Leukemia

Leukemia

1 Overview

Summary and Quick Facts

  • Leukemia is blood cell cancer. It happens when the bone marrow makes too many abnormal blood cells, which then build up in the blood and cause problems.
  • In this protocol, you’ll learn about the different types of leukemia and how they are treated. You’ll also learn about some exciting new therapies undergoing research that may improve the effectiveness of leukemia treatments.
  • Green tea extracts have been shown in several laboratory and clinical studies to have anti-leukemia properties.

Leukemia is a type of cancer of white blood cells (WBCs) and WBC precursors. Leukemias are classified as either acute or chronic, depending on how quickly they progress.

Some integrative interventions may complement conventional leukemia therapies, such as curcumin, vitamin D, and green tea.

Causes and Risk Factors

  • Men and older people are more likely to develop leukemia (except acute lymphoblastic leukemia, which is more prevalent in children)
  • Genetics: siblings of family members with cancer of the blood cells have 2.3 times the risk of developing leukemia
  • Smoking
  • High-energy radiation exposure and previous cancer treatment
  • Viral infections, including human T-cell lymphotropic virus type 1 (HTLV-1)

Signs and Symptoms

Some forms of leukemia, such as chronic myelogenous leukemia, are diagnosed during routine exams and are initially without symptoms. When there are symptoms, they can often resemble those caused by other, less severe illnesses:

  • Weight loss
  • Weakness, fatigue
  • Anemia
  • Infection, fever, swollen lymph nodes
  • Bruises, skin pallor, and bleeding

Diagnosis

  • A complete blood count (CBC) test can reveal elevated WBC count and additional blood cell abnormalities
  • Bone marrow biopsy to confirm the diagnosis and learn more about the specific leukemia cell type
  • Abnormal WBCs are tested for the presence of specific genetic mutations that can inform about type of leukemia and possible prognosis

Conventional Treatment

The specific treatment approach depends upon the type of leukemia and how aggressive the disease is.

  • First-line treatment is usually chosen based on the results of clinical trials in patients with the same type and stage of cancer. The complete list of chemotherapeutic drugs FDA-approved to treat leukemia are available at: http://www.cancer.gov/cancertopics/druginfo/leukemia.
  • Acute leukemia patients usually need to start chemotherapy immediately after diagnosis.
  • Tyrosine kinase inhibitors, bone marrow transplant, monoclonal antibody-based therapy, and interferon therapy are additional types of treatments for specific leukemias.

Novel and Emerging Strategies

  • A patients’ own T-cells modified to target and kill leukemia cells, a drug omacetaxine mepesuccinate derived from the evergreen tree Cephalotoxus harringtonia, and aurora kinase inhibitors are some of the strategies currently being developed against leukemia.

Dietary and Lifestyle Considerations

  • Maintain a healthy weight
  • Avoid smoking
  • Consume a diet high in dark green vegetables, seafood, nuts, seeds, and fruit; and lower in red meat and sugar

Integrative Interventions

  • Green tea and epigallocatechin gallate: In two studies involving adults with leukemia, green tea consumption was associated with a 50% decreased risk of leukemia. The risk was reduced as the number of cups of tea consumed per day and number of years of tea consumption increased.
  • Curcumin: Curcumin has been shown to inhibit metastasis, invasion, and angiogenesis in animal models and to induce cell death in leukemia cell lines.
  • Omega-3 fatty acids: Eicosapentaenoic acid (EPA), an omega-3 fatty acid found in fish and fish oil, has been associated with better weight maintenance and response to therapy, fewer complications, and improved survival in cancer patients. Docosahexaenoic acid (DHA), another marine omega-3 fatty acid, was able to kill acute myeloid leukemia (AML) cells without harming normal blood-forming stem cells in a cell culture experiment.
  • Vitamin D: Vitamin D helps promote healthy cellular differentiation, and several lines of data highlight vitamin D’s potential as a preventive and therapeutic agent in a variety of cancers, including leukemia.
  • Melatonin: Melatonin has demonstrated anti-aging, immunomodulatory, and anticancer properties. Several epidemiologic studies suggest high levels of melatonin may help prevent cancer, possibly by activating the tumor-suppressor molecule p53.

2 Introduction

Leukemia is a type of cancer arising from white blood cells (WBCs) and resulting from malignant transformation of different types of white blood cell precursors: lymphocytic leukemia is an overproduction of lymphocytes, and myeloid leukemia is an overproduction of myelocytes (Goldman 2012b; Wu 2014; Janeway 2001). Leukemic cells grow and divide uncontrollably, displacing healthy blood cells. This can lead to serious problems such as anemia, bleeding, and infection (Ntziachristos 2013; Goldman 2012a; LLS 2012b).

Leukemia is the sixth leading cause of cancer death in the United States, and the majority of cases occur in older adults. Leukemia is more common in men than women (Siegel 2013; NCI 2014a), and more than 52 000 new cases of leukemia are estimated to occur each year in the United States, with over 24 000 deaths attributed to leukemia annually (NCI 2014a; Siegel 2014).

Leukemias are also classified as either acute or chronic, depending on how quickly they progress (Wu 2014; Goldman 2012b; Goldman 2012a).

Acute leukemias, if left untreated, progress very rapidly, and without proper care the mortality rate is extremely high within several months of diagnosis. However, appropriate treatment can considerably improve prognosis and survival times for acute leukemia patients, and many can be cured (Goldman 2012a).

Chronic leukemias, on the other hand, may not cause any significant problems before diagnosis, though sometimes they cause nonspecific symptoms such as weight loss, fatigue, or abdominal pain. In many cases, abnormal blood cell counts found during routine blood work in people without symptoms may prompt a physician to suspect leukemia, which can be confirmed with further testing (Goldman 2012b).

Researchers are making great headway in the battle against leukemia. Innovative strategies including antibody-based therapies, interventions directed at leukemia stem cells, and novel targeted agents have shown promise in preliminary research and early clinical trials (Advani 2012; Thomas 2012; Hoelzer 2010; Zhao 2013; Lancet 2010).

Moreover, evidence suggests that some integrative interventions may complement conventional leukemia therapies. Several medicinal plants are excellent sources of chemopreventive phytochemicals that have been shown to be active against various leukemia cell lines, and some may modulate molecular targets known to be involved in leukemia development and progression (Fresco 2010; Huang 2010). For example, curcumin, green tea, and vitamin C have been demonstrated to kill leukemia cells in experimental models (Cragg 2006; Ghosh 2009; Angelo 2009; Han 2009; Yang 2012; Omoregie 2013; Kawada 2013).

In this protocol you will learn about the biology of leukemia and how this disease is typically diagnosed and treated; the causes of leukemia and risk factors that increase the likelihood of developing the disease will also be outlined. You will read about a number of natural compounds that may target specific mechanisms underlying some forms of leukemia, and research on a number of novel and emerging leukemia treatments will be summarized. Nutrition and lifestyle considerations that may mitigate some of the manifestations of leukemia will also be reviewed.

3 Types of Leukemia

Leukemia is categorized on the basis of how long the disease takes to progress and the kinds of blood cells affected.

Acute leukemia usually presents suddenly, and patients often develop symptoms right away. Chronic leukemia progresses slowly and may not cause symptoms for years (Siegel 2013; LLS 2012b).

Lymphocytic leukemia affects “T” and “B” white blood cells known as lymphocytes. Myeloid leukemia affects myeloid cells, which go on to form white blood cells other than lymphocytes (granulocytes and monocytes), red blood cells, and platelets.

Leukemia is classified into four main types: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML) (Siegel 2013; LLS 2012b).

There are several other types of leukemia as well, such as hairy cell leukemia, chronic neutrophilic leukemia, and acute megakaryocytic leukemia, but these are relatively rare (Pawarode 2006).

The Four Most Common Types of Leukemia (LLS 2012b; Siegel 2014; Garcia-Manero 2014; Cyopick 1993; LLS 2014b)

Leukemia Type

Cells Undergoing Uncontrolled Division

Age Group Affected

Estimated New Cases (2014)*

Acute lymphocytic leukemia (ALL)

Immature lymphocytes or “blasts”

Children (peak incidence in children ages 3-7), but can also affect adults

6020      

Acute myeloid leukemia (AML)

Primitive myeloid cells or blasts

Adults, typically over age 40

18 860

Chronic lymphocytic leukemia (CLL)

Mature-appearing lymphocytes

Older adults, especially over age 60

15 720

Chronic myeloid leukemia (CML)

Immature granulocytes

Middle-aged adults, rarely children

5980

*Rounded to the nearest 10; the numbers depict estimated new cases of leukemia in the United States in 2014.

Leukemias are further classified into subtypes depending on the molecular and genetic characteristics of leukemia cells. Correctly identifying the properties of each patient’s cancer is critical for prognosis and treatment (LLS 2012b; Wetzler 2012; Den Boer 2009; Vallespi 1991; Cripe 1997).

Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a group of leukemia-like disorders characterized by overproduction of dysfunctional blood cells in the bone marrow (Sekeres 2011), and the disease can arise without a clear cause or develop secondary to chemotherapy or radiation received as treatment for previous cancers, including leukemia (Saba 2007; Panizo 2003; Garcia-Manero 2014). MDS may be indolent, causing no or minimal symptoms, or aggressive (Cleveland Clinic 2014).

Signs and symptoms of MDS generally arise as a result of a reduction in the number of blood cells. For example, insufficient red blood cells (anemia) may cause fatigue or shortness of breath; too few white blood cells (leukopenia), which may increase susceptibility to infection; or too few platelets (thrombocytopenia), which can increase bleeding risk and cause spontaneous bruising (Cleveland Clinic 2014).

Current estimates suggest that approximately 13 000 new cases of MDS are diagnosed each year in the United States. The number of new cases appears to be increasing as the population ages (ACS 2014g). MDS is more common in older men and people who have had previous chemotherapy (Garcia-Manero 2014). MDS progresses into overt AML in about one-third of patients (Cleveland Clinic 2014).

Bone marrow transplantation offers curative potential for patients with MDS. Unfortunately, since bone marrow transplantation is complicated and has many adverse effects, especially in older individuals, and since most MDS patients are over age 60, only about 5–10% of patients are eligible for this procedure. Therefore, treatment strategies typically aim to reduce symptoms to a manageable level and improve quality of life. Blood transfusions can help overcome symptoms caused by low blood cell levels, and several drugs can help improve disordered blood parameters or, possibly, induce complete or partial remission (regression). These include thalidomide (Thalomid), lenalidomide (Revlimid), arsenic trioxide (Trisenox), amifostine (Ethyol), and immunosuppressive therapy. 5-azacytidine (Vidaza) may also be used and is the only FDA-approved drug to treat MDS. For those with less aggressive cases of MDS, treatment with growth factors such as granulocyte-colony stimulating factor (G-CSF) (Neupogen) or granulocyte macrophage colony-stimulating factor (GM-CSF) (Leukine) and erythropoietin (Procrit) may be useful (Cleveland Clinic 2014; Sekeres 2011).

4 Causes and Risk Factors

Gender and Age

Leukemia does not affect all populations equally. For instance, men are more likely to develop leukemia than women, and older people are typically at higher risk than younger people. ALL is an exception to this trend (ie, ALL is more common in children) (Siegel 2011; Siegel 2012; Siegel 2013). Leukemia accounts for almost one-third of all cancers diagnosed in children from birth to 14 years, and over 75% of these childhood leukemias are ALL. Leukemia is the leading cause of cancer death among men under age 40 (Siegel 2013).  

Genetics and Family History

There is strong evidence for a genetic component to some types of leukemia. People with at least one affected sibling with a hematological (blood-related) cancer have a 2.3 times increased risk of developing leukemia. Individuals reporting at least one sibling with leukemia showed three times the risk of developing CLL (Pottern 1991). In a study on twins, those with an identical twin affected by leukemia had a greatly increased chance of developing leukemia themselves (Kadan-Lottick 2006). Family history of other types of cancer may be a risk factor for adult leukemia as well (Poole 1999; Wang, Lin 2012).

Certain genetic abnormalities, such as Down syndrome, are associated with leukemia. Studies suggest that children with Down syndrome have an almost 20-fold greater risk of developing leukemia than the general population. In this population, the highest incidence of leukemia is observed in children less than 5 years of age (Ross 2005).

Among certain types of leukemia, patients with specific genetic abnormalities have an increased risk of developing resistance to therapy, and possibly a greater chance of relapsing after remission (Meijerink 2009; Estey 2010; Medeiros 2010). One example of this is a monosomal karyotype, a chromosomal abnormality that is a strong predictor of drug resistance and poor prognosis in patients with AML (Estey 2010; Medeiros 2010).

Alterations in specific genes play a role in some types of leukemia as well. For example, the FLT3 gene is important for normal growth and development of blood cell precursors. The protein encoded by this gene is not normally present in large amounts in mature blood cells (Karsunky 2003). However, mutations in the FLT3 gene are known to be common in AML, and FLT3 mutations are a strong predictor of poor prognosis in AML (Kottaridis 2001; Gilliland 2002).

Blood Disorders

Patients with certain pre-existing blood disorders may be at increased risk of developing some forms of leukemia. For instance, there is a higher risk of developing AML in people with chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. There is additional risk when treatment for these conditions includes some types of chemotherapy or radiation (ACS 2013a).

Smoking

Smoking cigarettes increases the risk of developing leukemia, particularly adult AML (Brownson 1993; Thomas 2004; Musselman 2013). In one study, the risk of leukemia increased according to the number of cigarettes smoked per day (Brownson 1993). Even children exposed to parental cigarette smoke prenatally or after birth appear to have an increased risk of childhood ALL (John 1991; Chang 2006). However, a 2013 study revealed encouraging evidence that leukemia risk decreases with increased time after quitting, and in long-term quitters (30 years or more) the risk was comparable to that of non-smokers (Musselman 2013).

Chemical Exposure

Exposure to certain chemicals has been found to elevate the risk of developing leukemia. For example, long-term exposure to benzene, a constituent of crude oil and known cancer-causing agent, increases the risk of leukemia (Snyder 2012; Li 2014; Yin 1996; Savitz 1997; Hayes 2001; ACS 2013b). Benzene is used as a starting material to make a wide variety of substances including plastics and pesticides. It is a common chemical in the environment throughout the United States, with high levels in the vicinity of gasoline stations and some industrial facilities, vehicle exhaust, and secondhand tobacco smoke (Brugnone 1997. Therefore, people who work in chemical plants, oil refineries, and gasoline-related industries may be exposed to high benzene concentrations (ACS 2013b). A major source of benzene exposure is tobacco smoke. Estimates suggest that benzene in cigarettes is responsible for about one-third of smoking-induced AML (Korte 2000; Vineis 2004). Formaldehyde is another environmental chemical potentially linked to leukemia. Formaldehyde is generated by automobile engines, is a component of tobacco smoke, and is released from household products, including furniture, particleboard, plywood, and carpeting (Zhang 2009). The association between formaldehyde exposure and leukemia risk is controversial, however, as some studies support the link (Schwilk 2010) while others do not (Checkoway 2012; Gentry 2013). Agent Orange, a chemical defoliant to which many soldiers were exposed during the Vietnam War, has also been associated with increased leukemia risk (Yi 2013; Baumann Kreuziger 2014). Parental pesticide exposure near the time of conception or during pregnancy has been associated with childhood leukemia, as has childhood exposure (Turner 2010; Turner 2011; Ferreira 2013). Among adults, living on or near a farm has been linked with a greater risk of developing or dying from leukemia, possibly as a consequence of increased agricultural pesticide exposure (Viel 1991; Jones 2014). Exposure to multiple pesticides may exacerbate the risk of malignancy, as experimental evidence shows that mixtures of pesticides, at low concentrations, can damage DNA to a similar extent as higher concentrations of single pesticides alone (Das 2007).

Radiation Exposure

Exposure to high-energy (ionizing) radiation (eg, atomic bomb explosions) is linked to leukemia. For example, there was a dramatic increase in leukemia risk among Hiroshima and Nagasaki atomic bomb survivors soon after the bombings (Hsu 2013; Preston 1994); and in one study, the excess risk persisted, especially for AML, even 55 years after the bombings (Hsu 2013). Also, exposure to lower doses of radiation from post-Chernobyl cleanup work has been associated with a significant increase in the risk of leukemia (Zablotska 2013). Some evidence suggests that low-dose radiation, such as from diagnostic X-rays, may be associated with increased leukemia risk as well. In one study, children who had undergone X-ray examinations were at increased risk of childhood leukemia (Shih 2014). Another study found similar results: children who had been exposed to post-natal X-ray examinations for diagnostic purposes had an increased risk of childhood ALL (Bartley 2010). Computed tomography (CT) scans also appear to increase cancer and leukemia risk in children, though it is thought that the diagnostic benefits generally outweigh the risks (Pearce 2012). Older CT scanning technology resulted in higher radiation exposure, though current CT scans are believed to still carry some degree of risk (Mathews 2013). Thus, non-radiative diagnostic measures in children, when appropriate, are considered preferable (Miglioretti 2013; Knusli 2013; ARSPI 2014).

The possibility of a relationship between living in close proximity to high-voltage electricity lines and the risk of childhood leukemia has been studied for decades (Washburn 1994). This remains a contentious issue (Magana Torres 2013; Clavel 2013); some studies failed to find a relationship (Pedersen 2014), while other studies found an association ranging from significant (Washburn 1994; Sohrabi 2010) to not achieving statistical significance (Sermage-Faure 2013). Those that found a relationship suggested risk increased markedly with closer proximity to such power lines (Sidaway 2013; Roosli 2013).

Previous Cancer Treatment

Aggressive chemotherapy and radiation therapy can improve outcomes for many cancer patients. Unfortunately, high-dosage treatment regimens also significantly increase the risk of development of subsequent leukemia (Huh 2013; Pedersen-Bjergaard 2000; Morton 2013; Kaplan 2011).

Therapy-related myelodysplastic syndromes are a major complication among patients treated for previous blood-related malignancies or solid tumors (Leone 2007; Leone 2010; Zompi 2002). A 2013 study examined the records of over 426 000 US cancer patients who were treated with chemotherapy for a primary tumor between 1975 and 2008. Among this group, a subsequent diagnosis of AML was 4.7 times more common than expected in the general population (Morton 2013). A similar study examined the records of over 5700 breast cancer patients diagnosed between 1990 and 2005. A 10.9-fold increased risk of MDS was found in breast cancer patients under age 65, and a 5.3-fold increased risk of AML was noted in the same population. The risk was higher for those who received a combination of chemotherapy and radiation compared to those who received chemotherapy or radiation alone (Kaplan 2011). Studies indicate that childhood cancer survivors are at an increased risk of developing malignancies during their later years compared to peers who did not have childhood cancer. In one study, children who survived more than five years after having AML had 3.9-times greater risk of a secondary cancer, and those who survived more than five years after having ALL had a 4.3-times greater risk compared with the general population. This study followed more than 4800 childhood cancer survivors for 14.5 years (Perkins 2013; Joh 2011). Overall, the risk of developing leukemia is increased as a result of cancer therapy. Thus, lifelong surveillance is recommended for cancer survivors (Vega-Stromberg 2003).

Chemotherapeutic drugs such as alkylating agents, nitrosoureas, procarbazine (Matulane), and topoisomerase II inhibitors have considerable potential to increase the risk of leukemia. Exposure to large, cumulative doses of alkylating agents is a prominent risk factor for leukemia secondary to chemotherapy (Leone 2010; Pedersen-Bjergaard 2000). In addition, some supportive agents administered along with rigorous chemotherapy have also been found to increase the risk of leukemia. For example, colony stimulating factor (CSF) use among elderly patients with non-Hodgkin’s lymphoma undergoing chemotherapy has been associated with an increased risk of developing leukemia (Gruschkus 2010).

Viral Infections

Human T-cell lymphotropic virus type 1 (HTLV-1), the first retrovirus shown to cause human malignancy, was identified as the causative agent of adult T-cell leukemia-lymphoma (ATLL) (Yoshida 1982; Beltran 2009; Zane 2014). HTLV-1 mainly affects specialized immune T cells (CD4+ T cells), causing infected T cells to transform into cancerous cells (Satou 2013). In addition, multiple studies have shown a correlation between maternal and childhood infections and subsequent risk of developing childhood leukemia. Some studies have also found a significantly increased risk of childhood leukemia in children whose mothers experienced infections during pregnancy (Sadrzadeh 2012). For example, children whose mothers experienced a reactivation of the Epstein-Barr virus during pregnancy were found to have an almost three-fold greater risk of developing ALL in one study (Lehtinen 2003).

5 Symptoms and Diagnosis

Symptoms of leukemia often resemble those caused by other, less severe illnesses, so it may not be immediately obvious to patients or physicians that symptoms are attributable to leukemia. Common signs and symptoms of leukemia include weight loss, weakness, fatigue, anemia, infection, fever, swollen lymph nodes, bruises, skin pallor, and bleeding. Enlarged spleen and liver are observed in some cases. Other possible symptoms include bone pain, and possible changes in mental status, usually in cases with central nervous system involvement (Maslak 2012; Rao 2013). Signs and symptoms vary with type and stage of leukemia (Bansal 2013; LLS 2012b). Patients with acute leukemia, especially AML, may require emergency treatment at the time of presentation (Sekeres 2009; Zuckerman 2012; Maslak 2012).

Individuals suspected of having leukemia are tested first for elevated white blood cell count. The complete blood count (CBC) test includes the white blood cell count and may reveal additional blood cell abnormalities, which can provide sufficient evidence for physicians to make a tentative diagnosis (Ferri 2014). Different types of leukemia can cause different abnormalities on a CBC, which may allow pathologists to better identify the type of leukemia the patient has (LLS 2012c). The blood may be further analyzed under a microscope to check for cell structure abnormalities indicative of leukemia. Flow cytometry may also be used in the diagnosis of CLL. This test detects markers on the surface of blood cells to help identify them (ACS 2014c). Blood analysis may be followed with a bone marrow biopsy to confirm the diagnosis and learn more about the specific leukemia cell type (ACS 2014c). In this procedure, a sample of bone marrow is aspirated from the hipbone or other large bone and leukemia cells are analyzed by a pathologist to determine their properties (ACS 2014c; Dorantes-Acosta 2013; Zhao 2014).

Additional indicators of leukemia include elevated levels of lactate dehydrogenase and uric acid, decreased fibrinogen, and increased fibrin degradation products as a result of disseminated intravascular coagulation in AML. Elevated vitamin B12 levels and elevated blood histamine levels are indicative of CML (Agis 2007; Iseki 1993; Ferri 2014). Leukocyte alkaline phosphatase (LAP) is an enzyme that plays a crucial role in mature white blood cells called granulocytes. The activity of LAP is reduced or absent in CML; this is a characteristic marker of CML (Dotti 1999).

Furthermore, abnormal white blood cells are tested for the presence of specific genetic mutations. The “Philadelphia chromosome,” present in more than 95% of patients with CML, is a mutation involving exchange of genetic material between chromosomes 9 and 22, leading to the fusion of the BCR and ABL genes (Kawasaki 1988; Foroni 2009). The Philadelphia chromosome, also present in about 20–30% of adults with ALL, is associated with a poor prognosis (Fielding 2010). A test called fluorescence in situ hybridization (FISH) is used to detect the BCR-ABL gene fusion. Another testing method, called quantitative polymerase chain reaction (PCR), can be used to quantify the number of cells in blood or bone marrow that contain the BCR-ABL fusion gene, and PCR may be useful for tracking response to treatment (LLS 2012c). Another mutation commonly found in leukemia is in the FLT3 gene. Under healthy conditions, FLT3 makes a protein that plays an important role in the survival and proliferation of blood-forming precursor cells. Mutations in the FLT3 gene lead to unlimited production of this protein, ultimately resulting in uncontrolled proliferation of the blood-forming precursor cells. FLT3 is mutated in about one-third of AML patients (Zaker 2010; Small 2006).

Imaging studies are also used to evaluate leukemia patients. Chest radiography is helpful in the evaluation of possible cancer spread, such as when mediastinal masses are suspected (the mediastinum is the part of the chest that lies between the sternum and the spinal column, and between the lungs) (Raj 2013; O'Donnell 2012; Ferri 2014). For patients with neurologic symptoms, lumbar puncture may be performed to collect cerebrospinal fluid, which is then tested for infection and inflammation. However, if the patient has circulating leukemia cells, lumbar puncture has the potential to introduce those cells into the cerebrospinal fluid. For this reason, lumbar puncture in acute leukemia patients is performed only after a dose of chemotherapy is injected into the fluid surrounding the spinal cord (Debnam 2009; Gajjar 2000). A CT scan or magnetic resonance imaging (MRI) scan of the head may follow. A CT scan of the abdomen may be performed to look for an enlarged liver (hepatomegaly) or spleen (splenomegaly) (Ferri 2014).

Staging

Staging is a critical aspect of the diagnosis of all cancers; it helps determine how aggressive the cancer is, whether it has spread, and what treatment choices are appropriate (ACS 2012). Since leukemias are not solid tumors, staging is largely based on results of blood tests, bone marrow analysis, and determination of the molecular properties of leukemia cells (ACS 2014a).

CLL. In the United States, CLL is typically staged using the Rai system. Originally developed in 1968, the Rai system divides CLL into five stages starting from the least severe stage, Rai stage 0, in which patients have an increase in overall lymphocyte count (lymphocytosis) but no enlargement of lymph nodes, spleen, or liver and near normal red blood cell and platelet counts. In the most severe stage, Rai stage IV, patients have lymphocytosis along with too few platelets, with or without anemia, and enlarged lymph nodes, spleen, or liver. Rai stages are associated with escalating levels of risk of the disease worsening or treatment being required. Rai stage 0 is considered low risk, stages I and II are intermediate risk, and stages III and IV are high risk (ACS 2014a).

CML. The approach to staging CML differs from that of CLL in that, rather than being assigned stage numbers, cases are grouped into one of three “phases”: chronic, accelerated, or blast. Untreated CML will usually progress from chronic to blast, which is sometimes referred to as “acute blast crisis” (UMMC 2014). There is some variation as to how patients are grouped into the three CML phases; the descriptions here are based on commonly used criteria proposed by the World Health Organization (ACS 2014d).

  • In chronic phase CML, patients have less than 10% blasts in their blood or bone marrow, usually have relatively mild symptoms, and respond well to standard-of-care treatment regimens. Most patients receive their diagnosis during this phase.
  • The accelerated phase is characterized by 10–20% blasts in the patient’s blood or bone marrow, elevated basophil count, elevated white blood cell count that does not respond to treatment, abnormal (very high or very low) platelet count not caused by treatment, and evidence of genetic abnormalities in leukemia cells. Patients in the accelerated phase may experience fever, loss of appetite, and weight loss; accelerated phase CML is not as responsive to treatment as chronic phase CML.
  • The blast phase may resemble an aggressive acute leukemia and is characterized by greater than 20% blasts in a blood or bone marrow sample. During this phase, the patient’s symptoms are often pronounced and include fever, poor appetite, and weight loss. Blast cells can spread to tissues and organs during the blast phase, and the prognosis worsens (UMMC 2014).

Acute leukemias. In the past, acute leukemias were classified in accordance with the French-American-British system, which was developed in the 1970s. However, this system has largely been superseded by classification based upon the morphologic, molecular, and genetic characteristics of leukemia cells. There are numerous subtypes of acute leukemias, and proper identification of each patient’s leukemia is critical because the treatment approach that works for one subtype may not work for others (ACS 2014e; ACS 2014f).

6 Conventional Treatment

The specific treatment approach depends upon the type of leukemia and how aggressive the disease is. Chemotherapy treatments compose the majority of leukemia therapy. Specialized drugs called tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for CML in most cases. These drugs work by interfering with the signaling of the BCR-ABL fusion gene, which is present in most CML patients and grants CML cells a survival advantage over normal cells (Bedi 1994; Guo 1996; Goldman 2012b; LLS 2012a). TKIs are also used in some ALL patients whose leukemia cells exhibit the Philadelphia chromosome (Fielding 2010; Wetzler 2012). Stem cell transplantation is also a viable option in some leukemia patients, especially those who fail to respond to first-line therapies or whose disease is considered high risk (Goldman 2012b; Goldman 2012a; Fielding 2010; Wetzler 2012).

First-line treatment is usually chosen based on the results of clinical trials in patients with the same type and stage of cancer. If the first-line treatment does not result in the desired outcome (ie, has serious side effects or does not induce an adequate response), oncologists usually recommend a second-line treatment (Baccarani 2009).

Patient-specific factors (eg, age) and disease-specific factors (eg, chromosomal characteristics of the type of leukemia) strongly impact prognosis and response to leukemia treatment. For many of the genetic mutations identified in the different leukemias, the impact on prognosis has not yet been determined (Liersch 2014). A notable example is the difference between ALL in children and adults. In children, ALL is a highly curable disease, with cure rates approaching 90% while in adults the cure rate is only 40% (Hunger 2012; ACS 2013d; UMMC 2013; Trigg 2008; Pui 2012).

Distinguishing “Cure” from “Complete Remission”

It is important that leukemia patients understand the meaning of various terms they may encounter during the course of their treatment. One area of potential confusion is the distinction between “cure” and “complete remission.”

When cancer has been completely eradicated from a patient’s body and is not expected to ever return, the patient is said to be “cured.” When all signs and symptoms of cancer have disappeared, but physicians cannot be sure that the cancer will never return, the patient is said to be in “complete remission.”

Physicians are often hesitant to say that a patient is “cured” of cancer because it is difficult to be certain that all the cancer has been eliminated from the patient’s body and that it will never return. Instead, physicians often say something along the lines of “there are no signs of cancer at this time.” However, some physicians may use the term “cured” to refer to patients who have been in complete remission for a long time, usually five years or more (NCI 2012).

Chemotherapy

Chemotherapy targets the growth of rapidly-dividing cells. Several drugs and drug combinations have been approved by the Food and Drug Administration (FDA) for the treatment of different types of leukemia. A complete list of drugs FDA-approved to treat leukemia is available at: http://www.cancer.gov/cancertopics/druginfo/leukemia.

Since chemotherapy destroys rapidly dividing cells, it also ends up destroying rapidly growing healthy cells, such as those of the gastrointestinal tract, skin hair follicles, nail matrix, mouth, reproductive system, and bone marrow (Mauch 1995; Tuncer 2012; Gradishar 1988; Kamil 2010; Herlofson 1997). This is why chemotherapy often causes unpleasant side effects, the most common of which are nausea and vomiting. Other side effects include changes in taste, fatigue, neuropathy, mouth sores, hair loss, and sexual dysfunction (CCS 2014). In addition, some leukemia cells develop drug resistance, resulting in treatment failure, which is one of the fundamental challenges facing patients, doctors, and the field of oncology (Wong 2012).

Acute leukemias. Patients diagnosed with acute leukemia usually need to start chemotherapy immediately after diagnosis. The first stage of chemotherapy is called the induction phase, in which the goal is induction of remission. During the induction phase, patients are administered intensive chemotherapy in attempt to eliminate leukemia cells from the blood and bone marrow. The exact combination of chemotherapy drugs used during the induction phase, as well as the duration and intensity of this phase, depend on several individual factors such as the patient’s age and health status, as well as the type and molecular characteristics of their leukemia. A port is placed, usually into a vein in the upper chest, to allow IV administration of the chemotherapy drugs. In AML, induction-phase treatment generally lasts about a week and usually takes place in a hospital setting. In ALL, treatment usually lasts a month or more and is intensive, requiring frequent doctor visits, with some patients spending part or all of the month in the hospital. If there is still evidence of leukemia cells in the patient’s blood and bone marrow after the first course of induction therapy, physicians may try a different combination of drugs (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

The second phase of chemotherapy, called post-remission therapy or consolidation therapy, consists of additional intensive chemotherapy and sometimes stem cell transplantation. The goal of post-remission therapy is to eliminate any remaining leukemia cells that linger, often in the bone marrow, after the induction phase. The duration of post-remission therapy depends on the characteristics of the leukemia, including cell type and other factors (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

Acute leukemia can infiltrate the brain and spinal cord; this is more common in ALL than AML (Schiffer 2003). In order to prevent this, chemotherapy is administered via injection into the spinal column; this is called central nervous system (CNS) prophylaxis. It is more common for ALL patients to receive CNS prophylaxis than patients with AML. Radiation therapy may also be employed during CNS prophylaxis (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

Chronic leukemias. For CLL, induction chemotherapy, antibody therapy, or a combination of the two is considered first-line treatment for patients with active, symptomatic disease or advanced disease. For CML, targeted drugs (particularly TKIs) represent first-line therapy, but chemotherapy is also used in some cases; stem cell transplantation is a therapeutic option for non-responsive cases and blast-phase patients (LLS 2012b; Paneesha 2014; Somervaille 2013). The goal of therapy is to produce a durable, lasting remission. Unfortunately, chronic leukemias are not considered curable by chemotherapy, but many patients achieve long-term remission (Paneesha 2014; Somervaille 2013; Goldman 2012b). The choice of chemotherapy drug(s) typically depends on the patient’s age and characteristics of their leukemia. For example, chlorambucil (Leukeran) is a standard drug used in CLL patients older than 65, while fludarabine (Fludara) is used in younger patients (Goldman 2012b; LLS 2012a; LLS 2011b).

Stem Cell Transplantation

Stem cells are primitive, undifferentiated cells that possess the ability to self-renew and differentiate into various cell types. Stem cell transplantation is the process of infusing healthy blood-forming stem cells to restore healthy bone marrow in leukemia patients that have undergone intensive treatment. When a patient’s own stored stem cells are transfused into their bloodstream, it is termed an autologous stem cell transplantation. Allogeneic stem cell transplantation, on the other hand, involves transplanting stem cells from a healthy donor whose tissue type closely matches the patient’s tissue type (ACS 2013c; Jaglowski 2012; Smolewski 2013).

When first introduced, allogeneic stem cell transplant, also known as bone marrow transplant, was called “the first important breakthrough in the evolution of CML treatment” as it was able to cure roughly 50% of the patients who underwent the procedure. These patients became Philadelphia chromosome-negative and BCR-ABL-negative. The greatest success of allogeneic stem cell transplant was in patients under the age of 40, but the median age at diagnosis for CML is close to 60 years (Baccarani 2014; ASCO 2013).

Tyrosine Kinase Inhibitors (TKIs)

The hallmark of CML is the Philadelphia chromosome, a breakage and fusion between regions on chromosomes 9 and 22. This gene fusion is referred to as BCR-ABL, and its product is a deregulated tyrosine kinase enzyme (Goldman 2008; Mauro 2001). Imatinib mesylate (Gleevec) is a TKI that targets leukemia cells harboring the BCR-ABL fusion gene; it showed unprecedented results in an early clinical trial involving 31 patients, inducing remission in all of them and eliminating evidence of the Philadelphia chromosome altogether in some. In a later study, the overall survival of patients who received imatinib as initial therapy was 89% at five years, and in another study, highly favorable responses were obtained in over 50% of patients who failed conventional therapies (Pray 2008; Druker 1996; Druker 2001; Druker 2006). Imatinib has two important limitations: it must be taken for life, or until it is no longer effective, and one of its side effects is serious water retention (edema) (Widmer 2006; ACS 2013e).

Specific mutations in the BCR-ABL gene make the enzyme resistant to imatinib therapy, as the drug is unable to target and stall the activity of BCR-ABL (Deininger 2005). Another troubling aspect of imatinib treatment is its cost-effectiveness. While imatinib has been shown to prolong life and improve quality of life in CML patients compared to conventional treatments, there is a significant cost associated with imatinib treatment (Gordois 2003; Warren 2004).

Other TKIs, referred to as second- and third-generation TKIs, have been developed and commercialized, namely dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif) and ponatinib (Iclusig). Clinical trials involving dasatinib and nilotinib have concluded that they are effective and generally well tolerated in CML patients who initially showed a suboptimal response to imatinib (Stein 2010; Baccarani 2014). Currently, dasatinib is approved as first-line treatment for all phases of CML as well as ALL patients with BCR-ABL gene fusion who respond suboptimally to imatinib (Hochhaus 2013). A third-generation TKI, ponatinib, has shown positive results in clinical trials on patients with the T315I mutation in BCR-ABL, which causes resistance to dasatinib and nilotinib (Breccia, Alimena 2014; Cortes 2013; Zhao 2013).

A major phase II clinical trial published in late 2013 examined the effects of ponatinib in patients with CML or Philadelphia chromosome-positive ALL. All subjects in this study had previously undergone intensive treatment and 1) were resistant to or had severe side effects from the second line TKIs dasatinib or nilotinib, or 2) had the BCR-ABL T315I mutation. Among 267 patients with chronic-phase CML, 56% had a “major cytogenetic response,” 46% had a “complete cytogenetic response,” and 34% had a “major molecular response.” Impressively, 91% of the “major genetic responses” were sustained for at least 12 months, and the researchers did not identify any single BCR-ABL mutation that caused resistance to ponatinib. Of 83 patients with accelerated-phase CML, 55% had a “major hematologic response” and 39% had a “major cytogenetic response.” Thirty-two of the trial participants had blast-phase CML, and 31% of them had a “major hematologic response” and 23% had a “major cytogenetic response.” Among 32 subjects who had Philadelphia chromosome-positive ALL, 41% had a “major hematologic response” and 47% had a “major cytogenetic response.” Common side effects included low platelet counts, rash, dry skin, and abdominal pain; serious treatment-related side effects were observed in 3% of subjects (Cortes 2013). Unfortunately, because of serious side effects involving blood clots, the indications for ponatinib use are limited to treatment of specific CML and ALL patient groups for whom no other TKI therapy is indicated (NCI 2014b).

Monoclonal Antibody-Based Therapy

Antibody-based therapy is a type of targeted therapy in which specific molecules called antibodies are administered to trigger the host’s immune system to target “markers” (called antigens) on cancer cells for elimination. Normally, antibodies are produced in the body by B cells. The antibodies identify disease-causing agents in the body, then trigger T cells and other components of the immune system to destroy them (Scott 2012; Lund 2010; Buss 2012; O'Mahony 2006; Vedi 2014).

Rituximab (Rituxan), a monoclonal antibody against the CD20 antigen on B cells, combined with chemotherapy is available for the treatment of B-cell ALL and CLL (Zhao 2013; Jaglowski 2010). Several studies suggest the addition of rituximab to intensive chemotherapy has improved the outcome for B-lineage ALL, particularly among younger adults. However, further investigation is needed to address the role of rituximab therapy in older patients (Thomas 2012; Hoelzer 2010). Another antibody being actively investigated is epratuzumab, which targets the CD22 antigen on B cells. One study investigated the addition of epratuzumab to the combination of Ara-C (Depocyt) and clofarabine (Clolar) in the treatment of one type of ALL in patients who relapsed or were resistant to previous therapy. The combination therapy resulted in a 52% response rate, whereas a previous trial of clofarabine/Ara-C alone only resulted in a 17% response rate (Advani 2012).

Another way antibodies are used in leukemia therapy is as a carrier for delivery of a cytotoxic drug directly to leukemia cells. This approach, called antibody-drug conjugation, is an active area of leukemia research (Cowan 2013; Ricart 2011; Vedi 2014; Wayne 2014). Combining therapeutic antibodies with specific toxins or radioactive agents holds the promise of greater efficacy compared to standard antibody-based therapy (Buss 2012). Gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin are composed of a toxin (a derivative of a toxic antibiotic with DNA-binding ability) linked to a human antibody against CD33 or CD22, respectively. CD33 and CD22 are specific markers of myeloid leukemia and B-cell malignancies, respectively (Cowan 2013; Ricart 2011).

Gemtuzumab Availability

After several clinical trials of gemtuzumab in patients with AML showed favorable results, the drug was given accelerated FDA approval in 2000. However, in 2010, it was withdrawn from the US and European markets due to lack of overall benefit in the entire study population in phase III studies and increased mortality observed in certain cases. The drug remained commercially available in Japan and received full regulatory approval (Ravandi 2012; Cowan 2013; ASH 2009). Recently, however, researchers have more rigorously analyzed data from large studies and concluded that gemtuzumab improved survival in well-defined subsets of leukemia patients with newly diagnosed non-APL AML. (Non-APL AML is characterized by the overproduction of primitive myeloid cells, or blasts.) Gemtuzumab may have similar efficacy in AML patients who have been genetically classified as low risk. Therefore, AML experts are asking the manufacturer and regulatory authorities to grant selected patients access to this potentially valuable medication (Ravandi 2012; Cowan 2013).

Interferon Therapy

Interferons are produced naturally in the body in response to viral infection, but they can also be synthesized and used as drugs (Pfeffer 1997; Perry 2005; Iqbal Ahmed 2003). Interferon-alpha (IFN-α) mediates anti-leukemic effects through diverse mechanisms involving stem cells and the immune system. For the past 50 years, various forms of interferon have been evaluated as therapy in a number of malignant and nonmalignant diseases (Jonasch 2001; Passegue 2009). Treatment of CML with IFN-α was introduced in the early 1980s and was found to be able to induce cytogenetic remission in 15-30% of patients, with a significant survival advantage compared to conventional chemotherapy (Baccarani 2014; Simonsson, Hjorth-Hansen 2011; Talpaz 1986). In several early studies, IFN-α, when combined with Ara-C, moderately improved clinical outcomes in CML patients (Ozer 1993; Robertson 1993; Kantarjian 1992; Simonsson, Hjorth-Hansen 2011).

A systematic review published in 2014 found that adding interferon to imatinib therapy in patients with CML was clinically more effective and led to earlier cytogenetic and molecular remission compared to imatinib alone. The combination was slightly more likely to cause hematologic side effects, but researchers concluded that it was safe in spite of this (Liu 2014).

Unfortunately, interferon therapy carries significant constitutional, neuropsychiatric, hematologic, and hepatic side effects, which can have a major impact on the patient’s quality of life (Jonasch 2001).

Recently, it was observed that a modified form of IFN-α, called PegIFNα2a (pegylated interferon alpha-2a), in combination with imatinib led to significant improvement in patients with low- or intermediate-risk CML and in chronic-phase CML. In this study, the combination required lower doses of IFN-α, which may enhance tolerability while retaining efficacy and could be considered in future combination therapies (Simonsson, Gedde-Dahl 2011; Johnson-Ansah 2013).

All-Trans Retinoic Acid

FDA-approved vitamin A-based therapies (retinoids) are available for the treatment of several malignancies (Bushue 2010; Tang 2011). In cancer, the therapeutic and preventive activities of retinoids are due to their ability to modulate the growth, differentiation, and survival of cancer cells (Altucci 2001). The influence of retinoids on cellular differentiation is of particular interest in the context of cancer (Gudas 2011). Cellular differentiation refers to the progression of a less-specialized cell to a more-specialized cell. Specialized cells originate from primitive precursor cells called stem cells. Stem cells are relatively undifferentiated in that they are not dedicated to function as a specific cell type – for example, as a white blood cell. As stem cells divide, they give rise to slightly more differentiated and specialized cells, which in turn divide and give rise to even more specialized cells. The process progresses until fully differentiated, specialized cell types are produced. In cancer, the process of cellular differentiation often becomes perturbed, giving rise to cells that may have the ability to divide and propagate, but do not function properly. Generally, the greater the degree of differentiation exhibited by cancer cells, the less aggressive they are and the more closely they resemble normal, healthy cells. Retinoids help regulate several genetic mechanisms that drive normal cellular differentiation, so they are used as cancer therapeutic agents in certain types of cancer (Gudas 2011; NCI 2014c; CIRM 2013; Nature Education 2014).

Vesanoid (Tretinoin) is a derivative of vitamin A. It is also referred to as all-trans retinoic acid (ATRA) (Bryan 2011). ATRA combined with arsenic trioxide is, as of the time of this writing, largely considered the treatment of choice for the AML subtype known as acute promyelocytic leukemia (APL) (Siddikuzzaman 2011; Watts 2014).

An early study that measured five-year disease-free survival in APL patients showed that chemotherapy supplemented with ATRA was more effective than daunorubicin (Cerubidine) and cytarabine (Depocyt) (Tallman 2002). In a study of newly diagnosed APL patients, the combination of ATRA and arsenic trioxide resulted in significant shortening of the time required to attain complete remission (Shen 2004). Later clinical studies showed that the combination of ATRA with regular chemotherapy treatment caused minimal toxicity and was highly effective in treating newly diagnosed APL patients (Hu 2009; Sanz 2008). In APL patients considered low-to-medium risk, the combination of ATRA and arsenic trioxide has made traditional chemotherapy unnecessary in many cases. In patients treated with ATRA and arsenic trioxide in the induction and consolidation phases of treatment, overall survival rates greater than 90% have been observed (Siddikuzzaman 2011; Watts 2014; Breccia, Cicconi 2014; Wang 2011; Chen 2014; Lo-Coco 2013).

In one study, the addition of ATRA to chemotherapy demonstrated increased rates of remission and survival in elderly patients with AML (Schlenk 2004). In laboratory studies examining resistance to the TKI medications imatinib, nilotinib, or dasatinib, ATRA blocked acquisition of BCR-ABL mutations and resistance to these medications (Wang 2014).

Surgery

Because leukemia is not isolated in a tumor but disseminated throughout the body in the blood, surgery is not a useful treatment for the majority of cases. However, surgery may be helpful in treating certain leukemia complications. For example, in some leukemia patients the spleen becomes enlarged and can compress nearby organs, causing discomfort or other complications. In these cases, when radiation or chemotherapy do not shrink the spleen, it can be surgically removed (splenectomy) (ACS 2014b).

Tumor Lysis Syndrome

Tumor lysis syndrome is a potentially life-threatening complication of cancer treatment. It occurs as a result of rapid decomposition of cancer cells after therapy, which can lead to metabolic imbalances and give rise to acute kidney injury, seizures, and cardiac arrhythmias. Most cases of tumor lysis syndrome occur in patients with blood-related cancers (Mughal 2010; Flombaum 2000).

Leukemia patients have an increased risk for developing tumor lysis syndrome. Therefore, it is important that they are carefully monitored by a physician for signs of tumor lysis syndrome (Ezzone 1999; Doane 2002; Gobel 2002).

Diligent preventive measures may help prevent tumor lysis syndrome. For a few days before therapy is initiated, the patient should be adequately hydrated, and a drug called acetazolamide (Diamox) may be administered to help alkalinize the urine. Allopurinol (Zyloprim), a drug to help prevent the buildup of uric acid in blood, is often used as well (Goldman 2012a).

7 Novel and Emerging Strategies

Autologous T-Cell Infusion

In an important clinical case report, researchers isolated T cells from a CLL patient and genetically modified them to target and kill leukemia cells. The modification of the T cells gave them a receptor that specifically binds to the CD19 molecule present on both normal and malignant B cells. Reinfusion of these modified T cells into the patient induced remission that persisted through follow-up at 10 months after the treatment. Although similar experimental treatments have been attempted in the past for several types of cancer, they did not have a clear effect on tumors, as the modified T cells would lose their ability to divide and did not persist inside the body for a sufficient length of time. In this instance, specific genetic modifications gave the T cells the ability to multiply several times. In fact, these modified T cells were found at high levels for 6 months in the patient’s blood and bone marrow and continued to express the specialized receptor (Porter 2011; Urba 2011; Peggs 2011).

Another clinical study, on two children with relapsed refractory pre-B-cell ALL, also showed encouraging results. T cells modified to produce an anti-CD19 antibody and another signaling molecule were administered, with complete remission in both patients; one patient remained in remission 11 months after therapy (Grupp 2013). In a clinical trial of modified T-cell therapy in 16 ALL patients who relapsed or whose leukemia had not responded to previous treatment, there was an 88% overall complete response rate, including those with high-risk BCR-ABL mutations. (“Complete response” refers to the disappearance of all signs and symptoms of cancer.) Only two patients did not respond to treatment (Davila 2014).

A potential limitation of this therapy, resulting from the persistence of the modified T cells, is its effect on normal B cell populations. Because both normal and malignant B cells are destroyed, immune suppression and increased risk of infection is considered a likely outcome. In the patient mentioned above, B cells were not present in blood or bone marrow for at least six months after the T cell infusion (Davila 2013).

Omacetaxine Mepesuccinate

Omacetaxine mepesuccinate (Synribo) is a substance derived from the evergreen tree Cephalotaxus harringtonia, which is native to China (Chen 2010). This drug was originally identified more than 35 years ago, and initial studies for CML showed promise (Wetzler 2011). Recently, omacetaxine has been shown to effectively kill leukemia stem cells in laboratory and animal studies. Omacetaxine was able to kill more than 90% of leukemic stem cells in leukemia cell lines bearing BCR-ABL mutations. In contrast, imatinib and dasatinib were only able to kill less than 9% and 25% of leukemic stem cells, respectively. Omacetaxine given to mice with CML and mutant BCR-ABL resulted in a marked reduction in both leukemia stem cells and total leukemia cells (Chen, Hu, Michaels 2009).

Targeting Leukemia Stem Cells

One of the most intriguing areas of current cancer research is the study of cancer stem cells. Stem cells represent a self-renewing reservoir of progenitor cells capable of sustaining a large population of mature cells. Healthy stem cells are essential for the maintenance and repair of tissue throughout the body. Cancer stem cells function much the same as healthy stem cells, but have become deregulated and, instead of giving rise to healthy cells, act as progenitors to malignant cells (Crews 2013; Ravandi 2006; SSM 2014).

Contemporary theory proposes that one of the problems with conventional cancer treatment is its failure to eliminate cancer stem cells (Crews 2013). Standard chemotherapeutic agents destroy rapidly dividing cells, such as cancer cells. However, cancer stem cells are able to become dormant; therefore, even if chemotherapy eliminates the bulk of existing tumor cells, it often cannot kill cancer stem cells, which eventually produce new cancer cells, causing relapse (Crews 2013; Ravandi 2006). Some evidence suggests that mature leukemia cells may be capable of reverting to leukemia stems cells, allowing them to evade cytotoxic chemotherapeutic agents (Crews 2013; Ravandi 2006; SSM 2014).

Research indicates that the key to eliminating cancer stem cells may be combination therapies that target multiple pathways. One of the goals of this type of treatment would be to act on cancer stem cells, but leave normal adult stem cells unaffected. Since cancers of the blood (eg, leukemias) allow for easier identification of cancer stem cells than do solid tumors, a great deal of scientific inquiry is focusing on leukemia stem cells, and several promising therapies are being developed on the basis of the findings from studies (Crews 2013).

One evolving area of leukemia stem cell research focuses on developing ways to prevent CML stem cells from becoming resistant to TKI therapy. Bcl-2 proteins help leukemia stem cells avoid destruction by TKIs, and several drugs that target these proteins are in development (Crews 2013; Ng 2012). Another opportunity is in the development of drugs that target signaling pathways involved in leukemia stem cell self-renewal, especially the Wnt/β-catenin and “Hedgehog” pathways. Laboratory evidence shows that administering an experimental Wnt/β-catenin inhibitor along with imatinib leads to an additive or synergistic inhibitory effect on CML cell proliferation (Nagao 2011). Several inhibitors of the hedgehog signaling pathway are being explored as possible therapeutic options for leukemia. Vismodegib (Erivedge), which is FDA-approved for the treatment of basal cell carcinoma, a type of skin cancer, is one of these (see Off-Label Use of Drugs that May Target Leukemia Stem Cells) (Crews 2013).

Numerous additional agents that target leukemia stem cells are in development, and some are being studied in clinical trials (Crews 2013). Since therapies that target leukemia stem cells are not yet widely available, individuals with treatment-resistant leukemia may wish to talk with their physicians about participating in a clinical trial. Information about ongoing clinical trials of leukemia stem cell therapies and other anti-leukemia agents can be accessed at www.clinicaltrials.gov.

Off-Label Use of Drugs that May Target Leukemia Stem Cells

Zileuton (Zyflo), an FDA-approved drug used to treat asthma (Watkins 2007), specifically inhibits the enzymatic activity of the inflammatory enzyme 5-LOX, the product of the ALOX5 gene (Sirois 1991; Knapp 1990). 5-LOX-inhibiting substances, including zileuton, have been shown to suppress proliferation and induce apoptosis (regulated cell death) in human CML cell lines (Anderson 1996; Anderson 1995). ALOX5 regulates the function of leukemia stem cells in mice with CML (Chen, Hu, Zhang 2009). In a rodent model, zileuton prolonged survival of CML mice with the T315I BCR-ABL mutation more effectively than imatinib alone, and the combination of the two was more effective than either alone. Zileuton deserves further attention for its potential role in leukemia treatment and leukemia stem cell-targeting.

Vismodegib was recently approved by the FDA to treat adult patients with basal cell carcinoma. Vismodegib inhibits hedgehog signaling (Fellner 2012). The hedgehog signaling pathway is essential for the maintenance of leukemia stem cells, and loss of this pathway impairs leukemia progression (Dierks 2008; Zhao 2009). In one preclinical trial, vismodegib in combination with ponatinib eliminated therapy-resistant T315I BCR-ABL1-positive leukemia cells (Katagiri 2013; Dao 2013). A phase II clinical trial is underway as of the time of this writing to determine the safety and efficacy of vismodegib in patients with relapsed/refractory AML (Hoffmann-La Roche 2014).

Aurora Kinase Inhibitors

Aurora kinases are a group of proteins required for the normal process of cell division. However, aurora kinases have been found to be overexpressed in various cancers, including leukemia (Goldenson 2014). Aurora kinase inhibitors have recently entered testing for leukemia treatment. One drug in development, danusertib, targets several aurora kinases, giving it the ability to target multiple cancer cell division pathways (Xie 2013). A 2012 study tested danusertib on a variety of acute lymphoblastic leukemia cells including the Philadelphia chromosome-positive (Ph-positive) ALL subclass. The researchers concluded, danusertib “represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells” (Fei 2012).

Aurora kinases A and B are present in excessive numbers in pediatric ALL and AML (Hartsink-Segers 2013). In a phase I study, AT9283, an inhibitor of aurora kinases A and B, was administered to leukemia patients and led to moderately successful results, with a more than 38% decrease in bone marrow blasts in almost one-third of AML patients. However, the drug showed serious side effects including myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multi-organ failure (Foran 2014). The toxicity and efficacy of an aurora B-specific inhibitor, barasertib (AZD1152), were tested in phase I and II clinical trials in patients with adult AML (Kantarjian 2013; Dennis 2012; Löwenberg 2011; Tsuboi 2011). Barasertib led to a better clinical response when used in combination with Ara-C compared to Ara-C alone (Kantarjian 2013). Alisertib (MLN8237), a novel inhibitor of aurora kinase A, is being tested for safety and efficacy in a phase I clinical trial in patients with blood-related malignancies (Hartsink-Segers 2013; Kelly 2013).

8 Dietary and Lifestyle Considerations

Maintain a Healthy Weight

An estimated 20% of all cancers are caused by obesity, and obesity is associated with an increased risk of developing leukemia (De Pergola 2013; Strom 2012). A study on 1068 leukemia patients and 5039 control subjects found that higher body mass index (BMI) was linked to greater risk of AML, CML, and CLL (Kasim 2005).

Avoid Smoking

Multiple studies have demonstrated that smoking cigarettes increases the risk of developing leukemia, particularly adult AML (Brownson 1993; Thomas 2004; Musselman 2013; Strom 2012; Kasim 2005; Ma 2010). 

Consume a Healthy, Varied Diet

A 2013 analysis of 323 adult AML patients and 380 controls found that AML risk was significantly decreased among those who consumed the most dark green vegetables, seafood, nuts, and seeds; risk was significantly increased among those who consumed the most red meat (Yamamura 2013). An analysis of dietary patterns in 2–20 year olds found that eating cured or smoked meat or fish more than once a week was associated with an increased risk of acute leukemia, but higher intake of vegetables and bean curd (tofu) was associated with reduced risk (Liu 2009). A subsequent study also found an association between higher levels of meat consumption and increased risk of AML (Ma 2010).

ALL is the most common cancer in children aged 1-7 and may develop in children in utero (while the mother is still pregnant) (Li 2013; LLS 2011c; Xu 2013). Several studies have concluded that when pregnant mothers eat a healthier diet, the risk of ALL in their children decreases. In a case control study, a significant 35% lower incidence of ALL was observed in children of mothers who ate more vegetables; the risk was 45% lower when mothers ate adequate protein and 25% lower when mothers ate more legumes (Kwan 2009). Another case control study found similar results: greater intake of fruit, vegetables, and seafood was associated with a 28%, 24%, and 28% lower risk, respectively. Greater consumption of sugars and syrups while pregnant increased childhood ALL risk by 32%, while greater red meat increased it by 25% (Petridou 2005).

An earlier study found that increased maternal consumption of the following foods in the 12 months prior to pregnancy was correlated with a reduced risk of childhood ALL: vegetables (47% lower risk); protein (60% lower); fruits (29% lower). Additionally, maternal diet rich in carotenoids such as beta-carotene (precursor to vitamin A), lycopene, and lutein was associated with a 35% lower risk of ALL (Jensen 2004).

Folate supplementation during pregnancy has also been found to be protective against ALL development in children (Thompson 2001). Higher maternal dietary intake of folate and vitamin B12 during pregnancy was protective against childhood ALL in another study (Bailey 2012; Petridou 2005).

9 Integrative Interventions

Balanced and adequate nutrition is especially important for cancer patients, and nutritional support may benefit individuals with leukemia (Begum 2012; Lobato-Mendizábal 1989; Viana 1994; Taj 1993). Conversely, malnutrition has been associated with worse outcomes in leukemia (Begum 2012; Lobato-Mendizábal 1989; Viana 1994), increased risk of infection (Scrimshaw 2010; Taj 1993), and poor therapy tolerance with increased risk of relapse (Viana 1994).

Green Tea and Epigallocatechin Gallate (EGCG)

Several human clinical trials have suggested that green tea decreases leukemia risk. In two such studies involving adults with leukemia, green tea consumption was associated with a 50% decreased risk of leukemia. The association was dose-dependent in that risk was reduced as the number of cups of tea consumed per day and number of years of tea consumption increased (Zhang 2008; Kuo 2009; Yuan 2011).

In animal models, EGCG has been shown to inhibit tumor growth, and in leukemia cell line experiments, it induced apoptosis via modulation of reactive oxygen species production (Nakazato 2005). Furthermore, laboratory studies showed using EGCG prior to curcumin induced apoptosis of CLL cells (Angelo 2009; Ghosh 2009). A study of a multi-nutrient mixture that included green tea extract found it suppressed tumor growth and induced apoptosis in a leukemia cell line (Roomi 2011). In AML, the genetic variation BCR-ABL is common and strongly correlates with increased risk of relapse and poor overall survival. EGCG suppressed the proliferation of AML cells harboring the FLT3 mutation in a study with four different leukemia cell lines (Ly 2013).

An important case series report from the Mayo Clinic detailed the cases of three early-stage CLL patients. On their own initiative, they began taking polyphenol-rich (EGCG) green tea extracts or green tea while under medical observation. All three had objective, measurable improvement in leukemia signs or laboratory indices, an indication of cancer regression, while taking only green tea extract and no other treatment. In two of these cases, disease regression after beginning green tea qualified as a “partial response” to treatment according to standard medical criteria. The authors pointed out that in all three cases, there was objective evidence of disease progression before taking green tea or green tea extract, and the observed disease regression began shortly after beginning green tea consumption. CLL ordinarily follows a gradual progressive course (Shanafelt 2006).

  • The first case was a 58-year-old woman with the small lymphocytic lymphoma (SLL) subtype of CLL. Twenty-nine months after diagnosis, she began developing enlarged lymph nodes; at 33 months, she began taking 630 mg green tea polyphenols per day. Over the next 12 months of taking green tea extract and no other treatment, the lymph nodes under her arms decreased in size by 50%, while her other lymph nodes became almost completely normal based on CT scan evidence. She did not require conventional cancer therapy during that time.
  • The second case was a 50-year-old woman diagnosed with early stage CLL. After five years, she developed fatigue and night sweats, and her lymphocyte count nearly doubled, a sign of leukemia progression. Shortly thereafter, she began taking 1200 mg green tea polyphenols daily; one month later, her white blood cell count had fallen 15%, and her lymphocyte count fell nearly 16%. After several months on green tea extract, she dropped the dose to 300 mg per day. Her lymphocyte count continued to move towards the normal range, and she continued without conventional treatment and without disease progression for 6.5 years at the time of the report.
  • In the third case, a 60-year-old woman was diagnosed with stage 0 CLL. She was followed for nine years, by which time her lymphocyte count had increased by over 60%. She commenced drinking eight cups of green tea daily; one week later, her white blood cell count had fallen 25% and her lymphocyte count fell over 20%. Over the next 4.5 months, her lymphocyte count continued to fall.

Omega-3 Polyunsaturated Fatty Acids (PUFAs)

Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid (PUFA) found in fish and fish oil, inhibits inflammation and has been associated with better weight maintenance and response to therapy, fewer complications, and improved survival in cancer patients (Murphy 2011; Gogos 1998; Jho 2004; Elia 2006; Zaid 2012).

Docosahexaenoic acid (DHA), another marine PUFA, was able to kill AML cells without harming normal blood-forming (hematopoietic) stem cells in a cell culture experiment (Yamagami 2009). Other evidence from cell culture studies shows that DHA enhances the toxic effect of imatinib on BCR-ABL-expressing human leukemia cell lines and increases arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant human leukemia cells (de Lima 2007; Quesenberry 2009).

Omega-3 PUFAs, in combination with chemotherapeutic drugs and radiotherapy, have shown beneficial effects in several cancers, including leukemia(Calviello 2009; Yamagami 2009).

In a clinical trial on Rai stage 0-I CLL patients, omega-3 fatty acids, in daily doses escalating from 2.4 g to 7.2 g, suppressed activation of the inflammatory regulator NF-κB and increased sensitivity of subjects’ lymphocytes to the chemotherapeutic drug doxorubicin (Adriamycin) (Fahrmann 2013).

Vitamin D

Vitamin D helps promote healthy cellular differentiation, and several lines of epidemiologic and preclinical data highlight vitamin D’s potential as a preventive and therapeutic agent in a variety of cancers, including leukemia (Piemonti 2000; Trump 2010; Kennel 2013). Low levels of vitamin D have been observed in AML patients, with further reductions noted following chemotherapy (Naz 2013). Moreover, low blood levels of vitamin D3 have been associated with adverse outcomes in newly diagnosed and intensively treated adult AML patients (Lee 2014).

In AML, normal blood-producing (hematopoietic) cells are replaced by cancerous myeloblasts. These myeloblasts multiply uncontrollably, are unable to follow the normal process of differentiation, and then accumulate in the bone marrow. Vitamin D may help these AML myeloblasts differentiate properly (Gocek 2012). Indeed, several studies suggest that vitamin D3 can induce both differentiation and apoptosis in leukemic cell lines (Suzuki 2006; Kim, Mirandola 2012; Bunce 1997; Hughes 2010; Hall 2013).

In a clinical trial, 29 older adult patients with AML were treated with cytarabine, hydroxyurea (Hydrea, Droxia), and 1,25-dihydroxyvitamin D (active form of vitamin D) for 21 days. After the treatment period, cytarabine and hydroxyurea were discontinued, but the subjects continued taking active vitamin D. Thirteen subjects achieved complete remission, and 10 subjects achieved a partial response, equating to an overall 79% response rate. The overall median survival for patients who responded to therapy was 14 months (Slapak 1992). Active vitamin D treatment showed an important benefit for a potential side effect of cancer treatment in a clinical trial in 16 children with ALL. After the first year of treatment, lumbar spine bone mineral density was improved among subjects whose initial bone mineral density was low (Diaz 2008).

Vitamin C

High concentrations of vitamin C have been shown to induce apoptosis in several cancer cell lines, including leukemia cells, in cell culture experiments (Kawada 2013; Gonçalves 2013; Terashima 2013; Roomi 1998; Yedjou 2009; Harakeh 2007). Clinical research on vitamin C in various cancers has been conducted over the years, with some studies concluding that intravenous, and possibly oral, vitamin C therapy may confer clinically meaningful benefits for cancer patients (Park 2013; Ohno 2009). In a study published in 2014, intravenous vitamin C in combination with arsenic trioxide was administered to 11 subjects with AML. Study participants received one gram intravenous vitamin C daily along with arsenic trioxide five days weekly for five weeks. One subject achieved a complete response, one achieved a complete response without complete recovery of platelet count, and blasts disappeared from the peripheral blood and bone marrow of four subjects (Aldoss 2014).

There is evidence that vitamin C requirements may be increased in leukemia patients. In a study of 28 children hospitalized with ALL and 30 healthy controls, it was found that although patients’ vitamin C intake was more than twice that of control subjects, their vitamin C plasma and urinary concentrations were dramatically reduced compared to controls (Neyestani 2007).

Curcumin

Curcumin, the main active ingredient in the spice turmeric (Curcuma longa), has anti-inflammatory and anticancer properties (Aggarwal 2003). Curcumin has been shown to inhibit metastasis, invasion, and angiogenesis in animal models and to induce cell death in leukemia cell lines (Kim 2008; Duvoix 2005; Duvoix 2003; Pae 2007). In CLL cells, curcumin induced apoptosis and inhibited proteins essential for survival in one cell culture study (Ghosh 2009).

Curcumin induces apoptosis via multiple mechanisms, which may make it difficult for cancer cells to develop resistance to it. Furthermore, curcumin selectively kills cancer cells while sparing normal cells (Ravindran 2009). Curcumin has several anticancer mechanisms:

  • It induces apoptosis of leukemia cells (Pae 2007; Ghosh 2009; Mukherjee Nee Chakraborty 2007; Hayun 2009; Rao 2011)
  • It modulates pathways required for cell survival (Pae 2007; Ghosh 2009)
  • It inhibits cell division and proliferation (Anand 2008)
  • It inhibits metastasis (Anand 2008)
  • It inhibits a pathway by which cancer cells acquire new blood supply (angiogenesis)

Curcumin has also shown promising results when tested in combination with chemotherapeutic agents. In a six-week clinical trial on 50 CML patients, treatment with turmeric powder along with imatinib led to greater reductions in nitric oxide levels compared to imatinib alone. Non-beneficial forms of nitric oxide are elevated in some leukemias, and its reduction as a result of combined therapy of imatinib and turmeric powder may help in the treatment of CML (Ghalaut 2012). The apoptotic action of arsenic trioxide increased greatly when combined with curcumin in human AML cells. Similar synergistic effects of curcumin are observed with lonidamine, a mitochondria-targeted anticancer drug (Sánchez 2010). Curcumin in combination with rapamycin (Rapamune) significantly induced apoptosis in cells obtained from patients with CLL (Hayun 2009). In leukemia cell lines, curcumin showed synergistic effects in combination with bendamustine (Treanda) and idarubicin (Idamycin) (Alaikov 2007). Also, sequential administration of curcumin following EGCG extract from green tea in CLL cells showed greater apoptotic activity than either did alone (Ghosh 2009).

Melatonin

Melatonin, a hormone produced by the pineal gland, regulates the circadian rhythm (sleep-wake cycle) (Haimov 1997). Melatonin has also demonstrated anti-aging, immunomodulatory, antioxidant, and anticancer properties (Di Bella 2013; El-Sokkary 2003). Several epidemiologic studies suggest that high levels of melatonin may help prevent cancer, possibly by activating the tumor-suppressor molecule p53 (Santoro 2012). Melatonin has been shown to augment the efficiency of some leukemia therapeutic regimens in laboratory and human studies (Granzotto 2001; Lissoni 2000). In one clinical trial, melatonin combined with interleukin-2 prolonged survival time in patients with blood-related malignancies (Lissoni 2000). In a small case series, four CLL patients who had not received any previous treatment underwent treatment with a combination of melatonin, retinoids, cyclophosphamide, somatostatin, bromocriptine (Cycloset, Parlodel), and adrenocorticotropic hormone and had long-lasting partial remission with no reported toxicity. After 10 years, these patients did not experience disease recurrence. Moreover, the patients were able to undergo the treatment at home, while maintaining their usual lifestyle and activities (Todisco 2009).

Resveratrol

Resveratrol is a plant-derived polyphenol (Borriello 2014) found in grape skin, various fruits, Japanese knotweed, and red wine (Chen 2013; Ahmad 2014; Estrov 2003). It has been shown to inhibit growth and induce cell death in several mouse and human leukemia cell lines without harming normal white blood cells (Dörrie 2001; Gautam 2000; Joe 2002; Surh 1999; Quoc Trung 2013). In a laboratory model, resveratrol reduced the viability and capability of leukemia cells to divide (Lee 2008). In an AML cell line, resveratrol blocked production of inflammatory molecules, inhibited proliferation, caused cell cycle arrest, and induced apoptosis (Estrov 2003).

Resveratrol has the ability to sensitize many types of cancer cells, including AML and promyelocytic leukemia cells, to a range of chemotherapeutic agents including vincristine, doxorubicin, cisplatin (Platinol), gefitinib (Iressa), 5-Fluorouracil, bortezomib (Velcade), and gemcitabine (Gemzar). Experimental studies indicate that resveratrol can help overcome the chemoresistance of malignant cells by modulating apoptotic pathways and down-regulating drug transporters and proteins involved in tumor cell proliferation (Gupta 2011). Some patients with CML develop resistance to imatinib treatment, and resveratrol has induced cell death in imantinib-resistant leukemia cell lines (Can 2012). Also, resveratrol induced cell growth arrest and apoptotis in doxorubicin-resistant AML cells (Kweon 2010).

Combining resveratrol with perifosine or bortezomib potentiated each drug’s ability to induce cell death in a laboratory study (Reis-Sobreiro 2009). In CLL cells, resveratrol plus fludarabine and resveratrol plus cladribine (Leustatin) caused a higher rate of apoptosis in comparison with the single drugs alone (Podhorecka 2011). Arsenic trioxide, a potent anticancer drug used in patients with APL, is severely toxic to the heart muscle. In a rodent model, resveratrol was able to protect the cardiovascular system and decrease oxidative damage and pathological alterations created by arsenic trioxide (Zhang 2013). These studies suggest resveratrol may be useful in combination with other chemotherapeutic drugs, especially in older patients for whom there are limitations on the use of some aggressive treatments.

Genistein

Isoflavones present in soy have been shown in animal models to have cancer-preventing activity. Genistein, an isoflavone found in large quantities in soy beans, has inhibited growth in leukemia cell lines (Raynal 2008; Zhang, Sun 2012) and caused apoptosis and arrest of cell cycle development in adult T-cell leukemia cells (Yamasaki 2010; Yamasaki 2013). Moreover, genistein enhanced the cytotoxic effects of chemotherapeutic agents including arsenic trioxide and bleomycin in several leukemia cell lines (Sánchez 2008; Lee 2004). In cancer, changes to DNA often inhibit the genes responsible for the suppression of tumor formation. Treating leukemia cells with genistein reactivates these tumor suppressor genes. In one study, leukemic mice fed a genistein-enriched diet lived significantly longer than expected. The authors pointed out that because the half-life of genistein is longer in humans than mice, a soy-enriched diet could yield plasma isoflavone concentrations that have produced anti-leukemia effects in laboratory studies (Raynal 2008).

Apigenin

Apigenin, a natural plant flavonoid found at high levels in celery, parsley, thyme, and several other herbs has demonstrated cancer chemopreventive activity in several experimental models (Gonzalez-Mejia 2010; Balasubramanian 2007). It inhibits cell proliferation in several types of cancer cells and reduces the number and size of skin tumors that develop in response to chemical carcinogen or ultraviolet B radiation exposure (Balasubramanian 2007). Apigenin is toxic to leukemia cells and induces apoptosis in several leukemia cell lines (Ruela-de-Sousa 2010; Budhraja 2012; Monasterio 2004; Jayasooriya 2012; Kilani-Jaziri 2012).

Quercetin

Quercetin is a naturally occurring phytochemical found in many fruits and vegetables as well as black tea and red wine. Numerous preclinical studies have found that quercetin possesses anti-leukemic activity through a number of mechanisms (Lee, Chen 2011; Kawahara 2009; Philchenkov 2010). In addition, cell culture studies have found that quercetin is capable of sensitizing CLL cells to several chemotherapeutic agents (Russo 2010; Spagnuolo 2012; Spagnuolo 2011; Russo 2013). Quercetin may have synergistic effects with other phytochemicals as well, as shown by one study in which quercetin in combination with resveratrol dose-dependently induced cell death in CLL cells (Gokbulut 2013). Several studies have shown that quercetin and quercetin derivatives inhibit several tyrosine kinases, an important anticancer mechanism (Huang 2009; Lee 2002; Huang 1999). Alone or in combination with chemotherapeutic drugs, quercetin might benefit patients with CLL and other forms of cancer (Spagnuolo 2012).

Astragalus

Astragalus membranaceus, a Chinese medicinal plant, contains bioactive flavonoids and polysaccharides with potential anti-leukemic activity through several mechanisms (Jia 2013; Huang 2012; Liu 2010; Yan 2009; Yin 2013). It has also been shown to restore the function of impaired T cells in cancer patients and activate the host’s anticancer immunity (Cho 2007a; Cho 2007b). In a clinical trial involving 44 children with acute leukemia in complete remission, 20 subjects received 90 g astragalus daily along with conventional chemotherapy and 24 subjects received chemotherapy alone for one month. The combination treatment improved the function of dendritic cells, which are important in the process of immune response, compared to chemotherapy alone (Dong 2005).

Panax Ginseng

Panax ginseng has been used in China for thousands of years for its anticancer properties (Helms 2004; Kang 2011). Experimental studies have used extracts of Panax ginseng to induce cell death in human leukemia cells (Lee 2000; Nguyen 2010). In another study, an extract of ginseng enhanced the ability of vitamin D to induce normal, healthy differentiation of leukemic cells (Kim 2009). Total saponins of Panax ginseng, one of the main effective components of ginseng, is capable of inducing differentiation in leukemia cells (Zuo 2009). Recently, protective effects of Panax ginseng were reported in children recovering from cancer treatment. The authors suggested a ginseng extract might stabilize the immune system and observed that the extract prevented the usual increase in inflammatory molecules (cytokines) in children who underwent chemotherapy or stem cell transplantation for cancer (Lee 2012).

Reishi

Reishi (Ganoderma lucidum) is a medicinal mushroom highly esteemed in traditional Chinese medicine. The dried powder of Reishi was used as an anticancer therapy in ancient China. Preclinical studies support its application for cancer prevention and treatment (Sliva 2003; Yuen 2005). Reishi extracts have been shown to induce cell death in various white blood cell cancers such as lymphoma, leukemia, and multiple myeloma (Müller 2006). In each of these cancer types, Reishi extracts have been shown to prevent new tumors from arising, and in many cases have shrunk existing tumors or pre-cancerous masses (Lu 2001; Lu 2002; Oka 2010; Joseph 2011).

Reishi extract was shown to enhance immune response in patients with advanced cancers in one study (Gao 2003). In a cell culture study, reishi extract inhibited the growth of leukemia cells (Wang 1997). In a rodent model, the beta-glucan fraction of reishi induced anti-tumor immunity (Ooi 2000). Aggressive chemotherapy often leads to bone marrow suppression and loss of immune function in leukemia patients. In a rodent model, reishi stimulated bone marrow recovery and increased production of both red and white blood cells (Zhu 2007). Reishi also exhibits anticancer properties by modulating the activity of immune cells including B lymphocytes, T lymphocytes, dendritic cells, macrophages, and natural killer cells (Xu 2011), as well as by enhancing both the number and function of several types of immune system cells (Jan 2011; Wang, Zhu 2012; Jeurink 2008). Furthermore, reishi promotes specialization of dendritic cells and macrophages, which are essential in allowing the body to react to new threats, vaccines, and cancer cells (Cao 2002; Lai 2010; Jan 2011; Ji 2011; Chan 2005).

Reishi has the apparent ability to enhance immune cell function in healthy cells. Although leukemias are characterized by prolific expansion of malignant immune cell populations, and reishi has been shown to promote the expansion of healthy immune cell populations, several preclinical studies have shown that reishi kills leukemic cells or promotes their differentiation (Fukuzawa 2008; Gao 2012; Hsieh 2013; Wang, Zhou 2012; Lee, Hung 2011; Hsu 2011).

Indole-3-Carbinol and Diindolylmethane

Indole-3-carbinol (I3C), a naturally occurring component of cruciferous vegetables such as broccoli, kale, cabbage, and cauliflower, is a promising chemopreventive and anticancer agent. I3C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and myeloid leukemia cells (Aggarwal 2005). Preclinical evidence has shown that I3C inhibits the viability of ATLL cells in a dose-dependent manner, meaning as the concentration of I3C increases, ATLL cell viability decreases (Machijima 2009). After treatment with I3C, signs of damage including DNA fragmentation and a decrease in cell cycle proteins were observed in leukemia cells. In leukemic mice, I3C showed beneficial effects such as increased T cells, reduction in weight of the liver and spleen, and increased activity of immune cells (macrophages) compared to the non-treated leukemic mice (Lu 2012). Another study in leukemia cells found that I3C suppressed the inflammatory molecule NF-ĸB as well as NF-ĸBrelated genes, which might be the anticancer mechanism of I3C (Takada 2005). Importantly, I3C did not exert any inhibitory effects on normal white blood cells. In fact, I3C has demonstrated a protective effect against chemically-induced carcinogenesis in animals (Machijima 2009). In addition, several rodent model studies have reported that I3C has liver-protective effects against multiple carcinogens (Aggarwal 2005).

Diindolylmethane (DIM) is an I3C-related compound also found in cruciferous vegetables. Studies have shown that it too possesses anti-leukemic properties. A two-part study found that DIM inhibited T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation in cell culture and also reduced growth of T-ALL cells implanted into mice when they consumed DIM in their diet (Shorey 2012). Another study found that a synthetic DIM derivative induced apoptosis and inhibited growth in cultured AML. The researchers concluded that “…these findings suggest that diindolylmethanes are a new class of compounds that selectively induce apoptosis in AML cells” (Contractor 2005).

DIM also effectively protected rodents from radiation injury, which is a leukemia risk factor. It appears to mediate this effect by aiding in DNA repair but has other properties as well, including inhibition of radiation-induced apoptosis (Connell 2013; Fan 2013). It is a powerful free-radical scavenger, and its derivatives have shown promising anti-tumor potential in cell culture studies (Benabadji 2004).

Sulforaphane

Sulforaphane, a natural isothiocyanate found in cruciferous vegetables, demonstrated anti-leukemic properties in preclinicalstudies using ALL cell lines and T and B lymphocytes from childhood ALL patients, induced apoptosis, and inhibited cell cycle survival pathways in several ALL cell lines. Sulforaphane has also resulted in reduction of cancer burden in mice with ALL (Suppipat 2012) and shown the potential to exert anticancer actions in multiple ways (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006; Choi 2008; Fimognari 2008):

  • detoxify cancer-causing compounds (carcinogens)
  • prevent the multiplication of cancer cells
  • promote cancer cell differentiation
  • enhance the activity of natural killer cells, a type of white blood cell charged with attacking tumors and virus-infected cells
  • combat metastasis (the spread of a tumor to different parts of the body)

In addition, sulforaphane has the ability to modulate the self-renewing properties of cancer stem cells (Kim, Farrar 2012). Sulforaphane resensitized leukemia stem cells when used in combination with imatinib (Lin 2012). Similarly, sulforaphane significantly enhanced the cytotoxic effect of arsenic trioxide and led to apoptosis in a panel of leukemic cell lines by inducing oxidative damage (Doudican 2010). Sulforaphane has been well tolerated in both animal and human trials (Zhang 2007; Lin 2012).

Garlic Extract

Epidemiologic studies, preclinical investigations, and clinical trials support the role of garlic extract as a potent anticancer agent (Yedjou 2012; Miron 2008). Ajoene, a natural sulfur-containing compound extracted from garlic, has anti-leukemia properties (Yedjou 2012; Dirsch 2002; Ahmed 2001; Hassan 2004). Apart from inhibiting proliferation and inducing apoptosis in several leukemia cell lines, ajoene was able to induce apoptosis in myeloblasts from CLL patients. Moreover, ajoene profoundly enhanced the cytotoxic effects of two chemotherapeutic drugs (cytarabine and fludarabine) in chemotherapy-resistant human myeloid leukemia cells (Hassan 2004; Ahmed 2001). Allicin, another compound derived from garlic, was shown to induce apoptosis in a leukemia cell line in one study (Miron 2008).

Olive Polyphenols

Epidemiologic evidence and animal studies suggest that olive oil may prevent the onset of cancer (Fabiani 2002; Escrich 2014; Fabiani 2006; Cardeno 2013). Virgin olive oil phenol extract prevented leukemia cells from multiplying by inducing apoptosis and differentiation in cell culture. It also prevented oxidative DNA damage, a hallmark of cancer, in leukemia cells (Casaburi 2013; Fabiani 2006; Fabiani 2008). Virgin olive oil contains the major antioxidant compound hydroxytyrosol, which exerted protective activity against cancer cells in a cell line study by arresting the cell cycle, thus stalling the multiplication of the cancer cells. No effect was observed after similar treatment of non-cancerous blood cells (Fabiani 2002).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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