Overview and Types

Leukemias are malignancies of the hematopoietic stem cells in the bone marrow. Although many varieties of leukemia exist, and can be distinguished by the affected cell type, four major categories are recognized. These are acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL).

About 30,000 new cases of leukemia are diagnosed in the United States each year. The acute leukemias have a rapid clinical onset and are nearly uniformly fatal within months without treatment. Chronic leukemias often have a subacute onset of symptoms with an average survival of 4 to 5 years after diagnosis for CML, and 8 to 12 years for CLL. Over time, chronic leukemias transform into a more aggressive disease with a terminal blast phase that resembles acute leukemia.

Acute Leukemias

ALL is a proliferation of lymphoid precursors, primarily of B-cell origin. AML is characterized by proliferations of myeloid precursors, called blasts. Untreated, acute leukemias are uniformly fatal.

ALL accounts for about 12% of leukemias in the United States, but represents 60% of leukemias in persons younger than 20 years. With intensive chemotherapy regimens, about 80% of children and 40% of adults with ALL will be cured.

In contrast, AML is particularly common in older adults, with a median age at diagnosis of 68. Intensive chemotherapy, including stem cell transplants in selected patients, results in about a 50% long-term, disease-free survival.

Chronic Leukemias

Chronic leukemias more commonly affect older patients. They are, in general, more indolent than acute leukemias. However, many cases ultimately lead to a terminal phase that resembles acute leukemia.

CLL is a malignancy of mature B cells. It is the most common adult leukemia, with more than 80% of cases occurring in patients over the age of 60. Worldwide incidence is highly variable; North America has the highest rate, while CLL is rare in Southeast Asia.

CML is characterized by uncontrolled production of neutrophils, eosinophils, and basophils. It accounts for only 5% of childhood leukemia and has a peak incidence around age 53. CML is identified by a typical translocation, called the Philadelphia chromosome, which results in a fusion protein (BCR-ABL) that releases controls on stem cell proliferation and blocks apoptosis.

Clinical symptoms of chronic leukemia are generally nonspecific and often occur due to proliferation of the affected cell line or to decreased production of other blood cells. Common presentations include anemia (pallor, fatigue, palpitations), thrombocytopenia (epistaxis, menorrhagia, bleeding, bruising), and leukopenia (fever, frequent infections). Weight loss, lymphadenopathy, splenomegaly, gingival hypertrophy, and bone pain may also occur. Many patients with chronic leukemia remain asymptomatic, with discovery of the disease occurring during routine blood tests.

Risk Factors

Age. ALL occurs mostly in children, with a peak age range of 3 to 5 years. AML incidence increases with age, peaking at about age 60. CLL and CML are also both diseases of adults, with onset most common in patients older than 50.

Gender. ALL, AML, and CLL are more common in males.

Race/Ethnicity. AML is more common in Caucasian populations, and CLL is more common in Eastern European Jews.

Viral exposure. Exposure to human T-cell lymphoma/leukemia virus (HTLV-1) and Epstein-Barr virus may increase the risk of some ALL subtypes.

Radiation exposure has been associated with ALL. Ionizing radiation is associated with increased risk for AML, and exposure to ionizing radiation is the only known risk factor for CML.

Tobacco. For AML, tobacco use is a strong risk factor, accounting for about 1 in 5 cases.

Chemicals. Exposure to benzene, petroleum products, and pesticides is associated with increased risk for AML. Prior chemotherapy is also a risk factor and accounts for up to 10% of AML cases. Some studies suggest that herbicides (including Agent Orange) and insecticides may increase risk for CLL.

Family history. For CLL, risk is increased in first-degree relatives of affected patients.

Down syndrome. Children with Down syndrome are at increased risk for both AML and ALL.

Diagnosis and Treatment

Diagnosis

Complete blood count with white blood cell (WBC) differential can give a presumptive diagnosis. For acute leukemias, the WBC count is usually >15,000 (and may exceed 100,000), with blast cells usually evident. However, a significant minority of patients will present with a decreased WBC count. Anemia and thrombocytopenia are usually present. Auer rods, azurophilic, rod-shaped inclusions in the cytoplasm of blasts, are almost diagnostic for AML.

The classic diagnosis for CLL requires an absolute lymphocyte count higher than 5,000 without another known cause for the lymphocytosis. Anemia or thrombocytopenia at presentation is correlated with a more aggressive clinical course.

In CML, the peripheral blood shows an increased WBC count with a significant left shift that includes cells usually seen only in the bone marrow. An increased number of basophils is almost always seen and can substantially predate an increase in WBCs. Thrombocytosis occurs in at least half of cases at presentation.

Bone marrow biopsy is often necessary for definitive diagnosis and staging. For CLL and CML, flow cytometry on peripheral blood can be diagnostic. For CML, polymerase chain reaction (PCR) on peripheral blood can demonstrate the presence of the Philadelphia chromosome.

Upon diagnosis, the following tests are typically indicated:

• Laboratory testing, which includes electrolytes, magnesium, phosphorous, renal function tests (blood urea nitrogen, creatinine), liver function tests (transaminases, alkaline phosphatase, bilirubin, lactate dehydrogenase), and coagulation studies (prothrombin time, partial thromboplastin time).
• Chest x-ray.
• HLA typing of the patient and siblings in potential transplant patients.
• Herpes simplex and cytomegalovirus serology.

Treatment

Acute leukemias are treated with chemotherapy, the goal being complete remission and cure of the disease. Stem cell transplantation is an option for some patients.

In CML, imatinib, a tyrosine kinase inhibitor, is currently the treatment of choice at diagnosis. Allogeneic stem cell transplant is appropriate (except in elderly patients) when imatinib cannot sustain a complete remission. Standard chemotherapy is currently used only in palliative efforts after progression.
 
Many patients with CLL can be observed without immediate treatment (up to one-third never require treatment). When initiated, treatment consists of chemotherapy and/or monoclonal antibody therapy. Allogeneic bone marrow transplantation is a potentially curative treatment for CLL in younger patients, but is not yet considered standard therapy. Radiation therapy may be indicated for palliation in patients with large, bulky masses that cause compression symptoms.

Nutritional Considerations

The body of scientific literature addressing the role of diet in leukemia risk is considerably smaller than for solid tumors. Epidemiologic evidence suggests that the following factors are associated with reduced risk, although all require further study.

Reducing or Eliminating Meat Consumption

The risk for leukemia attributable to meat, particularly processed meat, may be related to the intake of nitrates used as preservatives; these become highly carcinogenic N-nitroso compounds. Evidence indicates that children eating more than 12 hot dogs per month have 9 times the normal risk of developing childhood leukemia, and that a strong risk for childhood leukemia also exists for those children whose fathers eat 12 or more hot dogs per month.¹ A higher-than-average meat intake was also found in a study of over 13,000 male Iowa farmers who experienced a 25% greater risk for leukemia, compared with individuals who were not farmers and consumed less meat.²

High Vegetable and Fruit Intake

The risk for leukemia in adult women is inversely associated with vegetable intake,³ and increased maternal intake of fruits and vegetables is associated with reduced risk of childhood ALL.^4,5 Regular intake of oranges, orange juice, and bananas is also associated with roughly a 50% reduction in leukemia risk among children 2 to 14 years old.⁶

Breast-feeding

Short-term (< 6 months) and longer-term (> 6 months) breast-feeding is associated with reduced risk for childhood leukemias by 15% to 24%.⁷

Healthy Body Weight

Women who are overweight or obese have a 61% to 90% greater risk for leukemia than women of normal weight.^8,9 The obesity-leukemia relationship may be due to excess energy intake.^2,10 Among the hypothesized mechanisms are genetic polymorphisms in enzymes that reduce the oxidative stress brought on by excess calorie intake.¹¹ Avoidance of obesity may be especially important for pregnant women, because excess maternal weight gain is a known risk factor for macrosomia, a condition associated with a greater risk for infant leukemia.¹² Being overweight or underweight also reduces survival in children with acute myelocytic leukemia.¹³

Avoiding Alcohol

Maternal alcohol intake during pregnancy raises the risk of both ALL and AML in children.^{14, 15}

Orders

See Basic Diet Orders chapter.

What to Tell the Family

Leukemias make up a family of blood cancers that have highly variable courses and treatment. Acute leukemias are rapidly fatal without treatment, but may be curable with aggressive treatment. Chronic leukemias can be slow growing; CLL may not need initial treatment, and CML can usually be controlled with oral therapy for years. Bone marrow transplantation is often considered for patients less than 55 years of age.

Available evidence suggests a role for diet in preventing several types of leukemia.

References

1. Peters JM, Preston-Martin S, London SJ, Bowman JD, Buckley JD, Thomas DC. Processed meats and risk of childhood leukemia (California, USA). Cancer Causes Control. 1994;5:195-202.

2. Cerhan JR, Cantor KP, Williamson K, Lynch CF, Torner JC, Burmeister LF. Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States). Cancer Causes Control. 1998;9:311-319.

3. Ross JA, Kasum CM, Davies SM, Jacobs DR, Folsom AR, Potter JD. Diet and risk of leukemia in the Iowa Women's Health Study. Cancer Epidemiol Biomarkers Prev. 2002;11:777-781.

4. Petridou E, Ntouvelis E, Dessypris N, et al. Maternal diet and acute lymphoblastic leukemia in young children. Cancer Epidemiol Biomarkers Prev. 2005;14:1935-1939.

5. Jensen CD, Block G, Buffler P, Ma X, Selvin S, Month S. Maternal dietary risk factors in childhood acute lymphoblastic leukemia (United States). Cancer Causes Control. 2004;15:559-570.

6. Kwan ML, Block G, Selvin S, Month S, Buffler PA. Food consumption by children and the risk of childhood acute leukemia. Am J Epidemiol. 2004;160:1098-1107.

7. Kwan ML, Buffler PA, Abrams B, Kiley VA. Breast-feeding and the risk of childhood leukemia: a meta-analysis. Public Health Rep. 2004;119:521-535.

8. Pan SY, Johnson KC, Ugnat AM, Wen SW, Mao Y, and the Canadian Cancer Registries Epidemiology Research Group. Association of obesity and cancer risk in Canada. Am J Epidemiol. 2004;159:259-268.

9. Ross JA, Parker E, Blair CK, Cerhan JR, Folsom AR. Body mass index and risk of leukemia in older women. Cancer Epidemiol Biomarkers Prev. 2004;13:1810-1813.

10. Hursting SD, Margolin BH, Switzer BR. Diet and human leukemia: an analysis of international data. Prev Med. 1993;22:409-422.

11. Smith MT, Wang Y, Kane E, et al. Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood. 2001;97:1422-1426.

12. Hjalgrim LL, Westergaard T, Rostgaard K, et al. Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies. Am J Epidemiol. 2003;158:724-735.

13. Lange BJ, Gerbing RB, Feusner J, et al. Mortality in overweight and underweight children with acute myeloid leukemia. JAMA. 2005;293:203-211.

14. Shu XO, Ross JA, Pendergrass TW, Reaman GH, Lampkin B, Robison LL. Parental alcohol consumption, cigarette smoking, and risk of infant leukemia: a Children's Cancer Group study. J Natl Cancer Inst. 1996;88:24-31.

15. van Duijn CM, van Steensel-Moll HA, Coebergh JW, van Zanen GE. Risk factors for childhood acute non-lymphocytic leukemia: an association with maternal alcohol consumption during pregnancy? Cancer Epidemiol Biomarkers Prev. 1994;3:457-460.