Acute Lymphocytic Leukemia

Description

Alternative Names

Prognosis

Once a diagnosis of leukemia has been made, further tests are performed to assess the following properties:

• Whether the cells are myeloid or lymphocytic (i.e. the cell of origin).
• Stage of maturity of the ALL B-cell.
• Their immunologic features (the specific markers on the surface of the cancer cell that respond to antigens).
• Their cytogenetics (the genetic makeup of the cells).
• Their morphology (their physical characteristics).

Determining the Cell of Origin

First, the physician must determine the cell of origin (whether it is myeloid or lymphocytic). One method is to measure an enzyme called terminal deoxynucleotidyl transferase (TdT).

• About 95% of all ALL types (except the subtype B-cell) have elevated TdT.
• Only about 20% of cases of acute myeloid leukemia (AML) express TdT, however, so its use in determining the cell line is limited.

B-Cell Maturity

The stage of maturity of the leukemic B-cell helps determine prognosis. There are three stages:

• Early precursor-B. Approximately 80% of ALL patients have the early precursor-B subtype, which is the least mature. It also offers the best prognosis.
• Precursor-B. This is the intermediate stage.
• B-cell. This is the mature cell and ALL in this stage is identical to Burkitt's non-Hodgkin's lymphoma. It is therefore treated differently from other ALL cases.

Immunological Markers

A series of tests are used to determine the immunologic pattern of the leukemia cell (how it can be expected to interact with the immune system).

On the surface of malignant ALL cells are markers for certain antigens (molecules that set off a targeted attack by the immune system using antibodies). Such antigens are proving to be very helpful in predicting outcome.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Important ones include the following:

• CD10, more frequently referred to as cALLa (common ALL antigen). This antigen occurs in about half of all ALL cases and in about 80% of ALL B-precursor patients. It is associated with a good prognosis.
• CD95. Likewise, the presence of CD95 has a positive influence.
• CR19.
• DR.

The surfaces of T-cell ALL cancer cells express several antigens as well. For example the presence one of these, CD2, suggests a favorable prognosis.

Testing for Genetic Abnormalities

Genetic tests are useful for a number of important criteria:

• Diagnosing a specific ALL subtype.
• Designing appropriate treatment.
• Gauging prognosis.
• Monitoring patients throughout treatment and beyond.

Cytogenetics is a technique that researchers use to determine specific genetic abnormalities, which are found in nearly 65% of all leukemias. Detecting these genetic defects is helpful in making a full diagnosis of ALL and in planning the most appropriate therapy. Specific technologies called microarray chips are now capable of checking up to 48,000 different genes in a single experiment, which holds promise for assessing prognosis and developing very targeted therapies in the future. Research on DNA microarray analysis continues to reveal different prognostic subgroups of ALL. As the precision, logistics, and cost effectiveness of DNA microarray assays improve, they may be used more commonly in the clinical setting.

MTHFR Variants. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism, and variations in the MTHRF gene may also influence response to antifolate chemotherapy. A 2004 study showed that patients with one of two specific variations of the MTHFR gene had a lower probability of survival following treatment with methotrexate.

Translocations. Genetic translocations (defective alterations of genetic arrangements) may affect outlook. Examples include the following:

• Patients with the t(12;21) genetic translocation (also referred to as TEL-AML1 fusion) have an excellent prognosis.
• Patients who carry the defective gene called ETV6 often respond well to chemotherapy.
• The t(4;11), sometimes referred to as MLL, is the most common translocation in children under one year. Unfortunately, it carries a poor outlook in anyone who carries it. A 2001 study suggested that this genetic variant may actually be a unique leukemia and require treatments that differ from standard ALL.
• The Philadelphia translocation also t(9;22) indicates a poor outlook. It represents about 20% of adult cases and only about 5% of childhood cases.
• The t(1;19) location occurs in about 5% of ALL childhood cases and requires aggressive treatment.

Ploidy. Ploidy refers to the number of chromosomes. Additional copies (hyperdiploidy) or absence of copies (hypodiploidy) of chromosomes affect prognosis. For example, in children hyperdiploidy is associated with a more favorable outcome and hypodiploidy with a poorer outcome. (Hypodiploidy occurs only in 1% of children with ALL.)

Morphology

The morphology of a cell includes its physical characteristics, such as shape and structure. To determine the morphology of the leukemia cells, samples of the bone marrow are taken and particular contents of the cells are stained with a dye. They are then examined under a microscope.

Acute lymphocytic leukemia cells are grouped according to the French-American-British (FAB) classification system into three ALL morphologic types. (It should be noted that this system is subjective and is now used to complement other diagnostic tests as mentioned above):

• L1 cells. These are small blasts with scant amounts of cytoplasm (the substance in a cell between its membrane and nucleus). L1 cells usually contain a round nucleus and there is little variation among them. L1 represents the most common ALL morphology and offers the best prognosis. It occurs in about 85% of children and 30% of adults with ALL.
• L2 cells. These cells are larger than L1 and have more abundant cytoplasm. They vary significantly among each other and have an irregularly shaped nucleus. L2 morphology conveys a poorer prognosis than L1, although the two cells' types are treated similarly. Subtype L2 is the most common morphologic type in ALL adults; 64% of adults with ALL have this subtype compared with only 15% of children.
• L3 cells. These are uncommon. They resemble another malignancy called Burkitt's lymphoma and their treatments are now the same.

Determination of Minimal Residual Disease

Assays that test for cancerous cells are improving, allowing doctors to detect smaller and smaller amounts of hidden disease. For example, flow cytometry assays can detect 0.01% leukemic cells, and PCR assays can detect 0.001% leukemic cells. A new concept called minimal residual disease (MRD) is becoming an important prognostic factor in ALL. A more precise measure of disease response, MRD may soon replace existing measures such as complete response and partial response when assessing the effectiveness of ALL treatment. Ongoing studies of MRD in ALL may help identify patients in remission who are at risk of relapse. In addition, early therapeutic intervention based on the presence of MRD may improve outcome and prolong survival.

Drawing Conclusions from Cell Characteristics

Using the results of the tests described above, patients are classified into low-, average-, and high-risk groups, which have unique therapies. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment.

Physicians attempt to make a prognosis and determine an optimal treatment plan by assessing all the cell characteristics plus the white blood cell count. As examples:

• Patients who have an L1 or L2 morphology, a white blood cell count of less than 15,000 mm3, a t(12;21) genetic translocation, and a cALLa-positive antigen marker have an excellent outlook.
• On the other hand, patients who have an L2 morphology, a white blood cell count greater than 30,000 mm3, and who lack the cALLa marker have a poorer prognosis and require more aggressive treatment.