Author: Dr Frederick Appelbaum Fred Hutchinson Cancer Research Center Seattle 2008-07-28
Definition
Leukemia
is a term used to describe a number of related cancers of the
blood-forming cells, characterized by their abnormally increased growth
and impaired maturation.
Normal Blood Formation
Blood is made up of a pale yellow liquid (plasma) in which three general types of cells are found (see Figure 1). The
most numerous are red blood cells, which give blood its color and which
are responsible for carrying oxygen from the lungs to other organs to
allow glucose to be metabolized, creating energy. Platelets
are very small cells that help initiate the process of clot formation
and thus provide protection from bleeding. White blood cells (also
called leukocytes), are responsible for fighting infection, and come in
two general varieties, myeloid cells that primarily ingest bacteria and
other infectious agents, and lymphoid cells that help in the production
of antibodies. All of these cells are relatively
short-lived, surviving from a few months in the case of red cells, to a
few days in the case of platelets and most white cells. Thus, each day billions of new blood cells must be produced.
Figure 1. Normal blood as seen through a microscope. The red disks are normal red cells; the largest arrow points to a mature lymphocyte, the smaller arrow points to a mature myeloid cell, and the small arrowheads indicate platelets.
The
process of forming new blood cells is called hematopoiesis (hemato
[blood] + poiesis [production]) and takes place in the bone marrow, an
organ located in the hollow space within most bones of the body (see
Figure 2). Within the bone marrow is a population of
cells, termed hematopoietic stem cells, that have the capacity to divide
throughout an individual’s lifetime, each time reproducing itself and
creating an additional cell. The hematopoietic stem cell
and the additional cell it creates with each division are
undifferentiated or immature, that is, they have none of the features of
a normal mature red cell, platelet or white cell. Over a
period of days, the offspring of the stem cell divides multiple times
and matures into an adult red cell, white cell or platelet, depending on
the body’s needs. Once mature, the cell leaves the bone
marrow and enters into the arteries, veins and capillaries that make up
the peripheral blood circulatory system. The process of blood formation
is tightly regulated so that in normal individuals, the concentration of
red cells, white cells or platelets in the peripheral blood are
relatively constant throughout life.
Figure 2. Normal bone marrow seen through a microscope. The pink portions with asterisks are normal bone; the bluish cells between the bone structures are the cells of the bone marrow. The clear areas within the bone marrow are fat, which is a normal component of bone marrow.
The Molecular Basis of Leukemia
The
behavior of all normal cells, including hematopoietic cells, is
dictated by the sequence of DNA base pairs within its genes, which are
arranged along 46 chromosomes. Leukemia develops when the
DNA sequence in the genes of a blood forming cell is altered, either by
mutations (substitution of one DNA base for another), translocations
(exchange of DNA material between two chromosomes) or gains or losses of
DNA material in one or several chromosomes. These changes
in the genes of a blood-forming cell may cause it to produce too many
of itself, crowding out normal blood-forming cells, and also to not
mature sufficiently, so that the cells that are produced are unable to
function normally.
The
DNA alterations that lead to leukemia are found only in the abnormal
leukemic cells and, thus, are said to be “acquired”, a term that means
acquired after conception. These abnormalities are not
found in sperm or egg cells and so leukemia is not hereditary, although
in rare families there can be an inherited predisposition.
The Four Types of Leukemia
There are four major types of leukemia based on the rate of disease progression and on the type of normal cell the leukemia most resembles. The first major distinction is between rapidly progressive, or “acute” leukemias, and slowly progressive or “chronic” leukemias. In acute leukemias, the affected cells proliferate rapidly and fail to differentiate, filling the marrow with immature leukemic cells, sometimes termed “blasts” or “blast cells.” These cells crowd out normal blood-forming cells, leading to a rapid fall in normal red cell, platelet, and white cell production. The abnormal blasts soon spill out into the peripheral blood and into other organs of the body. If untreated, acute leukemia usually will result in death, most often from bleeding or infection, in a matter of weeks to a few months from diagnosis.
In contrast, chronic leukemias are characterized by a much slower build up of relatively mature leukemic cells. Eventually,
the increased production of leukemic cells will interfere with normal
blood production, or the number of abnormal cells in the peripheral
blood will impair normal organ function, but many months or years may
pass between the time of diagnosis until symptoms become
life-threatening.
The second major division between leukemia types is based on the normal cell the leukemia most resembles. Leukemias
that resemble in appearance myeloid cells are termed “myeloid”
leukemias, while those that resemble lymphoid cells are termed
“lymphocytic” leukemias. Thus, there are four major types of leukemia:
- acute myeloid leukemia (AML)
- acute lymphocytic leukemia (ALL)
- chronic myeloid leukemia (CML)
- chronic lymphocytic leukemia (CLL)
Each
of these four forms of leukemia is composed of several sub-categories,
and each requires a very different approach to diagnosis and therapy.
Epidemiology and Risk Factors
According
the American Cancer Society, in 2006 within the United States there
were approximately 35,000 new cases of leukemia diagnosed. [1] Approximately 39% of these cases were AML, 33% CLL, 13% ALL and 15% CML. Overall, the incidence of leukemia increases with increasing age, especially for AML and CLL. ALL is the most common form of childhood leukemia.
In
most cases of leukemia, the cause of the initial DNA sequence
alteration is unknown. Exposure to radiation or chemotherapy used to
treat other illnesses may increase the risk of leukemia, as can exposure
to cigarette smoke. There are rare medical syndromes of impaired DNA
repair that are associated with an increased incidence of leukemia. Leukemia is not contagious.
Signs and Symptoms of Leukemia
The signs and symptoms of leukemia are mostly the result of a lack of normal blood cell production. The
lack of normal red cell production results in anemia, which in turn
causes pallor, weakness, dizziness when standing up, headache and
shortness of breath with exercise. Failure to produce sufficient normal
white blood cells leads to increased susceptibility to infections, which
can result in non-healing skin lesions, fevers and chills or recurrent
urinary tract or peri-anal infections. Lack of adequate platelets leads
to gum bleeding, easy or spontaneously bruising and the development of
petechiae (very small red spots usually over the lower extremities).
In
addition to the problems caused by a lack of red cell, white cell and
platelet production, the increased production of abnormal blasts in the
bone marrow can lead to diffuse bone pain. The accumulation of leukemia
cells in the liver and spleen can cause enlargement of these organs
resulting in vague tenderness in the left or right upper quadrants of
the abdomen. In some cases, enlargement of lymph nodes in
the neck, under the arms and in the groin may occur. Occasionally the
leukemia blasts may infiltrate the gums causing pronounced swelling, or
the skin leading to small, raised lesions. Symptoms of acute leukemia
progress rapidly over days, while those of chronic leukemia may not
progress for months.
Diagnosis
The
diagnosis of leukemia is usually first suggested by the identification
of an abnormal number or appearance of cells in the peripheral blood. Confirmation of the diagnosis usually is made by examination of the bone marrow. Bone
marrow examination involves placing a needle in the marrow space of the
hip bone under local anesthesia, removing a small amount of marrow and
examining it under a microscope.
Laboratory Tests
A number of laboratory tests are commonly used in the diagnosis, classification and treatment of leukemia:
A
complete blood count (CBC) is a measure of the concentration of red
cells, white cells and platelets in the peripheral blood. The percent
volume of blood made up of red cells is termed the hematocrit and is
normally anywhere from 37-52%. A normal white cell count varies from 4,300 to 10,800 per mm3, and a normal platelet count is between 130,000 and 400,000 per mm3.
Morphology is the term used to describe the appearance of cells viewed by a pathologist using a microscope. Very
immature or young cells are characterized by having a large nucleus
with little cytoplasm and, as noted above, are called blasts (See Figure
3). Distinguishing normal from leukemic blasts under a
microscope is often not possible. A small percent of normal blasts can
be found in healthy bone marrow, but usually not more than 5%, and
blasts are almost never seen in the peripheral blood of a healthy
individual.
Figure 3a. A normal mature lymphocyte (left) and a lymphoblast (right). The leukemic blast is somewhat larger than a normal mature lymphocyte and has a larger nucleus.
Figure 3a. A normal mature lymphocyte (left) and a lymphoblast (right). The leukemic blast is somewhat larger than a normal mature lymphocyte and has a larger nucleus.
Figure 3b. A normal mature myeloid cell (left) and a myeloblast (right). The leukemic blast is slightly larger and has a much larger nucleus.
Cytogenetic
testing is a process in which the appearance of the separate
chromosomes in a cell is observed and alterations in number or structure
are noted (See Figure 4). For example, leukemic cells may
have too many chromosomes or too few, or they may be missing parts of
chromosomes. In other cases, part of one chromosome may be fused to
another (a phenomenon called translocation), or turned around in the
same chromosome (an abnormality called an inversion). Each chromosome
has a specific number, and each chromosome has a long arm (“q”) and a
short arm (“p”). A system has been developed to identify the chromosomal
abnormality seen. A “+” or a “-“ signifies that a
chromosome, or part of a chromosome, has been gained or lost; a “t”
means that a translocation between two chromosomes has occurred and
“inv” means that an inversion has occurred. Cytogenetic testing usually requires a bone marrow sample.
Figure 4. A cytogenetic analysis of a case of leukemia. A normal cell has 46 chromosomes, including two copies of chromosomes 1-22, and either two X chromosomes (in women) or an X and a Y chromosome (in men). In the case shown here, a piece of the long arm of chromosome 5 has been lost.
Florescence
in situ hybridization (commonly called FISH) testing is another method
for determining chromosomal alterations. FISH has the advantage of being
more rapid and able to sample a larger number of cells, but not all
abnormalities may be detected.
Polymerase
chain reaction (PCR) testing is a method capable of detecting very
small numbers of cells with a specific abnormality. While this
technique has the advantage of great sensitivity, only a limited number
of leukemia abnormalities are detectable by PCR and so the technique is
applicable to only a specific subset of leukemia patients.
Immunophenotyping is a technique that determines the specific proteins on a cell surface. Immunophenotyping is often useful in classifying subsets of leukemia. For example, the proteins on the surface of an AML cell are different from those on the surface of an ALL cell.
Treatment
The
standard treatment of leukemia varies greatly depending on the type of
leukemia (AML, ALL, CML, or CLL) and may be further influenced by the
patient’s age, general health and specific goals. Because
of the complexity of diagnosing, treating, and monitoring treatment
response, it is valuable to get medical care at a center where doctors
are experienced in treating patients with leukemia.
In
the case of the acute leukemias (AML and ALL), the initial goal of
treatment is to achieve a complete remission. Complete remission means
disappearance of all visible signs of the disease. Thus, patients who
have obtained a complete remission will have normal peripheral blood
counts, and less than 5% blasts in their bone marrow. To achieve a complete remission for acute leukemia, patients generally are treated with intensive “induction” chemotherapy. Complete
remission is not the same thing as cure, since if patients who achieve a
first complete remission are given no further therapy, the leukemia
will grow back in virtually every case. To delay or
prevent disease recurrence patients may be treated with further cycles
of intensive chemotherapy (termed “consolidation” chemotherapy), or low
dose “maintenance” chemotherapy. For a proportion of patients, hematopoietic cell transplantation (HCT) offers the best chance for cure
Patients
with chronic leukemia (CML and CLL) are generally treated with less
aggressive chemotherapeutic agents, but HCT may be appropriate for a
select subset.
Cure, Relapse, and Refractory Disease
The
term “cure” is generally used to describe a situation in which the
patient has no evidence of disease, and based on clinical evidence there
is no greater chance of that person re-developing leukemia than there
is of a healthy person developing the disease. Because
growth rates and treatment approaches differ, there is no single time
point following treatment when one can say that patients with leukemia
are cured. The vast majority of patients with AML who recur with their
disease do so within 3 years of starting treatment. Because
patients with ALL receive therapy for longer periods of time, relapses
can occur later from diagnosis, but most occur within 5 years. Because CML and CLL are much slower growing, late recurrences of these diseases are more common. The term “recurrence” or “relapse” is used to describe disease that regrows after an initial remission. Disease
that fails to respond to therapy at all is termed “refractory.”
Molecular studies indicate that when leukemia recurs, it is due to
regrowth of the original leukemia, rather than the development of a
second leukemia.
The
forms of therapy vary widely among the different types of leukemia and
therefore are discussed individually in separate below.
Clinical Trials
Patients
with leukemia and other malignancies are often invited to participate
in clinical trials. Clinical trials conducted by the major oncology
cooperative groups in the United States including the Eastern
Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG),
Cancer and Leukemia Group B (CALGB) and the Children’s Oncology Group
(COG), as well as those conducted at NCI designated cancer centers
undergo a rigorous review process. Phase 3 trials are usually randomized
studies that compare the best proven therapy with an approach that has
shown promise in earlier phase studies of providing even better
outcomes. Phase 2 trials are designed to allow physicians to learn more
about agents that have activity in a specific disease. Phase 1 studies
are focused on understanding more about the dose and toxicity of new
agents; such studies are usually reserved for patients who have failed
conventional therapy. Since not all is known about new therapies,
participation in clinical trials involves some measure of risk.
Investigational review boards exist to help assure that the degree of
increased risk is balanced with the overall benefit of the trial. The
advantages of participation in a carefully reviewed clinical trial are
that it helps assure that patients are receiving state-of-the-art
therapy, and by participating, patients are contributing to the
development of improved therapies for future generations.