Bone Marrow &
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.
Follow-up therapy for such patients may involve:
- supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients who have prolonged granulocytopenia; that is too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks);
- injection with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), which may help to shorten the period of granulocytopenia that results from induction therapy; and
- transfusions with red blood cells and platelets.
Patients with newly diagnosed disease also may be considered for stem cell transplantation (SCT), either from the bone marrow or other sources. Allogeneic bone marrow transplant (alloBMT) is reserved primarily for patients under 55 years of age who have a compatible family donor. Approximately half of newly diagnosed AML patients are in this age group, with 75% achieving a complete remission (CR) after induction and consolidation therapy. Allogeneic bone marrow transplant is available for about 15% of all patients with AML. Unfortunately, it is estimated that only 7% of all AML patients will be cured using this procedure.
People who receive stem cell transplantation (SCT, alloBMT) require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.
Treatment of central nervous system leukemia, if present, may involve injection of chemotherapeutic drugs (e.g., cytarabine or ara-C, methotrexate) into the areas around the brain and spinal cord.
Once the patient is in remission, he or she will receive consolidation or maintenance therapy, for example, consolidation therapy with high-dose ara-C (HDAC) with/without anthracycline drugs).
If, however, the AML patient has resistant disease (about 15%) or relapses (about 70%), second remissions sometimes are achieved by treating them with:
- conventional induction chemotherapy;
- high-dose ara-C (HDAC), with/without other drugs; and
- etoposide or other single chemotherapeutic agents.
Elderly AML patients have special treatment concerns. They may be less able to tolerate the septicemia (blood poisoning) associated with granulocytopenia, and they often have higher rates of myelodysplastic ('preleukemia') syndrome (MDS). Individuals who are over age 75 or who have significant medical conditions can be treated effectively with low-dose ara-C. High-dose post-induction chemotherapy is unlikely to be tolerated by elderly patients.
Until recently, the treatment plans and responses of children with AML did not differ much from those of adults. Yet new, more intensive induction and consolidation treatments have resulted in higher remission rates and prolonged survivals. Many induction trials have produced good results using combinations of cytarabine (ara-C) plus an anthracycline (e.g., daunorubicin, doxorubicin). In children under 3 years of age, the anthracycline used for induction should be chosen with care, since doxorubicin produces more toxicity and related deaths than daunorubicin.
Consolidation therapy is complex, but it should include at least two courses of high-dose ara-C (HDAC). Children who have hyperleukocytosis (too many white blood cells), especially monocytic M5 leukemia, have a poor prognosis.
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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 (GleevecT).
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.
Gleevec, is one of a new class of cancer drugs that disables an abnormal enzyme in the cancerous cell, kills it, but leaves healthy cells virtually untouched. Other cancer therapies, such as chemotherapy, attack healthy cells as well as cancer cells, leaving patients with unpleasant and often severe side effects.
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.
New drugs that are being studied in clinical trials of CML include homoherringtonine with interferon-alpha (INF-a), paclitaxel (Taxol®), QS21 (a plant extract that heightens immune responses), and amifostin (a chemical that lessens some side effects of chemotherapy). In addition, clinical trials are evaluating the potential benefits of substances such as vaccines, monoclonal antibodies (immunologic substances that can direct the patient's immune system to kill cancer cells), and hormones (e.g., growth factors, interleukins).
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 remission - that 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.
Follow-up therapy for ALL patients usually consists of:
A laboratory test known as polymerase chain reaction (PCR) is advisable for ALL patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. PCR testing is especially important for patients whose disease is B-cell in type. B-cell ALL usually is not cured by standard ALL therapy. Instead, higher response rates are achieved with the aggressive, cyclophosphamide-based regimens that are used for non-Hodgkin's lymphoma .
- supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks); and
- transfusions with red blood cells and platelets.
Among ALL patients, most children and more than 50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with ALL, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional ALL chemotherapy.
People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.
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).
Alternatively, patients with recurrent ALL may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.
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Chronic Lymphocytic Leukemia (CLL)
The unpleasant truth is that CLL is probably "incurable" by present treatments. But, fortunately, a large group of 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).
In general, the indications for treatment are:
If the patient experiences blood flow problems caused by high numbers of leukemia cells in the circulation, the physician may recommend leukapheresis, also known as apheresis, to separate out white blood cells, prior to chemotherapy.
- falling hemoglobin or platelet count
- progression to a later stage of disease
- painful, disease-related overgrowth of lymph nodes or spleen
- lymphocyte doubling time (an indicator of lymphocyte reproduction) of fewer than 12 months
- transformation of CLL to high-grade disease or aggressive non-Hodgkin's lymphoma
Symptoms that are related to enlargement of the lymph nodes in one area or an overgrown spleen may be treated by localized, low-dose radiotherapy, or surgical management by splenectomy (removal of the spleen). But if leukemia has invaded the lymph nodes at many different sites, total body irradiation (TBI) may be needed.
The chemotherapeutic plans that are used most often for CLL are:
People with intermediate (Rai Stage I and II) or advanced (Rai Stage III or IV) disease may be helped by participation in a clinical trial. At the present time, clinical trials are being conducted using immunologic compounds (e.g., interferons, monoclonal antibodies) as well as new chemotherapeutic agents (e.g., bryostatin, dolastatin 10, and PSC 83 - a cyclosporine drug given with chemotherapy to overcome drug resistance).
- combination chemotherapy with chlorambucil (Leukeran®) or cyclophosphamide (Cytoxan®) plus a corticosteroid drug such as prednisone, or
- single-agent treatments with nucleoside drugs such as fludarabine, pentostatin, or cladribine (2-chlorodeoxyadenisine; 2-CDA). However, such drugs usually are reserved for cases in which CLL is resistant (unresponsive to treatment) or returns after chemotherapy with chlorambucil or cyclophosphamide.
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).
Unfortunately, some younger patients develop HCL that is unresponsive to treatment. Clinical trials are being conducted with high-dose chemotherapy followed by stem cell transplantation.
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