other causing cell regulatory proteins to function abnormally.  With some exceptions, these tend to have a worse prognosis than the subtypes with ‘diploidy.  While there are many translocation types, the major ones are:

-t(9;22) BCR/ABL: The Philadelphia Chromosome. Abnormal tyrosine kinase activity.  Can be treated with Imatinib.

-t(1;19) E2A/PBX1: In B-precursor ALL. More in black children than white children.

-t(4;11) MYC/IGH: In mature B-cell ALL; more likely to have CNS disease

-t(1;14) TAL1/TCR: In T-cell ALL

-t(12;21) ETV6/RUNX1: actually favorable prognosis. Can be found in 20-25% of B-precursor ALL.

Therapy:

Treatment of ALL consists of multiple phases of chemotherapy (induction, consolidation, maintenance) with the goal being to eradicate all leukemic cells from the patient’s bone marrow, blood and sanctuary sites.

• Initial: transfusion support, correct electrolyte imbalances
• Induction:
• Vincristine, L-Aspariginase, and Corticosteroids plus intrathecal therapy
• >90-95% enter complete remission (CR) at the end of induction period
• CR: <5% in a bone marrow specimen with concomitant evidence of hematopoietic recovery
• Consolidation:
• Cytoxan, Etoposide, Methotrexate, Anthracycline, or alkylating agent for 4-6 months
• Maintenance
• Oral 6-MP or MTX

- Tumor Lysis Syndrome- secondary to killing leukemic cells and release of Potassium, Phosphate, and nucleic acids. May lead to renal failure.

Prognosis:

Overall, the diagnosis of ALL in children carries a relatively good prognosis, with an estimated 5-year survival rate of 78-85%, which is a dramatic improvement over just 30-40 years ago. There are certain factors which help to predict outcome, among them:

• WBC count at time of diagnosis may have an inverse relationship to cure
• Age at time of diagnosis- >10 years old have worse prognosis
• Cytogenetics (presence of Philadelphia chromosome has poor prognosis)
• Immunophenotype
• Response to induction therapy
•  

Approximately 20-25% of patients relapse, and among those who do, 60-75% do so within the first year. The risk of relapse declines by year so that >4 years after initial diagnosis and treatment, relapses are rare. Evidence to suggest that children who have undergone chemotherapy (and no radiation therapy) for ALL that have 310 years of event-free survival can expect normal long-term survival.

References

1. “Cellular Classification and Prognostic Variables”. Childhood Acute Lymphoblastic Leukemia Treatment; National Cancer Institute: National Institutes of Health (NIH). Web-site last modified May 24, 2011. http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional/page2

2. Pui HC et al. Extended Follow-up of Long Term Survivors of Childhood Acute Lymphobalstic Leukemia NEJM 2003; 349: 640-649

3. Pui HC. Drug Therapy Acute Lymphoblastic Leukemia NEJM 1998; 339: 605-615

4. Hutter J, Childhood Leukemias.  Pediatrics in Review.  June 2010

5.Howard S. et.al. The Tumor Lysis Syndrome.  New England Journal of Medicine May 12, 2011

 6.Terzah M, Steuber C. “Overview of the presentation and classification of acute lymphoblastic leukemia in children.” UpToDate.com, version 19.1. Topic last updated:  December 14, 2010.