Leukemia

Leukemia refers to cancers that begin in the blood-forming cells of the body. These abnormal cells grow and multiply in an uncontrolled way. As the disease progresses, leukemic cells move through the blood stream and invade other organs, such as the spleen, lymph nodes, liver, and central nervous system. In the US, more than 30,000 new cases of leukemia are diagnosed every year, and adult onset accounts for 90 percent of the new cases (Xie Y et al 2003).

Risk factors for leukemia include advanced age, poor nutrition, previous chemotherapy and radiation treatment for other cancers, and smoking. Medical treatment for leukemia primarily revolves around chemotherapy and radiation therapy. Nutritional supplements help support the healthy function of the immune system, and in particular, the white blood cells in leukemia patients. In addition, some nutritional supplements are able to kill leukemia cells. Key examples include vitamin A, genistein from soy extract, and curcumin from turmeric.

Types of leukemia

Leukemia can be classified into four major types based on whether the disease is acute or chronic and according to the type of white blood cell affected:

• Acute myelogenous leukemia (AML)
• Chronic myelogenous leukemia (CML)
• Acute lymphocytic leukemia (ALL)
• Chronic lymphocytic leukemia (CLL)

Myelogenous leukemia involves myeloid cells, granulocytes (neutrophils, basophils, and eosinophils) and monocytes (macrophages). Lymphocytic leukemia involves T and B cells (lymphocytes).

How does leukemia develop?

All cancers begin with damage to the cells’ deoxyribonucleic acid (DNA). Within a cell, DNA is found in structures called chromosomes, which are themselves made up of segments called genes. Leukemia begins with DNA damage in the white blood cells, which protect the body from infections. In leukemia, DNA damage can occur through chromosome translocations (shifting and re-arrangement of chromosome segments) or mutations. Any one type of leukemia can have several genetic abnormalities at its core — this further complicates the interaction with other healthy genes, as well as the individual’s nutritional status in the development of leukemia (Greaves MF 2004; Irons RD et al 1996).

Risk factors

Inherited, abnormal genes account for a small proportion of leukemia cases (Alter BP 2003; Bischof O et al 2001; Fong CT et al 1987). However, in most cases, the DNA damage that eventually results in the onset of leukemia is brought about by interactions between genes, age, and a variety of environmental or lifestyle factors such as nutrition and exposure to chemicals (Greaves MF 2004; Irons RD et al 1996).

Age. Since up to 70 percent of leukemia cases are in those over 50, age can be considered the biggest risk factor for developing leukemia (Fenech MF et al 1997; Russell RM 2000a). The chromosomes of white blood cells in older people are more fragile than those in young adults and are more vulnerable to the types of DNA damage (e.g., free radical damage) known to cause leukemia (Esposito D et al 1989; Mendoza-Nunez VM et al 1999).

A diet rich in fruits and vegetables and other antioxidants can help guard against DNA damage caused by free radicals (Ames BN et al 1993). However, the ability of the elderly to repair DNA damage is poor and is associated with suboptimal micronutrient status (Ames BN 1998; Fenech MF et al 1997). The metabolism of elderly people is altered in such a way that while they continue to efficiently absorb macronutrients such as fats and proteins, absorption of micronutrients such as vitamin B12 and vitamin D is compromised, leading to malnutrition (Russell RM 2000a). Suboptimal levels of micronutrients can cause DNA damage associated with leukemia and limit the ability to repair this damage (Ames BN 1998; Ames BN 1999).

Nutrition. Diets lacking in essential micronutrients are as detrimental as cigarette smoking in the cause of cancer and can cause the same kind of DNA damage as exposure to radiation (Ames BN 1998). Micronutrients shown to contribute to leukemia include folic acid and vitamins B12 and B6 (Ames BN 1999).

Folic acid deficiency causes chromosome breaks (Fenech MF et al 1997) and is a risk factor in the development of ALL. In folic acid deficiency, efforts to repair damaged DNA are compromised and lead to breakages in genes (chromosome breaks) (Ames BN 1999; Skibola CF et al 2002; Wickramasinghe SN et al 1994). Deficiencies in vitamins B12 and B6 are thought to act in the same way as folic acid deficiency in increasing the risk for both adult and childhood ALL (Ames BN 1999).

There is a possible relationship between the restricted nutrient intake of slimming diets and the development of acute leukemia (Visani G et al 1997). Another theory is that phenol and hydroquinone, chemicals mainly ingested from meat and protein-rich diets, known to produce DNA damage, and antibiotics, may cause leukemia (McDonald TA et al 2001).

Chemotherapy. Chemotherapy, used for the treatment of other cancers, can cause DNA damage and make increase the risk of developing some form of leukemia. For example, chemotherapy for the treatment of other cancers is the major recognized cause of AML in the young, referred to by clinicians as secondary or treatment-related AML (Felix CA 1998). Treatment-related AML is associated with therapy for breast cancer, ovarian cancer, Hodgkin’s disease and non-Hodgkin’s lymphoma, and accounts for up to 20 percent of AML cases (Kaldor JM et al 1990; Smith MA et al 1996). Treatment with epipodophyllotoxins (etoposide and teniposide) is associated with development of secondary AML (Hawkins MM 1991; Pedersen-Bjergaard J et al 1991). Cyclosporine A, used to treat suppressed red blood cell production, is associated with the development of secondary leukemia (Yamauchi T et al 2002).

Radiation. Exposure to high doses of radiation causes leukemia by inducing DNA damage through translocations (Kamada N et al 1987). Population studies show a link between radiation exposure from nuclear testing between 1951 and 1962 in the United States and the onset of leukemia (Archer VE 1987; Johnson CJ 1984). The incidence of leukemia was high in the United States in the years during and immediately after the nuclear testing. Utah showed high increases (up to five times the norm) in leukemia rates, which persisted as late as the 1980s (Archer VE 1987; Johnson CJ 1984). Exposure to radiation is linked to acute and myeloid leukemia in children (Archer VE 1987). The association between radiation exposure and leukemia was noted in survivors of the atomic bomb in Japan (Ichimaru M et al 1991) and in people who lived near the nuclear reactors in the Chernobyl disaster of 1986 (Noshchenko AG et al 2002). Leukemia caused by radiation typically appears 10 years after exposure (Tilyou SM 1990).

Chemicals. Long-term or occupational exposure to benzene is a cause of acute leukemia (Austin H et al 1988; Rinsky RA et al 1981). Long-term exposure to herbicides, pesticides, and other agricultural chemicals is linked to an increased risk of developing leukemia (Meinert R et al 2000). Hair dyes contain chemicals that cause cancer and are associated with leukemia (Sandler DP 1995), particularly the long-term use of permanent dyes (Rauscher GH et al 2004).

Smoking. Cigarette smoke contains leukemia-causing chemicals like benzene (Korte JE et al 2000). Although smoking in the young is associated with modest increases in the risk of developing leukemia, in those over 60 smoking is associated with a twofold increase in risk for AML and a threefold increase in the risk for ALL (Sandler DP et al 1993).

Genetics. Children with Down’s syndrome have a 10 to 20 times higher risk of developing leukemia than the general population (Fong CT et al 1987). This risk is not confined to childhood years and extends through adulthood. There are also inherited disorders, such as Fanconi’s anemia and Bloom’s syndrome, that are characterized by genetic instability and inability to repair DNA damage and are associated with an increased risk of leukemia (Alter BP 2003; Bischof O et al 2001).

Viruses. Acute T cell leukemia is associated with infection by the human T cell leukemia virus (HTLV); human lymphotrophic virus-1 causes leukemia in humans. In infected individuals, HTLV proteins attach themselves to proteins in the lymphocytes responsible for regulating cell growth and corrupt their functions resulting in the uncontrolled cell growth of leukemia (Uchiyama T 1997). This type of leukemia is rare in the United States and is generally found in Asia and parts of the Caribbean.

Diagnosis

Symptoms associated with leukemia include weakness, fatigue, unexplained weight loss, pain, (abdominal, bone, and joint), abnormal bleeding, infection, fever, excessive bruising, and enlarged spleen, lymph nodes, and liver.

The first step in diagnosing leukemia is a complete blood count (CBC). With a diagnosis of leukemia, further testing of cell samples obtained by bone marrow aspiration or lumbar puncture determines the specific type of leukemia. Specific treatment is then targeted for leukemia based upon a number of factors, including results of genetic tests and leukemic cell sub-type.

Conventional medical therapy

Chemotherapy and radiotherapy. Leukemia generally responds well to chemotherapy and radiation therapy, and these are often used in combination. Chemotherapy agents attack rapidly dividing cells; however, they do not distinguish leukemia cells from other rapidly dividing but non-cancerous cells. As a result, chemotherapy harms healthy red and white blood cells, blood-clotting platelets, hair follicles, and cells lining the gastrointestinal tract, thus creating unpleasant side effects.

The damage to white blood cells increases the risk of infection. Medications known as colony-stimulating factors (CSFs) increase white blood cell counts and are often given in combination with chemotherapy (Dale DC 2002; Lyman GH et al 2003). The use of CSFs in leukemia is discussed in the Immunomodulators and Enhancers section.

Successful treatment with chemotherapy and severity of associated side effects in leukemia may be positively influenced by nutritional status. Antioxidant levels are reduced in leukemia patients undergoing chemotherapy (Kennedy DD et al 2004). Low levels of antioxidant intake are associated with increases in adverse effects of chemotherapy in children with ALL (Kennedy DD et al 2004). Vitamins C, E, and beta-carotene are associated with reduced toxicity from chemotherapy and lower frequencies of infections (Gajate C et al 2003; Kennedy DD et al 2004). A discussion on chemotherapy, nutritional support, and natural strategies to counteract the associated side effects can be found in the Cancer Chemotherapy chapter.

Radiotherapy kills leukemia cells by exposing them to ionizing radiation that damages cell DNA. In clinical practice, radiotherapy is typically used in 4 percent of leukemia cases (Featherstone C et al 2005). This is partly due to chemotherapy alternatives (Peiffert D et al 1999). Irradiation of the spleen is sometimes used in the treatment of leukemia patients with enlarged spleens (McFarland JT et al 2003; Peiffert D et al 1999).

Interferon therapy. Interferons (IFN) are a group of naturally occurring substances sometimes used in the treatment of chronic leukemia (Guilhot F et al 2004; Zinzani PL et al 1994). Interferon reduces the growth and reproduction of leukemia cells and enhances the immune system's response to cancer (see Immunomodulators and Enhancers section). Interferon is particularly useful when used as a maintenance therapy in patients after partial or complete remission. Use of interferon in combination with all-trans retinoic acid (a synthetic vitamin A analog) may prolong the lives of patients with promyelocytic and other forms of leukemia (Sacchi S et al 1997; Zheng A et al 1996).

Stem cell therapy. As the chemotherapy required to kill leukemia cells also damages the rapidly dividing blood-forming cells, stem-cell therapy replenishes bone marrow. Stem-cell therapy is the transplantation of stem cells into the patient’s bone marrow following chemotherapy and/or radiation therapy to kill the leukemia cells (Isidori A et al 2005; Linker CA 2003; Reiffers J et al 1996). Stem cells may be obtained from the patient (autologous) or from a donor (allogeneic) who is a close tissue match to the patient (Isidori A et al 2005; Linker CA 2003; Reiffers J et al 1996). Autologous stem-cell therapy is a rare procedure due to the challenge of ensuring that the removed stem cells are not contaminated with leukemia cells. Stem cells can be obtained either by bone marrow aspiration or by a procedure called apheresis (also called peripheral blood stem-cell (PBSC) transplant), through which the cells are removed from the peripheral blood system. This type of therapy is still in the experimental stages.

Inhibiting cell-signaling pathways. Early in disease progression, many types of leukemia produce certain inflammatory and immunosuppressive cytokines (chemical messengers) and use cell-signaling pathways.

For example:

• Vascular endothelial growth factor (VEGF) is considered essential for leukemia cell growth, survival and spread (Podar K et al 2004). Expression of high VEGF levels is associated with shortened survival in chronic lymphocytic leukemia patients (Ferrajoli A et al 2001).
• Basic fibroblast growth factor (bFGF) is a potent mitogen (growth signal) and is essential for blood vessel growth and spread of cancer cells (Bieker R et al 2003).
• Hepatocyte growth factor (HGF) stimulates the growth and spread of leukemia cells (Aguayo A et al 2000). HGF is particularly over-expressed in AML, CML, CLL, and chronic myelomonocytic leukemia (Aguayo A et al 2000).
• Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine significantly elevated in all leukemias except for AML and myelodysplastic syndromes (Aguayo A et al 2000).
• Interleukin-6 (IL-6) is a pro-inflammatory and immunosuppressive cytokine. Elevated serum IL-6 is associated with a poor prognosis and shortened survival in CLL (Fayad L et al 2001).

Types of leukemia that over-express these cytokines are (Aguayo A et al 2000; Bieker R et al 2003; Fayad L et al 2001; Podar K et al 2004):

Regulating normal cell growth. The drug Gleevec® (formerly STI571) slows proliferation and causes apoptosis in Bcr-Abl cell lines and fresh leukemic cells from "Philadelphia chromosome positive" (Ph+) CML. Gleevec® (imatinib mesylate) is indicated for the treatment of patients with Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy. Although Gleevec® is an FDA-approved drug its effectiveness is continuously evaluated. The latest findings can be found on the website www.gleevec.com. It is interesting that a drug that functions through a mechanism similar to certain dietary supplements (e.g. curcumin and genistein) was put on the FDA's "fast-track" for approval.

Immunomodulators and immune enhancers. Substances that enhance the function of the immune system are used to support the conventional treatment of leukemia with chemotherapy and radiotherapy. These substances fall into three main categories:

• Hematopoietic growth factors
• Cytokines (glycoprotein messengers)
• Immunotoxins

The use of growth factors such as granulocyte-colony stimulating factor (G-CSF) during chemotherapy elevates the number of normal white blood cells, thus enabling patients to tolerate high chemotherapeutic doses and reducing infections (Dale DC 2002; Lyman GH et al 2003). G CSF (filgrastim, Neupogen®) treats low neutrophil counts (neutropenia) during CML therapy (Quintas-Cardama A et al 2004). Another growth factor, granulocyte-macrophage-colony stimulating factor (GM-CSF, sargramostim, LeukineTM), blocks the migration of myeloid cells and leukemia spread (Eubank TD et al 2004).

Cytokines are glycoprotein messengers that enhance the function of immune cells. The use of interferon in the treatment of chronic leukemia is common (Guilhot F et al 2004; Zinzani PL et al 1994). The use of the cytokine IL-2 in AML and CML patients reportedly improves immune responses (Morecki S et al 1992).

Antibodies, specifically targeted to molecules present on the surface of AML cells, exhibit anti-leukemic responses in clinical studies (Balaian L et al 2004; Feldman EJ 2003; Ritz J et al 1982). The binding of an antibody to a leukemia cell marks the cell as a target for destruction. Antibodies can be attached to cytotoxic agents that can be selectively delivered to leukemia cells (Feldman EJ 2003; Ritz J et al 1982). Antibody therapy is beneficial in treating CLL (Lin TS et al 2004) and hairy cell leukemia (Cervetti G et al 2004).

Cancer vaccines present an opportunity to manipulate the immune system into attacking leukemia cells (Lee JJ et al 2004). Research on this therapeutic option is still in the experimental stage and has focused on solid tumors.