Treatment of children with acute lymphocytic leukemia

The main treatment for children with acute lymphocytic leukemia (ALL) is chemotherapy, which is usually divided into 3 phases:

• Induction
• Consolidation (also called intensification)
• Maintenance

When leukemia is diagnosed, there are usually about 100 billion leukemia cells in the body. Killing 99.9% of these leukemia cells during the 1-month induction treatment is enough to achieve a remission, but it still leaves about 100 million leukemia cells in the body. These also must be destroyed. An intensive 1- to 2-month program of consolidation treatment and about 2 years of maintenance chemotherapy helps destroy the remaining cancer cells.

As mentioned earlier, children with ALL are typically divided into standard-risk, high-risk, or very high-risk groups to make sure that the correct types and doses of drugs are given. Treatment may be more or less intensive, depending on the risk group.

Induction

The goal of induction chemotherapy is to achieve a remission. This means that leukemia cells are no longer found in bone marrow samples, the normal marrow cells return, and the blood counts become normal. (A remission is not necessarily a cure.)

More than 95% of children with ALL enter remission after 1 month of treatment. This first month of treatment is quite intensive and requires frequent visits to the doctor. Your child may spend some or much of this time in the hospital, because serious infections or other complications can occur. It is very important to take all medicines prescribed. Sometimes complications can be serious enough to be life-threatening, but with advances in supportive care (nursing care, nutrition, antibiotics, red blood cell and platelet transfusions as needed, etc.) in recent years, these are much less common than in the past.

Children with standard-risk ALL often receive 3 drugs for the first month of treatment. These include the chemotherapy drugs L-asparaginase and vincristine, and a steroid (usually dexamethasone). A fourth drug in the anthracycline class (daunorubicin is the one most often used) is typically added for high-risk children. Other drugs that may be given early are methotrexate and/or 6-mercaptopurine.

Intrathecal chemotherapy: All children also need to get chemotherapy into the cerebrospinal fluid (CSF) to kill any leukemia cells that may have spread to the brain and spinal cord. This treatment, known as intrathecal chemotherapy, is given through a lumbar puncture (spinal tap). It is usually given twice (more often if the leukemia is high risk) during the first month and 4 to 6 times during the next 1 or 2 months. It is then repeated less often during the rest of consolidation and maintenance. Usually, methotrexate is used for intrathecal chemotherapy. Hydrocortisone (a steroid) and cytarabine (ara-C) may be added, particularly in high-risk children.

Along with intrathecal therapy, some high-risk patients (for example, those with T-cell ALL) and those with high numbers of leukemia cells detected in their CSF when the leukemia is diagnosed may be given radiation therapy to the brain. This was more common in the past, but recent studies have found that many children even with high-risk ALL may not need radiation therapy if they are given more intensive chemotherapy. Doctors try to avoid giving radiation to the brain if possible, especially in younger children, because no matter how low the dose is kept, it can cause problems with thinking and growth and development.

A possible side effect of intrathecal chemotherapy is seizures during treatment, which happen in a small portion of children. Children who develop seizures are treated with drugs to prevent them.

Consolidation (intensification)

The next, and usually more intense, consolidation phase of chemotherapy typically lasts about 1 to 2 months. This phase reduces the number of leukemia cells still in the body. Several chemo drugs are combined to help prevent the remaining leukemia cells from developing resistance. Intrathecal therapy (as described above) is continued at this time.

Children with standard-risk ALL are usually treated with drugs such as methotrexate and 6-mercaptopurine or 6-thioguanine, but regimens may differ among cancer centers. Vincristine, L-asparaginase, and/or prednisone may also be added.

Children with high-risk leukemia generally receive a more intense regimen of chemotherapy. Extra drugs such as L-asparaginase, doxorubicin (Adriamycin), etoposide, cyclophosphamide, and cytarabine (ara-C) are often used, and dexamethasone is substituted for prednisone. There may be a second round of intense chemotherapy with the same drugs.

Some children, such as those with Philadelphia chromosome-positive ALL, may benefit from the addition of a targeted drug such as imatinib (Gleevec) or from a stem cell transplant at this time.

Maintenance

If the leukemia remains in remission after induction and consolidation, maintenance therapy can begin. Most treatment plans use methotrexate and 6-mercaptopurine, given as pills, often along with vincristine, which is given intravenously, and a steroid (prednisone or dexamethasone). These latter 2 drugs are given for brief periods every 4 to 8 weeks. Other drugs may be added depending on the type of ALL and the risk of recurrence.

During the first few months of maintenance, most treatments include 1 or 2 repeat intensified treatments similar to the initial induction. These 4-week intensifications are called re-induction or delayed intensification.

Some leukemia patients at higher risk may receive more intensive maintenance chemotherapy and intrathecal therapy.

The total duration of therapy (induction, consolidation, and maintenance) for most ALL treatment plans is 2 to 3 years. Because boys are at higher risk for relapse than girls, many doctors favor giving them several more months of treatment.

Treatment of residual disease

These treatment plans may change if the leukemia doesn't go into remission during induction or consolidation. The doctor will probably check the child's bone marrow soon after treatment starts to see if the leukemia is going away. If not, treatment may be intensified or prolonged. If the leukemia seems to have gone away by standard lab tests, the doctor may do more sensitive tests to look for small numbers of leukemia cells that may remain. If any are found, then chemotherapy again may be intensified or prolonged.

Treatment of recurrent ALL

If the ALL recurs (comes back) at some point during or after treatment, the child will most likely be treated again with chemotherapy. Much of the treatment strategy depends on how soon the leukemia returns after the first treatment. If the relapse occurs after a long time interval, the same drugs may still be effective, so the same or similar treatment may be used to try to get a second remission. If the time interval is shorter, more aggressive chemotherapy with other drugs may be needed.

The most commonly used chemo drugs are vincristine, L-asparaginase, anthracyclines (doxorubicin, daunorubicin, mitoxantrone), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). The child will also receive a steroid (prednisone or dexamethasone). Intrathecal chemotherapy will also be given.

For children whose leukemia comes back within 6 months of starting treatment or for children with T-cell ALL who relapse, a stem cell transplant may be considered, especially if there is a brother or sister who is a good tissue type match. Stem cell transplants may also be used for other children who relapse after a second course of chemotherapy.

Some children have an extramedullary relapse, meaning that leukemia cells are found in one part of the body (such as the spinal fluid or the testicles) but are not detectable in the bone marrow. In addition to intensive chemotherapy as described above, children with spread to the spinal fluid may get more intense intrathecal chemotherapy, sometimes with radiation to the brain and spinal cord (if that area had not been already treated with radiation). Boys with relapse in a testicle may get radiation to the area, and in some cases may have the affected testicle removed by surgery.

Philadelphia chromosome-type ALL

For children with certain types of ALL, such as those with the Philadelphia chromosome or other high-risk genetic changes, standard chemotherapy for ALL (as outlined above) may not be as effective. A stem cell transplant may be advised if induction treatment yields a remission and a suitable stem cell donor is available.

Newer, targeted drugs such as imatinib (Gleevec) and dasatinib (Sprycel) are designed to kill leukemia cells that contain the Philadelphia chromosome. These drugs are taken as pills and seem to have limited side effects. Studies are now looking at whether adding these drugs to chemotherapy can help improve outcomes. Early study results have been promising so far.