- Posted by jdavis on August 24, 2011
Leukemia is not a single disease. Instead, the term leukemia refers to a number of related cancers that start in the blood-forming cells of the bone marrow. There are both acute and chronic forms of leukemia, each with many subtypes that vary in their response to treatment. In addition, children with leukemia have special needs that are best met by care in pediatric cancer centers. Such centers have trained medical professionals whose sole purpose is to address the unique concerns of children.
In general, there are five major approaches to the treatment of leukemia:
- chemotherapy to kill leukemia cells using strong anti-cancer drugs;
- interferon therapy to slow the reproduction of leukemia cells and promote the immune system’s anti-leukemia activity;
- radiation therapy to kill cancer cells by exposure to high-energy radiation;
- stem cell transplantation (SCT) to enable treatment with high doses of chemotherapy and radiation therapy; and
- surgery to remove an enlarged spleen or to install a venous access device (large plastic tube) to give medications and withdraw blood samples.
Oncologists administer these treatments in a variety of combinations. Each method has its advantages and drawbacks. It usually is worthwhile to get a second opinion about treatment before entering into a specific program; in some instances, a second opinion may be required by the patient’s insurance company. For example, stem cell transplantation (SCT) is very costly (more than $100,000) and entails a long stay in the hospital. Some insurance companies still consider this to be an “experimental” procedure and will not pay for SCT-related expenses.
The treatment of leukemia depends on a number of factors. The most important of these are the histopathologic (diseased tissue) type of leukemia, its stage, and certain prognostic features, such as the patient’s age and overall health.
Interferons are a class of proteins that are released by virus-infected cells. They help normal cells to make antiviral proteins. Interferons also help the body to reduce leukemia cell proliferation (growth and reproduction), while strengthening the body’s immune response.
Interferon-alpha (INFa) is a type of interferon that frequently is used to treat leukemia. In addition, based on a patient’s response to INFa, a physician can better predict the anticipated length of survival.
Interferon-alpha can be given by a number of methods—that is, by injection into a vein, into a muscle, or under the skin—although subcutaneous (under the skin) injection is the customary route. INF-a usually is offered to all newly diagnosed patients who are not candidates for stem cell transplantation. Often IFN-a is started at a low dose (e.g., 3 MIU daily), with gradual increases over time. Unfortunately, though, this drug is not without side effects. Possible IFN-related complaints include fevers, chills, muscle aches, bone pain, headaches, concentration difficulties, fatigue, nausea, vomiting, and general flu-like symptoms when starting the drug. Such symptoms usually last for 1 to 2 weeks, but may be lessened by drugs such as acetaminophen. Side effects recur if the INF-a dosage is increased, but they are temporary and usually improve after INF-a therapy is completed.
Stem Cell Transplantation
Cancer therapy (chemotherapy, radiation therapy, etc.) can damage or destroy normal cells, as well as cancer cells. Many chemotherapeutic drugs, in particular, can harm rapidly dividing cells such as the blood-forming stem cells of the bone marrow. Yet high drug doses are needed to treat leukemia effectively. So what can be done? Physicians have begun to solve this problem by performing stem cell transplantation (SCT). Stem cells are blood-forming (hematopoietic) cells of the bone marrow; they continuously divide to form the new blood cells that populate the arteries and veins. The SCT procedure enables physicians to give chemotherapy and radiotherapy in doses that are strong enough to eliminate leukemia cells. The injured bone marrow then is replenished by a transplant of stem cells, which can manufacture the necessary new blood cells.
Stem cells for SCT can be gathered from different sources:
- aspiration (suctioning) directly from the bone marrow at the back of the hip crest;
- leukapheresis (also known as apheresis), separation of white blood cells in blood from the bloodstream;
- umbilical cord cells (stem cells obtained from umbilical cord blood), usually from donations made by normal siblings who are born after a child who has leukemia.
The cells are carefully frozen and stored until the patient has completed high-dose treatments for leukemia. Such treatments usually consist of a 3-day course of chemotherapy (for example, with cyclophosphamide, cytarabine, etoposide, melphalan, or busulfan) with/without a 3-day course of total body irradiation (TBI). After therapy, the stem cells are thawed and given to the patient by means of a blood transfusion.
SCT are classified as autologous or allogeneic, based on characteristics of the cell donor. Autologous SCT, also known as autologous bone marrow transplant (autoBMT), is a procedure in which a patient’s own stem cells (immature cells from which all blood cells develop) are removed from the bone marrow. This type of transplant is not frequently used, because it is very difficult to guarantee that normal stem cells have been separated from leukemic cells, even after purging, that is treatment of stem cells with drugs, immunologic agents, heat, or other substances/methods to kill or remove leukemic cells.
Another form of autologous SCT is peripheral blood stem cell transplantation, or leukapheresis. The patient’s blood is passed through a machine that removes the stem cells, and then returns the blood to the patient. This procedure usually takes 3 or 4 hours to complete. The stem cells may or may not be treated with drugs to kill any remaining leukemia cells. The stem cells are stored until they are transplanted back into the patient. Leukapheresis may be performed alone or with autoBMT, although most physicians prefer to use leukapheresis by itself.
Allogeneic SCT, also known as allogeneic bone marrow transplant (alloBMT), is a form of transplant in which the stem cells are gathered from a donor whose tissue type closely matches the patient’s tissue type. Such donors usually are relatives (brother, sister, child) or, occasionally, a matched unrelated donor (MUD). AlloBMT usually is reserved for individuals who are younger than 55 and who have a compatible family donor – that is, a donor with compatible human leukocyte antigen (HLA), a protein found on the surface of some cells, such as leukocytes). Allogeneic donor cells actually may help to fight leukemia cells because they initiate a response known as the “graft versus leukemia” reaction.
If the person receives an allogeneic transplant, he or she must be treated with drugs that suppress rejection reactions (e.g., cyclosporine, methotrexate, prednisone, and antilymphocyte globulin [ALG] or antithymocyte globulin [ATG]). For example, “graft-versus-host disease” (GVHD) is a result of rejection reactions that occur in 25 to 50% of cases. The leukemia patient should ensure that SCT is performed at a qualified medical facility. The treatment staff should be experienced in all types of transplants, including MUD transplants, as well as patient care during the recovery period.
Transplant patients typically are kept in protective isolation in the hospital until their total white blood cell (WBC) count is above 500. During this time, the individual receives supportive care, such as intravenous nutrition, treatment with antibacterial and antifungal medications, and transfusions with red blood cells and platelets. Within 2 to 3 weeks, the stem cells usually begin to make white blood cells. Next, platelets are produced, followed several weeks later by the manufacture of red blood cells. Once the WBC count approaches 1000, the patient generally can be discharged from the hospital. Daily outpatient check-ups may be scheduled for several weeks, followed by regular appointments over a 6-month period. The individual’s oncologist usually will schedule an exam at the SCT clinic 1 year after treatment; thereafter, clinic appointments are made only if symptoms return.
Side effects due to SCT may occur shortly after treatment, or they may develop much later. Early complications usually are related to the cellular injury caused by high-dose chemotherapy and radiotherapy (for example, temporary hair loss, anemia, leukopenia, thrombocytopenia, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Long-term or chronic complications may include:
- Chronic graft-versus-host disease – or GVHD that occurs after 100 days. This autoimmune disorder develops when donor stem cells make immune cells that attack tissues of the patient’s skin, gut, mouth, genitalia, and other organs. Typical features include dry mouth and eyes; skin changes such as thickening, hair loss, dryness, and rashes; fatigue; muscle pain and weakness; and infection.
- Irreversible sterility in men and women who have received total body irradiation (TBI) or high-dose busulfan chemotherapy. Women will experience radiation-induced menopause and will require gynecological observation after the first 100 days. Hormone replacement therapy (HRT) will be needed in pre-menopausal women.
- Endocrine (hormonal) system malfunction, particularly of the thyroid gland. Hypothyroidism (low thyroid activity) is frequent, so regular thyroid screening is needed after SC.
- Bone marrow toxicity (poisonous damage), especially when manifested as asceptic necrosis – bone cell death without infection. Severe bone and/or joint damage may require surgical replacement.
- Respiratory symptoms and impairment (e.g., shortness of breath) due to radiation-related lung damage.
- Cataract, an abnormality of the lens of the eye which blocks light and impairs vision.
- Thrombotic microangiopathy (TM), clot formation in the small blood vessels), a condition that includes hemolytic uremic syndrome (HUS; bloody urine) and thrombocytopenic purpura (TTP; purplish discoloration of the skin caused by internal hemorrhaging related to a low platelet count). TM has multiple causes and, unfortunately, often does not respond well to therapy.
Surgery does not play a major role in the management of leukemia. The reasons for this are two-fold: (1) leukemia cells usually are widespread throughout the body at the time of diagnosis, so they cannot be “cut out” like other forms of cancer; and (2) surgery is not needed for diagnosis, since bone marrow aspiration usually is adequate to confirm the disease.
Aside from the insertion of a venous access device (a plastic tube that is surgically implanted into a large vein in the chest or upper arm) to reduce the need for repeated needle sticks during drug injections or removal of blood samples, splenectomy (removal of the spleen) may be the only surgical procedure performed during the treatment of leukemia.
The spleen normally helps to filter out old and damaged blood cells from the circulation. If leukemia causes substantial spleen enlargement of more than 4 centimeters (> 4 cm), it may press upon other organs and cause abdominal symptoms. In addition, an overgrown spleen may become too effective in removing blood cells and cause a shortage of red blood cells or platelets. Therefore, surgical removal of the spleen is a form of therapy that may improve symptoms and blood profiles in some leukemia patients, such as individuals with chronic lymphocytic leukemia (CLL) or hairy cell leukemia. The primary danger of splenectomy, especially in people with compromised immune systems, is infection in the blood or tissues (sepsis). Microorganisms commonly involved in such sepsis include pneumococci, meningococci, E. coli, Haemophilus influenzae, and staphylococci.
Further Treatment Options by Type of Leukemia
Acute Myelogenous Leukemia (AML)
Many different chemotherapeutic plans are available for the treatment of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission (lessening of the disease) and a lower risk of disease resistance.
Consolidation or “maintenance” treatments may be given to prevent disease recurrence once remission has been achieved. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with added drugs. By contrast, maintenance treatment typically involves drug doses that are lower than those administered during the induction phase.
In addition, specific treatment plans may be used, depending on the type of leukemia that has been diagnosed. Whatever the plan, it is important for the patient to understand the treatment that is being given and the decision-making process behind the choice.
Initial treatment of AML usually begins with induction chemotherapy using a combination of drugs such as daunorubicin (DNR), cytarabine (ara-C), idarubicin, thioguanine, etoposide, or mitoxantrone.
Chronic Myelogenous Leukemia (CML)
The challenge of treating newly diagnosed CML is to determine the best overall strategy to control the disease.
General strategies for management include a variety of options:
- Leukapheresis, also known as a peripheral blood stem cell transplant, with stem cell cryopreservation (frozen storage) prior to any other treatment. The patient’s blood is passed through a machine that removes the stem cells and then returns the blood to the patient. Leukapheresis usually takes 3 or 4 hours to complete. The stem cells may or may not be treated with drugs to kill any cancer cells. The stem cells then are stored until they are transplanted back into the patient.
- HLA (human leukocyte antigen) typing of all patients under age 60, as well as typing of siblings, parents, and children, if available. This procedure will determine whether a compatible donor is available for stem cell transplantation.
- Pre-treatment fertility measures (e.g., cryopreservation of semen prior to treatment; completion of a pregnancy prior to treatment) in young patients who have not completed their families.
- Interferon-alpha (INF-a) therapy.
- Chemotherapy with drugs such as hydroxyurea (Hydrea®), busulfan (Myleran®) or imatinib mesylate (Gleevec®).
In general, CML treatment options are divided into two groups: those that do not increase survival and those that do. Chemotherapeutic drugs such as hydroxyurea (Hydrea®) and busulfan (Myleran®) can normalize the blood count for a period of time, but they do not increase survival. They often are used to control blood counts in patients who cannot undergo SCT or who do not respond to interferon therapy because of age or medical considerations.
Imatinib mesylate (Gleevec®) is used as initial treatment for certain types CML. This drug blocks an enzyme called tyrosine kinase that causes stem cells to develop into white blood cells. It prevents abnormal cell growth, without damaging healthy cells. Other cancer therapies, such as chemotherapy, destroy healthy cells as well as cancer cells, causing unpleasant and often severe side effects. Imatinib mesylate should be used with caution in patients who have liver disease.
In June of 2006, the U.S. Food and Drug Administration (FDA) approved the oral tyrosine kinase inhibitor dasatinib (Sprycel™) to treat CML that does not repond to other therapy.
One treatment that does impact on CML survival is allogeneic bone marrow transplantation, the use of high dose chemotherapy and radiation followed by infusion of a donor bone marrow. This procedure removes the chromosomal abnormality in a large percentage of patients and for them is curative. In addition, there is treatment with interferon (INF). About 20% to 30% of patients taking interferon show elimination of the abnormal chromosome and improved survival. Recent findings also suggest that low-dose cytarabine (ara-C), in combination with interferon, may be more beneficial than interferon alone. For patients who do not respond to interferon, autologous or allogeneic stem cell transplantation is the only alternative.
Patients with advanced-phase disease may be treated with cytotoxic drugs. For example, individuals showing myeloid transformation may be given drugs that are used to induce remission in AML—that is, daunorubicin and cytarabine, with or without 6-thioguanine or etoposide. Blast cell numbers will be reduced temporarily, but they will increase again within 3 to 6 weeks. Individuals showing lymphoid transformation have a slightly better outlook. They are treated with drugs used in the management of acute lymphocytic leukemia (ALL)—that is, prednisone, vincristine, and daunorubicin, with or without L-asparaginase.
Acute Lymphocytic Leukemia (ALL)
Proper management of ALL focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS).
In general, ALL treatment is divided into several phases:
- Induction chemotherapy to bring about remissionthat is, leukemic cells are no longer found in bone marrow samples. For adult ALL, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs (prednisone, L-asparaginase, and vincristine) for the first month of treatment. High-risk children may receive these drugs plus an anthracycline such as daunorubicin.
- Consolidation therapy (1-3 months in adults; 4-8 months in children) to eliminate any leukemia cells that are still “hiding” within the body. A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance. Patients with low- to average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.
- CNS prophylaxis (preventive therapy) to stop the cancer from spreading to the brain and nervous system. Standard prophylaxis may consist of (1) cranial (head) irradiation plus spinal tap or intrathecal (IT; into the space around the spinal cord and brain) delivery of the drug methotrexate; (2) high-dose systemic and IT methotrexate, without cranial irradiation; or (3) IT chemotherapy. Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
- Maintenance treatments with chemotherapeutic drugs (e.g., prednisone + vincristine + cyclophosphamide + doxorubicin; methotrexate + 6-MP) to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase. In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy.
Recurrent ALL patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by allogeneic bone marrow transplant (alloBMT).
Chronic Lymphocytic Leukemia (CLL)
First, a very important point: Most CLL patients do not require therapy. Studies suggest that people with Stage A CLL (that is, individuals who have fewer than three areas of enlarged lymphoid tissue) do not benefit from early treatment. They may, in fact, suffer drawbacks because of it. Therefore, most oncologists base CLL treatment upon both the stage and symptoms of the patient.
For example, in older patients (60+ years) who have low-risk, early stage disease (Rai Stage 0) a conservative “watch and wait” approach may be taken.
By contrast, older individuals with CLL-related complications or more advanced disease (Rai Stage III or IV) may benefit from chemotherapy and treatment with a corticosteroid (e.g., prednisone, prednisolone).
Corticosteroids are first-line agents for people in whom the immune systems has been altered by CLL. CLL may cause autoimmune syndromes in which the patient’s immune system attacks and destroys his or her own blood cells. When the red blood cells are affected, the condition is known as immunohemolytic anemia, characterized by decreased numbers of red blood cells, which may cause fatigue, dizziness, and shortness of breath. When the blood platelets are affected, it is called immune-mediated thrombocytopenia, in which a decreased numbers of platelets may lead to bleeding).
For younger patients who are experiencing symptoms, the physician may consider early chemotherapy, plus allogeneic or autologous bone marrow transplantation (alloBMT; autoBMT).
Hairy Cell Leukemia (HCL)
In the recent past, HCL patients who were symptom-free typically did not receive any treatment for the disease. However, they did undergo routine follow-up exams every few months to monitor leukemia progression and identify any new symptoms. Now oncologists treat almost all newly diagnosed HCL cases with chemotherapeutic drugs known as purine analogs or nucleosides. In most cases, such treatment will produce a prolonged remission and perhaps a cure.
Specifically, if the patient shows signs and symptoms such as low blood cell counts, frequent infections, bleeding/bruising, or fatigue, the oncologist may recommend chemotherapy with the purine analog cladribine (2-chlorodeoxyadenosine; 2-CDA).
If the patient’s HCL becomes resistant to 2-CDA, chemotherapy with the purine analog pentostatin (2-deoxycoformycin; “DCF”) or immunotherapy with interferon-alpha (INF-a) may be used instead.
In limited cases, the patient may benefit from splenectomy (removal of the spleen) or treatment with colony-stimulating factors (e.g., granulocyte colony-stimulating factor, a substance that helps to shorten the period of granulocytopenia resulting from chemotherapy).