Treatment to Achieve Remission:

The aim of induction therapy, the first treatment 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

Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatanib (Sprycel) may be added for patients with Philadelphia chromosome-positive ALL.

For children, the standard drugs are:

• Vincristine (Oncovin), a vinca alkaloid drug
• Prednisone or dexamethasone. These drugs are corticosteroids. Dexamethasone may be more effective than prednisone, but it increases the risk for infections and other serious side effects.
• Asparaginase. Generally provided as pegaspargase (Oncaspar) in place of L-asparaginase (Elspar) for treating newly diagnosed ALL in children. With pegaspargase, patients need only 3 injections over a 20-week period instead of the 21 injections required for L-asparaginase.

For adults, the standard drugs are:

• Vincristine
• Prednisone
• Anthracycline drug, such as such as doxorubicin, daunorubicin, or epirubicin. Some adult chemotherapy regimens also add on an asparaginase drug or cyclophosphamide (Cytoxan).

Preventing Central Nervous System Disease (CNS Prophylaxis)

The induction chemotherapy described above does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain. 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 50 - 70% of children who don't receive prophylactic preventive treatment. The brain is one of the first sites for relapsing leukemia.

For children, CNS prophylaxis uses intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. Intrathecal chemotherapy is given with methotrexate alone or a combination of methotrexate, cytarabine, and hydrocortisone.

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, may significantly reduce the risk for mental impairment. Cranial radiation is also associated with increased risks for stroke and secondary cancers.

Adult CNS prophylaxis is performed in one of three ways:

• Cranial radiation plus intrathecal chemotherapy with methotrexate
• High-dose systemic infusion of methotrexate plus intrathecal methotrexate without cranial radiation
• Intrathecal methotrexate chemotherapy alone

Evidence of Remission after Induction Treatment

Survival in acute leukemia depends on complete remission. Although not always clear-cut, remission is indicated by the following:

• All signs and symptoms of leukemia disappear.
• There are no abnormal cells in the blood, bone marrow, and cerebrospinal fluid.
• The percentage of blast cells in the bone marrow is less than 5%.
• Blood platelet count returns to normal.

Induction can produce extremely rapid results, and the shorter the time to remission the better the outlook:

• A complete remission usually occurs within the first 4 weeks. Patients who show low disease levels within 7 - 14 days have an excellent outlook, particularly if they have favorable genetic factors, and may need less-intensive treatments afterward.
• Patients with high disease levels at 14 days or who require more than 4 weeks to achieve remission are at higher risk for relapse and most likely need more aggressive treatment.

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen and radiation therapy are common, are more severe with higher doses, and increase over the course of treatment. Administering drugs for shorter duration can sometimes reduce toxicities without affecting the drugs' cancer-killing effects.

Common Side Effects. Typical side effects include:

• Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects.
• Diarrhea
• Hair loss
• Weight loss
• Depression

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 infection. The patient at high risk for infection may need very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells. Patients should make all efforts to minimize exposure to bacteria and viruses. (See “Preventing Infection” in the Home Management section of this report.)

Other serious side effects include:

• Liver and kidney damage
• Immediate and short-term risks of radiation therapy may include seizures, stroke, and paralysis
• Very high levels of uric acid in the blood, which can damage the kidneys
• Very high levels of calcium in the blood
• 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
• Suppression 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. Seizures can often be treated successfully with anti-epilepsy medications.
• Delayed puberty. The effects of treatment in the brain can affect regions that regulate reproductive hormones, which may affect fertility later on. Chemotherapy, cranial radiation, or both can impair fertility in male and female patients. Cranial radiation can also result in impaired growth.
• 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 and impaired insulin response. Chemotherapy-induced beta cell damage may persist after therapy has been stopped.
• Heart damage. Some of the treatments increase risk factors for future heart disease, including unhealthy cholesterol levels and high blood pressure. Anthracyclines (doxorubicin, daunorubicin, epirubicin) have been associated with later development of heart failure. Lower doses used for many ALL children may not pose a high risk to the heart. Patients treated for ALL should be regularly monitored for heart risks.
• Stroke. Survivors of childhood leukemia are at increased risk of later stroke, especially if they received treatment with cranial radiation.
• Obesity. Children treated for ALL are at higher risk for obesity, possibly because the treatments trigger an earlier than normal occurrence in childhood weight gain. Corticosteroid drugs used in treatments also increase appetite, which contributes to the problem.
• Central nervous system. Radiation and intrathecal MTX therapy may be associated with an increased risk of mood disturbances (such as depression) among adult survivors of childhood ALL. Cranial radiation and drugs used in chemotherapy, especially specific corticosteroids and spinal injection treatments, may also impair mental functioning and cause neurologic problems, such as movement problems.
• Secondary Cancers. Studies indicate that survivors of childhood ALL are at increased risk of later developing other types of cancers, including brain and spinal cord tumors, basal cell skin carcinoma, and myeloid (bone marrow) malignancies. Radiation and older types of chemotherapy are mainly responsible for this risk. Newer types of ALL treatment may be less likely to cause secondary cancers.