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Acute lymphocytic leukemia
Highlights
Acute Lymphocytic Leukemia (ALL)
There are four major types of leukemia. ALL is the most common type of leukemia diagnosed in children, and the least common type diagnosed in adults. About 5,200 people are diagnosed with ALL each year. Children account for two-thirds of these cases. In general, children with ALL have a better prognosis than adults. Most children with ALL can be cured of this cancer.
Symptoms and Diagnosis
Symptoms of ALL include fatigue, pale skin, recurrent infections, bone pain, bruising, and small red spots under the skin. Doctors use various tests, including blood counts and bone marrow biopsies, to diagnose ALL.
Treatment
ALL is treated with chemotherapy and, sometimes, radiation. Children receive different types of chemotherapy regimens than adults. Patients with advanced cancer that has not responded to these treatments may need a stem cell transplant.
Infection Prevention
Both chemotherapy and transplantation increase the risk for infection. Patients must take serious precautions to avoid exposure to germs. Ways to prevent infection include:
- Practice good hygiene including regular handwashing and dental care (brushing, flossing)
- Avoid crowds, especially during cold and flu season
- Eat only well-cooked foods (no raw fruits or vegetables)
- Boil tap water before drinking it
- Do not keep fresh flowers or plants in your house as they may carry mold
- Make sure you are up to date with vaccinations. Children may need to be reimmunized
Introduction
The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the blood-forming cells of the bone marrow.
White blood cells (leukocytes) evolve from immature cells referred to as blasts. Malignancy of these blast cells is the source of leukemias, which generally progresses as follows:
- Normally, blasts constitute 5% or less of healthy bone marrow. In leukemia, however, these blasts remain immature and multiply continuously, eventually constituting between 30 - 100% of the bone marrow.
- Eventually these malignant blast cells fill up the bone marrow and prevent production of healthy red cells, platelets, and mature white cells (leukocytes).
They spill out of the marrow into the bloodstream and lymph system and can travel to the brain and spinal cord (the central nervous system). As the number of normal cells decline, dangerous symptoms develop, which, if untreated, become lethal.
Leukemias are divided into two major types:
- Acute (which progresses quickly with many immature white cells)
- Chronic (which progresses more slowly and has more mature white cells)
Some blasts are called lymphoblasts (which become mature cells called lymphocytes) and others are called myeloblasts (which mature to myeloid cells). Acute leukemias are in turn subdivided into two classifications according to whether the malignant blasts are lymphocytes or myeloid:
- Acute lymphocytic leukemia (ALL), which is the subject of this report
- Acute myeloid leukemia (AML), which is not covered in this report
Acute Lymphocytic Leukemia
Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. The majority of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in T-cell or B-cell lymphocytes.
- T cell ALL is diagnosed in 15% of children and adults with ALL.
- About 85% of ALL cases are of the B-cell lymphocyte lineage (often referred to as "early" or "pre" B-cell lineage).
Blood Cell Lines and the Lymph System
Blood Cell Lines
In adults, blood cells are produced by the bone marrow, the spongy material filling the body's bones. The bone marrow produces two blood cell groups, myeloid and lymphoid.
Myeloid Cell Line. The myeloid cell line includes the following:
- Immature cells called erythrocytes that later develop into red blood cells
- Blood clotting cells (platelets)
- Some white blood cells, including macrophages (which act as scavengers for bacteria and other foreign particles), eosinophils (which trigger allergies and also react to parasites), and neutrophils (the main defenders against bacterial infections)
Lymphoid Cell Line. The lymphoid cell line includes the lymphocytes, which are the body's primary infection fighters. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign substances (antigens).
Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
Lymphocytes and the Lymph System
Understanding how acute lymphocytic leukemia (ALL) arises requires knowledge of lymphocytic development and function:
- B cells develop and mature in their final form (known as differentiation) in the bone marrow.
- T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone. This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
- Lymphatic vessels begin as tiny tubes and lead to larger lymphatic ducts and branches. They drain into two ducts in the neck, where the fluid re-enters the bloodstream.
- Along the way, the fluid passes through lymph nodes, which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or are added to the contents of the node.
- Both leukemia and lymphomas (Hodgkin’s disease and non-Hodgkin’s lymphomas) are cancers of lymphocytes. The difference is that leukemia starts in the bone marrow while lymphomas originate in lymph nodes and then spread to the bone marrow or other organs.
Causes
The causes of the disease are not known, but researchers believe that ALL develops from a combination of genetic, biologic, and environmental factors.
Genetic Translocations
Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be shuffled or swapped between a pair of chromosomes.
- The most common genetic translocation in ALL is the Philadelphia (Ph) chromosome where DNA is swapped between chromosomes 9 and 22 [t(9:22)]. It occurs in about 20 - 30% of adults and 3 - 5% of children with ALL.
- Another common translocation in ALL is t(12;21), which is referred to as TEL-AML1 fusion. It occurs in about 20% of patients with ALL. Researchers believe that this translocation may occur during fetal development in some patients.
Risk Factors
Age
ALL in Children. ALL is the most common type of cancer diagnosed in children. ALL accounts for about 75% of cases of childhood leukemia. Each year, about 3,600 American children and adolescents are diagnosed with ALL. ALL can strike children of all ages, but is most likely to occur when children are 2 - 4 years of age. It is slightly more common in boys than in girls.
ALL in Adults. ALL is the least common type of leukemia among adults. About 1 in 3 cases of ALL occur in adults.
Race and Ethnicity
Caucasian and Hispanic children have a higher risk for ALL than African-American children.
Hereditary Disorders
ALL does not appear to run in families. But certain inherited genetic disorders may increase risk. For example, children with Down syndrome have a 20-times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Klinefelter syndrome, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.
Radiation and Chemical Exposure
Previous cancer treatment with high doses of radiation or chemotherapy can increase the risk for developing ALL. Prenatal exposure to x-rays may also increase risk in children. Lower levels of radiation (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.
Symptoms
The symptoms of ALL may be difficult to recognize. ALL usually begins abruptly and intensely, but in some cases symptoms may develop slowly. They may be present one day, and absent the next, particularly in children. Symptoms develop when:
- There are not enough healthy mature white blood cells (leukocytes) to mount a defense against infection.
- There are not enough healthy platelets to prevent bleeding.
- The depleted oxygen-bearing red blood cells can't provide enough oxygen to organs.
Symptoms include:
- Fatigue
- Paleness -- patients may have poor coloring from anemia caused by insufficient red blood cells
- Recurrent minor infections
- Fever without known cause
- Bone pain
- Abdominal swelling
- Bruising -- may result from only slight injury
- Poor healing of minor cuts
- Uncontrolled bleeding -- bleeding events increase as the bone marrow fails to produce enough platelets to make a normal blood clot, a condition called thrombocytopenia.
- Small, red spots on the skin (petechiae)
- Vision changes (rare)
Diagnosis
ALL is diagnosed based on various tests.
Physical Examination
The doctor will examine a patient for signs of enlarged lymph nodes or enlarged liver or spleen. The doctor will also look for any signs of bruising or bleeding.
Blood Tests
A complete blood cell count (CBC), which checks for numbers of white cells, red blood cells, and platelets, is the first step in diagnosing ALL. Patients with ALL generally have a higher than normal white blood count and lower than normal red blood cell and platelet counts.
Click the icon to see an illustrated series detailing a complete blood cell count test.
Blood tests are also performed to evaluate liver, kidney, and blood clotting status and to check for levels of certain minerals and proteins.
Bone Marrow Biopsy
If blood test results are abnormal or the doctor suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps. These are very common and safe procedures. However, because this test can produce considerable anxiety, particularly in children, parents may want to ask the doctor if sedation is appropriate for their child.
- A local anesthetic is given.
- A needle is inserted into the bone, usually the rear hipbone. There may be brief pressure or pain. A small amount of marrow is withdrawn. Marrow looks like blood.
- A larger needle is then inserted into the same place and pushed down to the bone. The health professional will rotate the needle to obtain a specimen for the biopsy. The patient will feel some pressure.
- The sample is then taken to the lab to be analyzed. All the results are completed within a couple of days.
Click the icon to see an image of bone marrow removal.
Normal bone marrow contains 5% or less of blast cells (the immature cells that ordinarily develop into healthy blood cells). In leukemia, abnormal blasts constitute between 30 - 100% of the marrow.
Spinal Tap
If bone marrow examination confirms ALL, a spinal tap (lumbar puncture) may be performed, which uses a needle inserted into the spinal canal. The patient feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache. This can be difficult, particularly for children, so parents should plan reading or other quiet activities that will divert the child during that time. Parents should also be certain that the professional performing this test is experienced.
Click the icon to see an image of a spinal tap.
A sample of cerebrospinal fluid with leukemia cells is a sign that the disease has spread to the central nervous system. In most cases of childhood ALL, leukemia cells are not found in the cerebrospinal fluid.
Tests Performed after Diagnosis
Once a diagnosis of leukemia has been made, further tests are performed on the bone marrow cells:
- Cytochemistry, flow cytometry, immunocytochemistry, and immunophenotyping tests are used to to identify and classify specific types of leukemia. For example, cytochemistry distinguishes lymphocytic leukemia cells from myeloid leukemia cells. Immunophenotyping shows if ALL cells are T cells or B cells based on the antigen located on the surface of the cell.
- Cytogenetics and fluorescent in situ hybridization (FISH) are used for genetic analysis. Cytogenetic testing can detect translocations (such as Philadelphia chromosome) and other genetic abnormalities. FISH is used to identify specific changes within chromosomes. Genetic variations may help determine response to treatment.
Cell Classification
The results of cytogenetic, flow cytometry, immunophenotyping, and other tests can help provide information on types and subtypes of ALL cells. The particular subtype of cell can aid in determining prognosis and treatment.
An older classification system called the French-American-British (FAB) classification grouped ALL into L1, L2, and L3 subtypes. A newer classification system classifies ALL B cells or T cells based on their stage of maturity.
B-Cell ALL Subtype Classfication:
- Early Pre-B
- Common ALL
- Pre-B ALL
- Mature B-cell ALL (Also called Burkitt leukemia)
T-Cell ALL Subtype Classifcation:
- Pre-T ALL
- Mature T-cell ALL
Prognosis
Acute lymphocytic leukemia is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now at an all-time high.
According to the American Cancer Society, certain factors can help determine prognosis:
- Age. Younger patients (especially those younger than age 50) have a better prognosis than older patients.
- Initial white blood cell (WBC) count. People diagnosed with a WBC count below 50,000 tend to do better than people with higher WBC counts.
- ALL subtype. The subtype of T cell or B cell affects prognosis. For example, patients with T-cell ALL tend to have a better prognosis than those with mature B-cell ALL (Burkitt leukemia.)
- Chromosome translocations. People who have Philadelphia chromosome-positive ALL tend to have a poorer prognosis, although new treatments are helping many of these patients achieve remission.
- Response to chemotherapy. Patients who achieve complete remission (disappearance of signs and symptoms of cancer) within 4 - 5 weeks of starting treatment tend to have a better prognosis than those who take longer. Patients who do not achieve remission at any time have a poor prognosis. Evidence of minimal residual disease (presence of leukemia cells in the bone marrow) may also affect prognosis.
Other factors, such as central nervous system involvement or recurrence, may also indicate a poorer prognosis.
Outlook in Children with ALL. More than 95% of children with ALL attain remission.
Certain children are at higher risk for a poor outcome than others:
- Infants and children age 10 years and older tend to have a poorer outcome than young children (ages 1 - 9 years).
- Some studies indicate a better prognosis for girls than boys. This may be partly due to boys’ risks for testicular cancer.
- Survival rates for African-American and Hispanic children are lower than Caucasian and Asian children, but this may be due to poorer access to treatment.
Responding well to early treatment is a good sign regardless of the risk category. Other positive predictors include:
- Less than 5% of cells being blasts after 7 - 14 days of treatment
- Less than 1,000 blasts per microliter on peripheral smear after 7 days
Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the same ALL genes. Still, 60 - 80% of adults with ALL can expect to achieve full remission with standard treatments, and 35 - 40% survive beyond 2 years with aggressive treatments. Younger adults with ALL have better long-term survival rates than older adults with the disease.
Treatment
Treatment Phases
There are typically four treatment stages for the average-risk patient with ALL:
- Induction therapy in order to achieve a first remission
- Central nervous system prophylaxis (preventive treatment), usually given along with induction therapy
- Consolidation, intensive therapy to prevent relapse after remission has been achieved
- Maintenance treatment, lower intensity therapy given for several years to prevent relapse after remission
Specific Treatments Used in ALL
The following are specific treatments used for ALL:
- Chemotherapy is the primary treatment for each stage.
- Radiation to the brain and spinal cord is also administered in some cases.
- A bone marrow transplant is often recommended for relapsed ALL or in cases that cannot be induced into remission (refractory disease). It is also sometimes considered after remission is achieved for certain high-risk ALL types. The timing of bone marrow transplantation can be controversial, particularly after a first remission, although it has produced excellent long-term survival rates in appropriate patients.
- New drugs known as biological therapies are also being used.
Supportive Treatment
Drugs Used to Prevent Infections During Treatment. Half of all patients with ALL develop fever in the early stages, especially if patients also have low levels of the white blood cells called neutrophils (a condition called neutropenia).
Neutropenia, common in ALL, is a significant risk factor for serious infection. Doctors are increasingly concerned about fungal infections, which are becoming more common in these patients, particularly after transplant procedures.
- Antibiotics and Antifungal Medications. The use and timing of antibiotics and antifungal medications depend on the particular organisms and severity of the infection. In some cases of neutropenia, patients may need preventive antibiotics.
- Granulocyte Colony-Stimulating Factor. Granulocyte colony-stimulating factor (lenograstim, filgrastim) is often given to patients who receive chemotherapy in order to stimulate the growth of infection-fighting white blood cells. This helps prevent neutropenia.
Intravenous Fluids. Patients may also need to receive intravenous fluids and be treated for fluid imbalances, which can cause abnormal levels of sodium, potassium, calcium, and uric acid. Such treatments might include sodium bicarbonate, allopurinol, and aluminum hydroxide or calcium carbonate.
Transfusions. Red blood cell or platelet transfusions may be needed. (Patients who may need allogeneic transplantations should not receive transfusions from potential donors.)
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.
Treatment During Remission
Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse. The specific treatment choices and degree of aggressiveness after induction therapy depend on a number of factors, particularly the risk factors for relapse.
Consolidation (or Intensification) Therapy
Consolidation therapy is additional treatment that is administered after induction therapy and before maintenance therapy. This is an intense regimen that is designed to prevent the high relapse rates that occur with induction therapy alone. (The benefits of this therapy are clearer in children than in older adults, who may just be given maintenance.)
Consolidation therapy usually continues for about 6 months and uses 1 - 6 courses of chemotherapy, depending on risk factors for relapse.
Examples of consolidation regimens for children at standard risk:
- A limited number of courses of intermediate- or high-dose methotrexate, one of the oldest drugs used for leukemia.
- An anthracycline drug, such as daunorubicin (Cerubidine), used for reinduction followed by cyclophosphamide (Cytoxan, Neosar) 3 months after remission. These are very powerful drugs, but when used in this way toxicity is limited.
- Extended use of an asparaginase drug.
More intense regimens are used for children at high-risk for relapse.
Instead of chemotherapy alone as consolidation therapy, some high-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone may undergo allogeneic stem cell or autologous stem cell bone marrow transplant after the intensive chemotherapy regimens. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.
- Allogeneic transplantation is an option when a well-matched donor is available. Although this treatment can be effective in keeping the leukemia away, significant complications -- such as graft versus host disease, blood clots, liver problems, and lung damage -- can occur and may be a cause of death even without a return of cancer.
- Autologous stem cell bone marrow transplant (using the patient's own bone marrow cells) seems to be helpful also and may be as effective as allogeneic transplantation.
Maintenance
The last phase of treatment is maintenance, or continuation therapy:
- Maintenance therapy typically uses weekly administration of methotrexate (usually in oral form) and daily doses of mercaptopurine.
- Treatment continues for 2 - 3 years for most children with ALL (with the exception of those with mature B-cell leukemia). It is not yet clear if prolonged maintenance therapy benefits adults with ALL.
- If children were not given CNS prophylaxis before, it may be given now.
- Vincristine and a corticosteroid drug (generally dexamethasone) are often added to standard maintenance therapy, although some studies indicate that they do not provide additional benefit.
A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Some studies, however, indicate that overall survival could further be improved with more-aggressive maintenance therapies, including:
- Vincristine and a corticosteroid added to the standard maintenance regimen
- Longer term low-dose maintenance
- Intense regimens similar to induction (called reinduction)
Maintenance is typically ongoing until complete remission has lasted 2 - 3 years.
Investigation is ongoing to determine the best drugs and schedules to use. For example, doctors have debated whether thioguanine is a better choice than mercaptopurine. Researchers are also trying to pinpoint patients who would best benefit from aggressive maintenance treatments.
Risk Factors for Relapse after a First Remission
The following are factors that increase the risk for relapse after initial treatments:
- Microscopic evidence of leukemia after 20 weeks of therapy (minimal disease)
- Age over 30
- A high white blood cell count at the time of diagnosis
- Disease that has spread beyond the bone marrow to other organs
- Certain genetic abnormalities, such as the presence of the Philadelphia chromosome or MLL gene translocations
- Patients with high disease levels after 7 - 14 days of induction therapy
- The need for 4 or more weeks of induction chemotherapy in order to achieve a first complete remission
Patients with one or more of these risk factors may be candidates for bone marrow transplantation once they are in first remission.
Treatment After Relapse
Between 50 - 70% of children and 40 - 50% of adults who achieve complete remission after initial therapy but then suffer a relapse may be able to go into a second complete remission.
Treatment for relapse after a first remission may be standard chemotherapy or experimental drugs, or more aggressive treatments such as stem cell transplants.
The decision depends on a number of factors:
- Children who relapse 3 or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
- Those who relapse fewer than 6 months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually fewer than 6 months.
Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.
Candidates for transplantation include:
- Patients who relapse following initial remission with standard chemotherapy.
- High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.
- Patients who fail to achieve a complete remission during initial chemotherapy.
Transplantation procedures do not appear to offer any additional advantages for patients at low or standard risk.
Chemotherapy Drugs Used After Relapse
Many different drugs are used to treat ALL relapses. These drugs include vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). Corticosteroids, such as prednisone or dexamethasone, may also be used.
In 2004, the Food and Drug Administration (FDA) approved clofarabine (Clolar) for treatment of relapsed or refractory ALL in children. This drug was the first new leukemia treatment approved specifically for young patients in more than a decade. In 2005, nelarabine (Arranon) was approved to treat adults and children with relapsed or refractory T-cell acute lymphocytic leukemia (T-ALL). In 2006, the FDA approved imatinib (Gleevec) for treating patients with Philadelphia chromosome-positive ALL that has not responded to or has returned after treatment. Also in 2006, the FDA approved dasatinib (Sprycel) for patients who are not helped by imatinib.
Investigational Drugs
Tyrosine kinase inhibitors. Tyrosine kinase is a growth-stimulating protein. Tyrosine kinase inhibitor drugs block the cell signals that trigger cancer growth. Several tyrosine kinase inhibitors, including imatinib (Gleevec) and dastinib (Sprycel), have recently been approved for treating Philadelphia chromosome-positive ALL. However, because patients can develop resistance to these drugs, new tyrosine kinase inhibitors are being investigated. For example, nilotinib (AMN-107) is being studied for patients with Philadelphia chromosome positive ALL who are resistant to imatinib.
Transplantation Procedures for Acute Lymphocytic Leukemia
In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.
Collecting the Stem Cells
Sources of Cells. Stem cells must first be collected either from:
- Bone marrow (bone marrow transplantation)
- Blood (peripheral blood stem cell transplantation)
Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:
- If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogeneic transplants from genetically matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to work as well as those from matched siblings. This approach is still reserved for patients in second remission or beyond. Allogeneic transplant may also be a good treatment option for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib (Gleevec).
- If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in patients with ALL are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.
The Blood Stem Cell Collection Procedure
- The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
- The donor (or patient in an autologous procedure) then undergoes apheresis. With this process, the blood is withdrawn from one of the patient's veins and passed through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
- The stem cells are then frozen.
The Transplant Procedure
- The patient is given high-dose chemotherapy with or without radiation -- a treatment known as conditioning. The point is to inactivate the immune system and to kill any residual malignant cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with drugs.
- A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
- The patient is kept in a protected environment to minimize infection, and the patient usually needs blood cell replacement and nutritional support.
Success Rates
Two- to 5-year survival rates after transplantation plus chemotherapy range from 40 - 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogeneic bone marrow transplant from a closely matched related donor.
Side Effects and Complications
Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.
Blood stem cell transplantation itself is fairly dangerous and has a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now, mortality rates are below 5%.
Potentially serious complications include:
Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 - 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally
Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis jerovicii (a fungus) are among the most important life-threatening infections.
It is very important that patients take precautions to avoid post-transplant infections. (See Home Management section of this report.)
Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. To reduce the risk for GVHD, doctors remove some immune T cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T cell depletion.
Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.
Chronic GVHD can develop 70 - 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.
Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.
Other potentially serious complications include:
- Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
- Infertility
- Organ complications to the liver, heart, kidney, or lungs
- Failure of the transplant
- Muscle problems, including stiffness, cramps, and joint pain
- Frequent urination and bladder control problems
- Older patients should be screened for osteoporosis (thinning of bones) and hypothyroidism (underactive thyroid)
Home Management
A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:
- Any fever of 101°F or higher
- Any signs of a flu or cold
- Shortness of breath
- Severe diarrhea
- Blood in the urine or stools
- Trouble urinating
Tracking Neutrophils. Parents should track their child's absolute neutrophil count. This measurement for the amount of white blood cells is an important gauge of a child's ability to fight infection.
- Counts over 1,000 usually provide sufficient protection so that children can engage in normal activities, including school and other functions where they are exposed to other children.
- If the count is between 500 - 1,000, the child should avoid large groups.
- If it falls between 200 - 500, the child should stay at home and should see only healthy visitors who have washed their hands vigorously.
- Neutrophil counts below 200 indicate that the child is at high risk for infection and should have no visitors.
Preventing Infection
It is very important to take precautions to prevent infection following chemotherapy or transplantation. Guidelines for infection prevention and control include:
- Discuss with the doctor what vaccinations are needed and when. Children with ALL may need reimmunization. In general, it is best to have immunizations prior to chemotherapy and to avoid live virus vaccines during treatment,
- Avoid crowds, especially during cold and flu season.
- Be diligent about hand washing and make sure that visitors wash their hands. Alcohol-based handrubs are best.
- Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
- Boil tap water before drinking it.
- Dental hygiene is very important, including daily brushing and flossing. Use a soft toothbrush to prevent gum bleeding. Schedule regular visits with your dentist.
- Do not sleep with pets. Avoid contact with pets' excrement.
- Avoid fresh flowers and plants as they may carry mold. Do not garden.
- Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
- Report to the doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
- Report to the ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.
- Some of the drugs used for leukemia cause extreme sun sensitivity. Children should wear sunblock and be covered with sun-protective clothing when going outside to avoid sunburn, which can cause skin infection.
Resources
- www.leukemia-lymphoma.org -- Leukemia and Lymphoma Society
- www.cancer.org -- American Cancer Society
- www.cancer.gov -- National Cancer Institute
- www.marrow.org -- National Marrow Donor Program
- www.asco.org -- American Society of Clinical Oncology
- www.cancer.net -- Cancer.Net
- www.candlelighters.org -- Candlelighters Childhood Cancer Foundation
References
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
