Treatment to Achieve Remission

The aim of induction therapy, the first phase, is to reduce the number of leukemia cells to undetectable levels. The general guidelines for induction therapy are as follows:

• Patients are given intensive chemotherapy that uses powerful multi-drug regimens. (Infants require special regimens not discussed here.)
• For both children and adults, some of these therapies are administered orally, others intravenously.
• Hospitalization is usually necessary at some point to help prevent infection and to administer blood products. However, much of this therapy can be given on an outpatient basis.
• After the first cycle of induction, bone marrow tests are done to determine if the patient is in remission.
• Another bone marrow test is sometimes done about a week later to confirm the first results.
• A bone marrow transplant is considered for patients who do not respond at all to induction treatment.

Drugs Used for Induction Chemotherapy

Drugs Used for Standard or Low-Risk Patients. A three-drug regimen is typically used for standard or low-risk patients. (A fourth drug, such as cyclophosphamide, may be added for adult patients.) Examples of drugs used in regimens for children include:

• Vincristine
• Corticosteroids (prednisone or dexamethasone) --a 2003 study reported better survival rates with dexamethasone compared to prednisone.
• Asparaginase -- several forms are available. Investigation on a potent form called E-coli asparaginase (Asparaginase medac) is promising for preventing relapse, particularly second relapses, but this drug is very toxic and increases the risk for blood clots.

When this regimen is used together with CNS prophylaxis, remission rates of greater than 95% have been achieved in children. In a 2001 study, researchers reported that the most effective regimen for many children uses dexamethasone after the first month with a longer duration for asparaginase (30 rather than the standard 20 weeks).

Drugs Used for High-Risk Children. A four or five-drug regimen is used for many high-risk children. An example of a four-drug regimen would be vincristine, prednisone/dexamethasone, plus asparaginase, and an anthracycline (such as doxorubicin, daunorubicin, or epirubicin).

Drugs Used for Specific High-Risk Adults. Adult patients have a poorer outlook than children do, and investigators and looking for more effective chemotherapy regimens. For example, cyclophosphamide-based regimens are used in adult patients with certain types of ALL. In a 2005 study, patients treated with an investigational regimen of cytabarine and high-dose mitoxantrone experienced a much higher rate of remission and survival than patients treated with the standard L-20 chemotherapy regimen of vincristine, prednisone, cyclophosphamide, and doxorubicin. Patients with the Philadelphia chromosome also benefited from the investigational treatment.

Preventing Central Nervous System Disease (CNS Prophylaxis)

CNS prophylaxis is critical for preventing disease that has spread to the brain, spine, and testes (called sanctuary disease sites). Although only 3% of children with ALL have evidence of leukemia in the central nervous system (CNS) at the time of diagnosis, leukemia will spread to this region in between 50 - 70% of children without preventive (prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.

CNS prophylaxis is usually:

• Administered together with induction therapy before moving to consolidation, the next standard treatment phase, particularly if there are any leukemic cells detected in the spinal fluid.
• Given through  intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. The drugs used are either methotrexate alone or a combination of methotrexate, hydrocortisone, and cytarabine. (Induction chemotherapy does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain.)
• In some cases, methotrexate, with or without other drugs, is given as systemic (widespread) therapy at the same time as intrathecal chemotherapy. The addition of this treatment is effective in preventing relapse in the central nervous system and can substitute for radiation to the skull.

Cranial Radiation Therapy. Some high-risk children also receive radiation to the skull (cranial irradiation), radiation to the spine, or both at the same time. This combination can be very toxic and can cause later learning problems. It is generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis. Later complications can include learning and neurologic problems. Using lower-dose units of radiation, however, is proving to be effective and to significantly reduce the risk for mental impairment. Cranial radiation is also associated with later risk factors for heart disease.

A 2003 study reported the long-term effects of cranial or craniospinal radiation therapy during initial treatment for ALL. Among patients who achieved at least 10 years of event-free survival, those who received radiation therapy had a significantly higher risk of a second neoplasm, a slightly elevated mortality rate, and higher unemployment rate than patients who did not receive radiation therapy.

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment. Toxicities can be reduced without loss of cancer-killing effects in some cases by administering the drugs for shorter duration.

Common Side Effects. Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, nearly all patients who took a combination of dexamethasone (a steroid) in combination with ondansetron within 24 hours of chemotherapy experienced either a significant or complete reduction in nausea and vomiting.
• Diarrhea
• Hair loss
• Weight loss
• Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days a month.

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used. Infection from suppression of the immune system or from severe drops in white blood cells is a common and serious side effect. Patients should make all efforts to prevent them. The patient at high risk for infection may require very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (e.g. lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells.

Other side effects include:

• Liver and kidney damage
• Abnormal blood clotting
• Allergic reaction
• Low blood sugar (hypoglycemia) -- a rare complication in young, thin children who are taking purine analogues such as mercaptopurine and thioguanine
• Shrinking of adrenal glands in children who take short-term, high-dose corticosteroids such as prednisolone

Long-Term Complications.

• Fatigue is very common after chemotherapy and can be significant and long-lasting.
• Combinations of intrathecal chemotherapy plus brain radiation in children can cause some serious complications, including seizures and problems in learning and concentration. Methotrexate is particularly toxic. (The effects of intrathecal chemotherapy alone on mental functioning, however, did not seem significant.) Seizures can often be treated successfully with anti-epilepsy medications.
• Late puberty. The effects of treatment in the brain can affect regions that regulate reproductive hormones, which may affect fertility later on.
• Bone loss can occur after chemotherapy, particularly with corticosteroids and after bone marrow transplantation. Drugs are available, particularly bisphosphonates, which may help reduce this risk.
• Pancreatic beta-cell damage. A 2004 study reported that children who have been off treatment for at least 1 year have a higher risk of impaired insulin response. This suggests that chemotherapy-induced beta cell damage persists after therapy has been stopped.
• Anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin) have been associated with later development of congestive heart failure. Of some encouragement, a 2000 study reported that low doses used for many ALL children may not pose a high risk to the heart. Some anthracyclines (e.g., DaunoXome, Myocet, Doxil) are now being delivered in tiny protective capsules that may reduce toxic effects.
• Mood disorders. According to a 2003 study, CNS radiation and MTX therapy were associated with an increased risk of mood disturbances (such as depression) among adult survivors of childhood ALL. This suggests that patients undergoing CNS radiation and MTX therapy may benefit from psychosocial support.
• Self worth issues. According to a 2004 study, adult survivors of childhood ALL have significantly lower global self-worth than their healthy siblings. Unemployed survivors who reported that their cancer treatments impaired their employability were particularly likely to demonstrate low self-worth.

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Review Date: 12/17/2005
Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital