Leukemia is the most common cancer in children less younger than age 15. Eighty percent of children and teens diagnosed with leukemia have acute lymphoblastic leukemia (also called acute lymphocytic leukemia or ALL). Approximately 2,900 children and teens in the United States are diagnosed with ALL each year, and today approximately 90 percent of children younger than age 15 survive the disease. ²

Childhood ALL is most commonly diagnosed in children ages 2 and 3. In the United States, ALL is more common in Hispanic children than in other racial and ethnic groups, and boys have a slightly higher incidence than girls.

Description

ALL is a cancer that begins in the blood-forming tissues of the bone marrow—the spongy center of the bones that produces blood cells. In ALL, the bone marrow creates too many immature lymphocytes (a type of white blood cell) that cannot perform their normal function of fighting infection. As the bone marrow floods the bloodstream with these white blood cells, production of healthy white cells, red cells (which carry oxygen), and platelets (which form clots to stop bleeding) slows and stops. The blood carries the leukemic cells to organs such as the lungs, liver, spleen, kidneys, and testes. Leukemic cells can also cross the blood-brain barrier and invade the central nervous system (CNS)—made up of the brain and spinal cord.

Treatment

Treatment of childhood ALL is one of the major medical success stories of the last 3 decades. In the early 1960s, children with ALL usually lived for only a few months, but by 2010, about 90 percent of children younger than age 15 who receive optimal treatment survive. The appropriate treatment for each child with ALL is determined by an analysis of a multitude of clinical, biologic, and clinical features. Most childhood cancer treatment centers describe a child’s risk of relapse using the terms “standard risk,” “high risk,” or “very high risk,” and children with high-risk or very high-risk disease receive the most intensive therapy.

To determine the risk level, the following prognostic factors are considered:

• Initial white blood cell count

• Age at diagnosis

• Presence of CNS leukemia or testicular leukemia at diagnosis

• Presence or absence of chromosomal changes in the leukemic cells

• Response to treatment

Chemotherapy

The most common treatments for ALL are chemotherapy and CNS prophylaxis (i.e., chemotherapy and/or radiation to the CNS to prevent the spread of cancer to the brain). For standard-risk patients, treatment is typically divided into three phases: induction, consolidation/intensification, and maintenance.

Induction is the most intensive phase of treatment because its purpose is to kill as many leukemia cells in the shortest amount of time possible. The majority of ALL induction programs include the following chemotherapy drugs: methotrexate, cytarabine (ARA-C), vincristine (Oncovin ^® ), prednisone and/or dexamethasone (Decadron ^® ), cyclophosphamide (Cytoxan ^® ), asparaginase, and sometimes daunorubicin (Cerubidine ^® ) or doxorubicin (Adriamycin ^® ).

CNS treatment is an essential component of treatment for ALL. Because leukemia cells can hide in the brain and spinal cord, the CNS was a frequent site for relapse prior to the use of cranial radiation, high-dose systemic chemotherapy, or chemotherapy injected directly into the cerebrospinal fluid (called intrathecal or IT). Standard-risk patients usually receive several doses of intrathecal methotrexate or triple IT therapy—methotrexate, hydrocortisone, and ARA-C—to prevent the spread of leukemia to the CNS.

Consolidation/intensification is begun after remission is achieved to destroy any remaining cancer cells. A combination of some of the following drugs is used: methotrexate, cyclophosphamide, cytarabine, mercaptopurine (6-MP, Purinethol ^® ), asparaginase, prednisone, dexamethasone, vincristine, thioguanine, etoposide, and doxorubicin. A delayed intensification phase is administered prior to maintenance in current protocols.

Maintenance therapy consists of daily low-dose chemotherapy and continues for 2 to 3 years. The backbone of maintenance therapy in most protocols is daily mercaptopurine and weekly methotrexate. In addition, monthly doses of vincristine and prednisone (or dexamethasone) may be given. ALL protocols also include intrathecal methotrexate during maintenance.

Radiation

For very high-risk patients, cranial radiation is sometimes needed to prevent the spread of leukemia to the CNS. Children who have leukemia in the cerebrospinal fluid at diagnosis require cranial and spinal radiation. Infants who are in the high-risk group are not given radiation to the brain, or it is delayed until they are older. Boys with disease in their testes are treated with testicular radiation.

Late effects

Children with standard-risk ALL often have few or no long-term effects. Children with high-risk ALL, or those who have relapsed and require more intensive treatment, sometimes pay a higher price. The following information briefly outlines some common and uncommon late effects from treatment. Remember that you may develop none, a few, or several of these problems in the months or years after treatment ends. Your individual risk depends on a number of different factors.

Learning disabilities. Treatment for childhood ALL may result in learning disabilities. Radiation and/or methotrexate can damage children’s central nervous systems. The degree of damage depends on the dose of radiation, the child’s age, and the child’s sex, with younger female children more at risk than older children or teens. These cognitive difficulties can develop years after treatment ends. Typically, areas of difficulty are mathematics, memory, organization, planning, spatial relationships, problem solving, attention span, concentration skills, and social skills. For more information, see Chapter 8 .

Growth. Radiation can affect growth. Children who receive 2400 centigray (cGy) or more of cranial radiation or spinal radiation often fail to grow to their potential height. Some children (most often girls) who receive 1800 cGy or more at an early age may also have shortened stature as adults. Radiation can cause early, delayed, or accelerated puberty. For more information, see Chapter 9 .

Female fertility. Female fertility usually is not affected by treatment for leukemia unless a girl had spinal radiation that included the ovaries or had very high doses (more than 7.5 grams/m ² ) of cyclophosphamide. In the vast majority of cases, girls treated for leukemia exhibit normal sexual development and fertility. The chances of having a normal pregnancy and birth are the same as in the general population. For more information about growth, sexual development, and fertility, see Chapter 9 , and Chapter 3 .

Male fertility. Cyclophosphamide causes a rapid decrease in sperm count in males who have entered puberty. Normal sperm production and motility generally return during maintenance or after treatment. Boys who go through puberty after leukemia treatment usually experience a normal puberty. However, boys who received very high doses of cyclophosphamide (more than 7.5 grams/m ² ) and/or radiation to the testes should have testosterone levels and sperm count checked. Most males treated for leukemia with chemotherapy alone have normal growth, sexual development, and fertility. For more information about growth, sexual development, and fertility, see Chapter 9 , and Chapter 3 .

Heart problems. Heart problems can occur months or years after treatment with anthracyclines (i.e., doxorubicin, idarubicin, or daunorubicin) or mitoxantrone. Symptoms include shortness of breath, fatigue, wheezing, anxiety, poor exercise tolerance, rapid heartbeat, and irregular heartbeat. The number of leukemia survivors who develop this late effect is small, but regular checkups are crucial. Survivors often have no symptoms, but problems may be found on cardiac tests such as echocardiograms, electrocardiograms (EKGs), and Holter monitors. For more information, see Chapter 12 .

Hepatitis C. Infection with the hepatitis C virus can develop in survivors who had blood transfusions prior to July 1992. For more information, see Chapter 15 .

Fatigue. After treatment for leukemia, most children resume normal activities at age-appropriate levels, but some children have persistent weakness and/or fatigue. This late effect usually only occurs in survivors who received cranial radiation. For more information, see Chapter 7 .

Obesity. A small number of survivors of ALL become overweight during or after treatment. An association has been noted between learning disabilities and obesity in ALL survivors—both effects are probably related to the effects of radiation on the brain. Some ALL survivors develop osteopenia or osteoporosis (low bone density). For more information, see Chapter 17 .

Dental problems. Dental abnormalities, such as failure of the teeth to develop, arrested root development, unusually small teeth, increased periodontal disease, and enamel abnormalities may occur after chemotherapy or radiation. For more information, see Chapter 11 .

Less common problems. Less common late effects include osteonecrosis (death of blood vessels that nourish bones) from high-dose steroids, especially dexamethasone; bladder problems (i.e., hemorrhagic cystitis and bladder fibrosis) from cyclophosphamide; hypothyroidism (from cranial radiation); cataracts (from cranial radiation); and secondary cancers (from cranial radiation). Information about the late effects from stem cell transplants (including bone marrow transplants) is found at the end of this chapter.