Blood cancers and bone marrow stem cells

Blood and Lymph Cancers

The blood and lymph cancers, also called hematologic malignancies (hema is Greek for blood), are a complicated group of diseases that are related by their common origin in cells that comprise the blood and lymph systems of the body. All blood and lymph cells are born in the bone marrow. Some remain there, some circulate in the bloodstream, and others populate the lymph tissues found throughout the body, most prominently the lymph nodes and spleen. There are three major categories of hematologic malignancies:

1. Leukemia

2. Lymphoma

3. Multiple myeloma

Because these cancers grow in the bone marrow and/or the lymph nodes and spleen, they cause alterations of blood counts, enlargement of lymph nodes, or defects in the body’s immune defenses, resulting in infections. Any one of these changes may prompt an evaluation that leads to the diagnosis of leukemia, lymphoma, or myeloma. Unlike many carcinomas, these cancers cannot be screened for or caught at a preventable stage because their natural growth patterns lead them to be present in many locations in the body at the time of detection. For example, leukemia and myeloma affect the bone marrow (throughout the body), and lymphomas often affect different lymph node regions in the body. Because of this, they nearly always require treatments that travel throughout the body-namely, drug therapies.

Surgery plays a minor role in managing blood and lymph cancers. Radiation therapy may be used in conjunction with drug therapies, depending on the clinical situation: a patient with a large mass of Hodgkin or non-Hodgkin’s lymphoma in the chest, for example, is usually treated with chemotherapy followed by radiation therapy, resulting in a very high cure rate. Isolated tumors of multiple myeloma (called plasmacytomas) may be treated with radiation. Leukemia is not treated with radiation except as part of a stem cell transplant procedure, when it is given to the whole body in an effort to eradicate the disease. These examples do not encompass the full spectrum of radiation use in these cancers.

The care of a patient with a hematologic malignancy is usually managed by a physician trained in both oncology and hematology. Advances in treating these cancers are occurring rapidly, and many new promising drugs are being developed each year that require testing in clinical trials. Hematologists/oncologists in the community and those in large cancer centers often work together to plan a treatment strategy for their patients, which may include a stem cell transplant or participation in a research trial testing new medicines.

Despite their similarities, each of these three disorders is distinct. Each arises from a different type of bone marrow cell, grows differently in the body, causes different symptoms, requires specific treatments, and has varied rates of curability. In order to gain an appreciation for the blood cancers, it is helpful to have a working knowledge of how normal blood and lymph cells are produced in the body.

Bone marrow stem cells give rise to all blood cells

When I refer to blood cells, I mean the white blood cells, red blood cells, and platelets that circulate in the bloodstream and do the work of the blood system. Their levels are routinely measured by a blood test called a CBC (complete blood count). White blood cells are part of our immune system and protect us against infection; red blood cells carry oxygen throughout the body and maintain our energy; platelets enable blood to clot. Under normal circumstances, there is one main kind of circulating red cell and one kind of platelet, but there are several types of white blood cells. The two most important are neutrophils, which help us fight bacterial infections such as strep throat, caused by a bacterium called streptococcus; and lymphocytes, which attack viruses, produce antibodies against infectious agents, and create a memory bank of past infections that is rapidly activated on reinfection with the same bug (this is an example of immunity). There are two main types of lymphocytes, T-cells and B-cells. The T or B designation relates to whether the cell matures in a special lymph gland in the chest, called the thymus (T-cells), or in the bone marrow (B-cells). Like B-cells, T-cells are born in the bone marrow, but they migrate to the thymus, where they develop further.

The bone marrow is so named because it is found inside our bones, in a place called the marrow cavity. Nearly all bones contain bone marrow. Bones are constructed of a thick outer shell, called the cortex, that has been likened to ivory and can support the weight of our bodies. Inside the cortex, in the marrow cavity, the bone thins out in a fine lacework that is filled with a spongy mixture of fibers and cells called stroma. The stroma provides a nutrient-rich, nestlike environment on which the blood cells develop and is critical to their growth.

Another word for stroma is microenvironment. Stroma exists in every organ and represents the source of blood and nutrients that all cells, including cancer cells, need in that location. The bone marrow stroma supports the growth of all cancers that grow there, whether they are the hematologic malignancies that originate from bone marrow cells or other types of cancer that metastasize to the marrow; metastatic cancers of the prostate, breast, lung, and kidney frequently involve the bone and bone marrow.

My reasons for introducing concepts such as stroma and microenvironment are not purely educational. New cancer therapies targeting the stroma, rather than the cancer, are now being used to treat cancer patients. Three prominent examples include: (1) angiogenesis inhibitors, a class of drugs that blocks the blood supply to tumors; (2) bisphosphonates (Aredia and Zometa are examples), medicines that block the ability of cancers growing in bone to cause fractures by altering the bone environment; and (3) the related drugs thalidomide (Thalomid) and lenalidomide (Revlimid), which are effective treatments for multiple myeloma in part because they disrupt the connections between myeloma cells and the surrounding bone marrow stroma.

The bone marrow is the most active organ in the body, churning out billions of blood cells daily. Amazingly, all the different mature blood cells derive from a mother cell, called a bone marrow stem cell. These stem cells are continuously renewing themselves and maintaining normal levels of mature blood cells at all times; when necessary, they increase blood cell production. For example, during anemia, when the red blood cell count falls below normal levels, the stem cells make more red cells. And when a bacterial infection strikes the body, the stem cells ramp up production of white blood cells to fend off the invader (leading to an elevation in the white blood cell count on a CBC). The hormone that stimulates stem cells to produce red blood cells has been made into a drug marketed under several names, including erythropoietin (Procrit, Epogen) and darbopoietin (Aranesp). These drugs improve the anemia and fatigue caused by kidney failure and chemotherapy and help avoid the need for blood transfusions. New concerns about the safety of these medicines have limited their use. When used according to guidelines established by experts in the field, however, these medicines are safe and helpful.

Similarly, the molecules that the body produces to stimulate stem cells to make white blood cells have been made into drugs, called filgrastim (Neupogen), sargramostatin (Leukine), and pegfilgrastim (Neulasta). These medicines have greatly improved the ability of cancer patients to fight and prevent infections and receive chemotherapy at the recommended intervals in order to treat their cancer optimally. A medicine that helps raise platelet counts, called oprelveken (Neumega), is also available. New drugs that stimulate the bone marrow are in development. White blood cells, red blood cells, and platelets are the final products of a complex biological process that converts an immature stem cell into these mature blood elements. Many types of cells are formed along the pathway leading from stem cell to mature cells, resulting in the wonderful diversity of cells that one sees in a normal bone marrow biopsy specimen. In a blood or lymph cancer, this diversity is replaced by a monotonous population of cancer cells, such as the blast cells of acute leukemia or plasma cells of myeloma. The result is a fall in normal blood production and low blood counts, leading to many of the symptoms experienced by patients with leukemia, myeloma, and certain lymphomas.

To diagnose a blood cancer, a bone marrow biopsy is performed as part of the initial workup. Although leukemia and myeloma always affect the bone marrow to some extent, lymphoma does not always do so. In addition to pathologic analysis of the specimen, a small amount of liquid marrow may be sent for specialized testing. These tests include:

1. Chromosome analysis and molecular testing to determine if the chromosomes of the cancer cells have been altered or if genetic abnormalities associated with specific diseases can be identified. For example, if a physician suspects that a patient has chronic myelogenous leukemia, the presence of a gene called Bcr/Abl in the marrow confirms the disease.

2. Flow cytometry, a procedure in which the cancer cells are passed through a sophisticated machine called a cytometer that determines the specific molecules present on their outer surface. This procedure can determine, for example, if a lymphoma is of B-cell or T-cell origin and whether it contains a protein called CD20, which is the target of several effective antibody treatments for lymphoma (Rituxan, Zevalin, and Bexxar).