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Leukemia
Leukemia refers to a group of cancers in which the malignant cells circulate in the bloodstream: the word leukemia derives from the joining of two Greek terms, leukos, or white, and -emia, meaning of the blood. Because blood cells are created in the bone marrow, the marrow is always involved in cases of leukemia. There have been tremendous advances in our understanding of the scientific basis of leukemia. Thousands of genetic changes that are critical to leukemia development have been documented, and probably more is known about the science of leukemia than about any other cancer. This knowledge has recently begun to pay off in dramatic improvements in treatment, especially for chronic myelogenous leukemia.
I have found that when a person is first referred to me with an abnormal blood count, the disease he or she fears most is leukemia. This is because most people think of leukemia as being a rapidly fatal disease. The truth is that although some types of leukemia can indeed be rapidly fatal if not treated successfully, others may not need to be treated for twenty years or more.
There are four main types of leukemia: acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Acute leukemias (AML and ALL) usually need to be treated soon after diagnosis, whereas chronic leukemias usually do not need urgent treatment because they grow more slowly, often do not cause symptoms, and may remain stable without therapy for months or, in the case of CLL, several years. Leukemia can be treated with chemotherapy, more specific targeted therapies, stem cell transplantation, or a combination of these approaches. Space limitations prevent a discussion of each type, so I focus here on CML, a disease that has become the model for the future treatment of all cancers, and on CLL, the most common type of leukemia.
Chronic myelogenous leukemia
Chronic myelogenous leukemia is characterized by an initial slowgrowing phase, followed three to five years later by an aggressive and uniformly lethal phase (if not treated). Fortunately, we know more about CML than about any other cancer. In fact, CML is a disease of firsts. It was the first disease to be labeled leukaemia, in 1845 by the famous German pathologist Rudolf Virchow, who described several patients with elevated levels of colorless corpuscles (representing white blood cells) and enlarged spleens. In what marks a turning point in cancer research, CML was the first cancer to be associated with a specific chromosomal abnormality, termed the Philadelphia chromosome, after the city in which the discovery was made; this established, for the first time, that cancer is marked by alterations to DNA. Most recently, CML came to be the first cancer to be treated with startling success by a new wave of cancer treatments called targeted therapies.
CML arises when a bone marrow stem cell experiences a genetic mutation that results in the exchange of genetic material between two chromosomes. As a result, a gene called Bcr becomes joined to another gene called Abl. The resulting Bcr/Abl fusion gene gives rise to a powerful mutant protein that makes the cell grow faster, resist cell death, and acquire the characteristics of a leukemia cell. Bcr/Abl is essential for the development of CML; the discovery of ways to inhibit its function has revolutionized the treatment of this disease.
For many years the only hope for cure of CML was a bone marrow transplant from another person. In 1999 a drug called imatinib (Gleevec) was approved by the FDA based on extremely positive results in the first stages of testing. Gleevec is a pill that is well tolerated by patients and specifically shuts down the action of Bcr/Abl. CML cells die when Bcr/ Abl stops functioning, and many patients achieve a complete remission of their disease.
It is too early to tell if Gleevec is curing CML permanently, but the drug has enabled many patients to delay, if not completely avoid, the need for bone marrow transplantation. Remarkably, for those patients in whom CML grows after an initial response to Gleevec, new drugs such as dasatinib (Sprycel) and nilotinib (Tasigna) are effective in reestablishing remission in many cases. It is hoped that CML will remain a disease of firsts and become the first leukemia to be cured by medicines that work with pinpoint accuracy rather than with intensive chemotherapy or transplantation.
Chronic lymphocytic leukemia
Unlike the three other types of leukemia, the cell of origin in CLL is not the bone marrow stem cell but rather a mature lymphocyte (lymph cell). This cell does not have the innate explosive growth capacity of a stem cell or the ability to form any cell other than another lymphocyte. These differences account, in part, for the less aggressive course of CLL in comparison to the other leukemias. CLL is often diagnosed when routine blood testing reveals an elevated white blood cell count and all other laboratory tests are normal. The abnormal lymphocytes of CLL may reach very high levels in the bloodstream without causing ill effects.
CLL is the most common form of inherited leukemia, although the vast majority of cases do not run in families. Patients with a family history of CLL may wish to help researchers discover the genes responsible for this inheritance pattern by donating a sample of blood. They can ask their oncologist or a genetics counselor for the name of a center that is researching familial CLL. Like other leukemias, CLL cells are found in the circulation and bone marrow. Unlike the others, however, CLL is also typically found in the spleen and lymph nodes. CLL is staged in the United States according to the Rai Classification, which segregates patients into low-, intermediate-, and high-risk groups. All patients have an elevation of the lymphocyte count (called lymphocytosis). Low-risk CLL includes stage 0 (lymphocytosis only); intermediate-risk disease includes stage I (enlarged lymph nodes) and stage II (enlarged liver or spleen); high-risk CLL includes stage III (anemia) and stage IV (low platelet count). The higher the risk category, the greater the need for treatment.
The growth of CLL in lymph nodes is very similar to the pattern of growth of lymphomas. Indeed, oncologists think of CLL more as a lymphoma than a leukemia, and it is treated most successfully with the same chemotherapy drugs and antibody treatments used to treat lymphoma. Although the treatment of CLL improves every year, the only known way to cure CLL is with a stem cell transplant from another individual. However, because CLL mainly affects older individuals and this procedure is risky, only a small percentage of CLL patients are suitable candidates for it. For any patient, treatment recommendations are based on the stage of the disease, the patient’s health, and estimates of the aggressiveness of the CLL, which varies from patient to patient. I recently met a seventy-four-year-old man in excellent health who was referred to me after he was incidentally noted to have an elevation of the lymphocyte count on routine blood testing by his primary care physician. Doug was a retired businessman who played tennis six days a week and worked around the house on the seventh day. He had never felt physically better in his life. I could tell from looking at a slide of his blood under the microscope that the leukemia cells in his circulation were characteristic of CLL. Specialized testing of the blood with flow cytometry would later confirm the diagnosis (a bone marrow biopsy is not essential to make the diagnosis of CLL).
Because he felt so well, Doug was understandably dumbfounded when I told him he had leukemia. As is often the case in CLL, however, certain features of his disease indicated that he would not likely need any treatment for many years. Instead, he would see me four times a year to monitor the disease, a policy called observation or watch and wait (also called watch and worry by some patients).
In contrast, I also care for Susan, a forty-five-year-old woman who required treatment with two chemotherapy drugs (Fludara and Cytoxan) plus an immune therapy (Rituxan) for CLL that had grown to the point that the lymph nodes in her neck were bulging visibly and her energy was declining. After one course of treatment, her lymph nodes could no longer be felt. She continued to work throughout her six courses of treatment and is now back to having the CLL merely observed. Susan will ultimately require additional treatments when the disease returns, but it cannot be predicted when this will occur.
These two cases illustrate the range of behaviors of CLL. To some, CLL is a problem only in name; it will not shorten their life span. To others, it is a life-threatening cancer. To help predict the future behavior of each newly diagnosed case, oncologists often test the CLL cells (which can be obtained from the blood or bone marrow) in several ways. These include:
1. Analysis of the chromosomes of the CLL cells; some abnormalities portend an indolent or slow course, whereas others predict a more aggressive course.
2. Assessment (by flow cytometry) of whether the cells possess two markers, ZAP-70 and CD-38. CLL that contains both markers tends to be more aggressive, whereas CLL that contains neither marker tends to be the least aggressive; the presence of one marker predicts an intermediate aggressiveness.
3. Determination of the status of a segment of CLL DNA called IgVH (pronounced I, G, V, H). IgVH status is either mutated or nonmutated; the mutated group carries the more favorable prognosis.