Leukemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Leukemia Microchapters
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Patient Information
Overview
Classification AML CML ALL CLL
Differentiating Leukemia from other Diseases
Epidemiology and Demographics
Prognosis

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Overview

Leukemia or leukaemia (Greek leukos, “white”; haima, “blood”) is a cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms.

Symptoms

Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional. This could cause the patient's immune system (white blood cells etc.) to start attacking other body cells.

Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea. All symptoms can be attributed to other diseases; for diagnosis, blood tests and a bone marrow examination are required.

Some other related symptoms:

• Fever, chills, night sweats and other flu-like symptoms
• Weakness and fatigue
• Swollen or bleeding gums
• Neurological symptoms (headaches)
• Enlarged liver and spleen
• Frequent infection
• Bone pain
• Joint pain
• Dizziness
• Nausea
• Swollen tonsils
• Diarrhea
• Paleness
• Malaise
• Unintentional weight loss

The word leukemia, which means 'white blood,' is derived from the disease's namesake high white blood cell counts that most leukemia patients have before treatment. The high number of white blood cells are apparent when a blood sample is viewed under a microscope. Frequently, these extra white blood cells are immature or dysfunctional. The excessive number of cells can also interfere with the normal function of other cells.

Some leukemia patients do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells which disrupt the normal production of blood cells. However, the leukemic cells are staying in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For an aleukemic patient, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.

Classification

Leukemia is clinically and pathologically subdivided into several large groups. The first division is between its acute and chronic forms:

• Acute leukemia is characterized by the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children in the US than any other type of malignant disease). Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Central nervous system (CNS) involvement is uncommon, although the disease can occasionally cause cranial nerve palsies.
• Chronic leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.

Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:

• In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes.
• In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red cells, some types of white cells, and platelets.

Combining these two classifications provides a total of four main categories:

Four major kinds of leukemia

Cell type	Acute	Chronic
Lymphocytic leukemia (or "lymphoblastic")	Acute lymphoblastic leukemia (ALL)	Chronic lymphocytic leukemia (CLL)
Myelogenous leukemia (also "myeloid" or "nonlymphocytic")	Acute myelogenous leukemia (AML)	Chronic myelogenous leukemia (CML)

Within these main categories, there are typically several subcategories. Finally, hairy cell leukemia is usually considered to be outside of this classification scheme.

• Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older. Standard treatments involve chemotherapy and radiation. The survival rates vary by age: 85% in children and 50% in adults.

• Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 75%. It is incurable, but there are many effective treatments.

• Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The five-year survival rate is 40%.

• Chronic myelogenous leukemia (CML) occurs mainly in adults. A very small number of children also develop this disease. Treatment is with imatinib (Gleevec) or other drugs. The five-year survival rate is 90%.

• Hairy cell leukemia (HCL) is sometimes considered a subset of CLL, but does not fit neatly into this pattern. About 80% of affected people are adult men. There are no reported cases in young children. HCL is incurable, but easily treatable. Survival is 96% to 100% at ten years.

Causes and risk factors

There is no single known cause for all of the different types of leukemia. The different leukemias likely have different causes, and very little is certain about what causes them. Researchers have strong suspicions about four possible causes:

• natural or artificial ionizing radiation
• certain kinds of chemicals
• some viruses
• genetic predispositions

Leukemia, like other cancers, result from somatic mutations in the DNA which activate oncogenes or deactivate tumor suppressor genes, and disrupt the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances and are likely to be influenced by genetic factors. Cohort and case-control studies have linked exposure to petrochemicals, such as benzene, and hair dyes to the development of some forms of leukemia.

Viruses have also been linked to some forms of leukemia. For example, certain cases of ALL are associated with viral infections by either the human immunodeficiency virus (HIV, responsible for AIDS) or human T-lymphotropic virus (HTLV-1 and -2, causing adult T-cell leukemia/lymphoma).

Fanconi anemia is also a risk factor for developing acute myelogenous leukemia.

Until the cause or causes of leukemia are found, there is no way to prevent the disease. Even when the causes become known, they may prove to be things which are not readily controllable, such as naturally occurring background radiation, and therefore not especially helpful for prevention purposes.

Treatment options for leukemia by type

Chronic Lymphocytic Leukemia (CLL)

CLL is probably incurable by present treatments. But, fortunately, a large group of CLL patients do not require therapy. Studies suggest that people with Stage A CLL (that is, individuals who have fewer than three areas of enlarged lymphoid tissue) do not benefit from early treatment. They may, in fact, suffer drawbacks because of it. Therefore, most oncologists base CLL treatment upon both the stage and symptoms of the patient.

For example, in older patients (60+ years) who have low-risk early stage disease (Rai Stage 0) a conservative "watch and wait" approach may be taken.

By contrast, older individuals with CLL-related complications or more advanced disease (Rai Stage III or IV) may benefit from chemotherapy and treatment with a corticosteroid (e.g., prednisone, prednisolone).

Corticosteroids are first-line agents for people in whom the immune systems has been altered by CLL. CLL may cause autoimmune syndromes in which the patient's immune system attacks and destroys his or her own blood cells. When the red blood cells are affected, the condition is known as immunohemolytic anemia, characterized by decreased numbers of red blood cells, which may cause fatigue, dizziness, and shortness of breath. When the blood platelets are affected, it is called immune-mediated thrombocytopenia, in which a decreased numbers of platelets may lead to bleeding.

For younger patients who are experiencing symptoms, the physician may consider early chemotherapy, plus allogeneic or autologous bone marrow transplantation (alloBMT; autoBMT).

In general, the indications for treatment are:

• falling hemoglobin or platelet count
• progression to a later stage of disease
• painful, disease-related overgrowth of lymph nodes or spleen
• lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months

Transformation of CLL to high-grade disease or aggressive non-Hodgkin's lymphoma

If the patient experiences blood flow problems caused by high numbers of leukemia cells in the circulation, the physician may recommend leukapheresis, also known as apheresis, to separate out white blood cells, prior to chemotherapy. Symptoms that are related to enlargement of the lymph nodes in one area or an overgrown spleen may be treated by localized, low-dose radiotherapy, or surgical management by splenectomy (removal of the spleen). But if leukemia has invaded the lymph nodes at many different sites, total body irradiation (TBI) may be needed.

Chemotherapy for CLL

The chemotherapeutic plans that are used most often for CLL are:

• combination chemotherapy with chlorambucil (Leukeran®) or cyclophosphamide (Cytoxan®) plus a corticosteroid drug such as prednisone, or
• single-agent treatments with nucleoside drugs such as fludarabine, pentostatin, or cladribine (2-chlorodeoxyadenisine; 2-CDA). However, such drugs usually are reserved for cases in which CLL is resistant (unresponsive to treatment) or returns after chemotherapy with chlorambucil or cyclophosphamide.

People with intermediate (Rai Stage I and II) or advanced (Rai Stage III or IV) disease may be helped by participation in a clinical trial. At the present time, clinical trials are being conducted using immunologic compounds (e.g., interferons, monoclonal antibodies) as well as new chemotherapeutic agents (e.g., bryostatin, dolastatin 10, and PSC 83 - a cyclosporine drug given with chemotherapy to overcome drug resistance).

Hairy Cell Leukemia (HCL)

Hairy cell leukemia is an incurable, indolent blood disorder in which mutated, partly matured B cells accumulate in the bone marrow. Its name is derived from the shape of the cells, which look like they are covered with short, fine, hair-shaped projections. Unlike any other leukemia, HCL is characterized by low white blood cell counts.

Patients with hairy cell leukemia who are symptom-free typically do not receive immediate treatment. They engage in "watchful waiting" with routine bloodwork and exams every three to six months to monitor disease progression and identify any new symptoms.

Treatment is generally considered necessary when the patient shows signs and symptoms such as low blood cell counts (e.g., infection-fighting neutrophil count below 1.0 K/ul), frequent infections, unexplained bruises, anemia, or fatigue that is significant enough to disrupt the patient's everyday life.

Patients who need treatment, which includes most newly diagnosed HCL cases, usually receive either cladribine or pentostatin, which are both in a class of chemotherapeutic drugs known as purine analogs or nucleosides. In most cases, one round of treatment will produce a prolonged remission.

Other treatments include rituximab infusion or self-injection with Interferon-alpha. In limited cases, the patient may benefit from splenectomy (removal of the spleen). These treatments are not typically given as the first treatment for a new patient because their success rates are lower than cladribine or pentostatin.

In the short term, especially when neutrophil counts are low, an immune system hormone called granulocyte colony-stimulating factor may be taken to increase white blood cell counts. This is believed to help prevent or treat an infection. Many patients also take antibiotics until their white blood cell counts have recovered to normal levels.

Research

Significant research into the causes, diagnosis, treatment, and prognosis of leukemia is being done. Hundreds of clinical trials are being planned or conducted at any given time. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for patients, or appropriate care in remission or after cure.

External links

Images of leukemias

• UVA Healthsystem -- Images of acute leukemias by stage

Research organizations

• The Therapeutic Advances in Childhood Leukemia (TACL) Consortium -- US research group
• "Chromosomes, Leukaemias, Solid Tumors, Hereditary Cancers" in AtlasGeneticsOncology.