Conventional Medical Therapy
Chemotherapy and radiotherapy. 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 Immune 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 Immune 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.
- 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):
Chronic myeloid leukemia
VEGF, bFGF, HGF, TNF-alpha, IL-6
Acute myeloid leukemia
VEGF, bFGF, HGF
Chronic myelomonocytic leukemia
VEGF, bFGF, HGF, TNF-alpha
Acute lymphoblastic leukemia
bFGF, HGF, TNF-alpha
Chronic lymphocytic leukemia
VEGF, bFGF, HGF, TNF alpha, IL-6
VEGF, bFGF, HGF
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)
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.