INTRODUCTION — Acute myeloid leukemia (AML) is a type of cancer of the blood. It affects a group of white blood cells called myeloid cells. Normally, myeloid and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with AML, this production process is abnormal and large numbers of immature cells are produced and released into the blood stream.
The overproduction of myeloid cells prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells, and platelets. This results in a variety of systemic symptoms, anemia, bleeding, and an increased risk of infection.
GENERAL INFORMATION ABOUT TREATMENT — A number of chemotherapy medications are effective against AML. Studies are in progress to find the best medicines, doses, and treatment schedules for patients with AML. Researchers have discovered that the genetic makeup of the leukemia cells can vary, which affects how a particular patient responds to treatment. Alterations in treatment can be made depending upon careful analysis of this genetic material. Leukemia research centers are constantly investigating new treatment regimens to improve outcomes.
Treatment of AML also depends upon the age of the patient. Regimens that tend to work well in young patients may not work as well or have dangerous side effects in patients over age 60 (see "Treatment in older patients" below).
Side effects of treatment depend on the dose, schedule, and type of medication used. Many of the chemotherapy medicines used to treat AML cause loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available and is generally quite effective.
The usual treatment of AML is divided into two phases: induction of remission and postremission therapy.
INDUCTION OF REMISSION — The most common remission induction regimen includes cytarabine (cytosine arabinoside, Ara-C, or Cytosar), given continuously for seven days through an intravenous (IV) line. Daunorubicin (Daunomycin, Cerubidine, or Rubidomycin) is given in a single IV dose for the first three days of treatment. This is sometimes known as the "7+3" regimen. In some medical centers a variation of this regimen is used, in which daunorubicin is replaced by idarubicin, or cytarabine is given alone in much higher doses. In some cases, other medicines such as etoposide or 6-thioguanine may be added to the "7+3" regimen.
This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. The induction phase usually consists of one or two cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover.
Chemotherapy drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Induction of remission frequently results in a complete remission of the AML, meaning that there are no detectable leukemic cells in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional, postremission chemotherapy is given.
POSTREMISSION THERAPY — There are three basic treatment choices for postremission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation).
Additional chemotherapy — The same chemotherapy regimen used for remission induction can be repeated for one or more cycles, referred to as consolidation chemotherapy. Genetic analysis of the leukemia (done before the initial induction of remission treatment) is useful in deciding which chemotherapy regimen is best. In some cases, other chemotherapy agents may be used. High dose cytarabine is sometimes given to younger patients. Some regimens call for periodic chemotherapy cycles given for up to three years, which is known as remission "maintenance" therapy. Side effects and potential toxicities vary depending on the medications used.
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or radiation. This is intended to kill cancer cells, but it also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (ie, the bone marrow) is no longer functional. After the treatment, the patient must have a healthy supply of very young blood cells (called stem cells) reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
Stem cell transplantation is not recommended for all patients with AML. Complications are higher than those seen with chemotherapy. In certain groups of patients, there is no clear benefit of stem cell transplantation over chemotherapy. However, transplantation may be appropriate in some patients, such as those with more aggressive forms of AML, those who have a relapse following remission, or those patients who fail to achieve a remission following initial induction therapy.
There are two main types of stem cell transplantation: allogeneic and autologous. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). One other possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. In an autologous transplant, the patient's own normal stem cells are removed while he/she is in remission, before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemia cells that may be present, then they are frozen for later use. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient by transfusion.
Because the transplanted stem cells do not come from another person, there is no "graft versus host" disease. This helps reduce some of the side effects of treatment, but in general it also makes autologous transplantation somewhat less effective than allogeneic transplantation in fighting the leukemia, because of the lack of a "graft versus leukemia" effect.
TREATMENT IN OLDER PATIENTS — In general, patients over 60 years old do not respond as well to treatment for AML. This is related to the following factors: Adverse characteristics of the leukemia cells may be more common in older people An increased prevalence of previous blood disorders (such as polycythemia vera or myelodysplasia) makes AML more difficult to treat The presence of other disorders, such as diabetes, kidney, lung, or heart disease, increase the risk of treatment related complications
Treatment decisions for older patients with AML are best made on a case by case basis. Sometimes, induction of remission is a reasonable goal. In an otherwise healthy older patient who does not have high-risk genetic findings, administration of standard chemotherapy induction regimens may be advised. In other patients, the expected benefit in terms of long-term outcome may not be worth the anticipated discomfort, hospitalization, and toxicity of chemotherapy or other treatments.
In some patients, supportive care can provide benefits that are equivalent to chemotherapy with a lower risk of complications or toxicity. There are cases in which the AML does not progress quickly, and these patients may do better with an approach that treats AML related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Patients and families should get information from their healthcare provider about the type of AML, expected benefits of various treatments, possible side effects and toxicities, and long term outlook. These discussions are critical in determining the best course of action for the individual patient.
TREATMENT OF RELAPSED OR RESISTANT DISEASE — A limited number of agents are effective in the treatment of AML. Thus, when patients fail to respond or relapse after initial chemotherapy, management is more difficult: Approximately 50 percent of patients with long first remissions (greater than one year) have a second induction of remission with daunorubicin and cytarabine or high-dose cytarabine (HDAC), but the duration of the second remission is usually shorter than the first. Because of this, hematopoietic cell transplantation should be considered for any patient who relapses after their initial treatment. Patients who relapse within 12 months of initial diagnosis usually have significant drug resistance and a lower rates of a second complete remission. Medicines specifically approved for use in patients with relapsed AML (eg, Mylotarg) or experimental agents may be useful in this setting, with hematopoietic cell transplantation considered for responding patients.
LONG TERM MONITORING — Patients in complete remission need long term monitoring so that any reemergence (relapse) of the disease can be detected and treated. Typically, patients undergo examination of the bone marrow every three to six months for at least two years following remission. Patients with AML who maintain complete, continuous remission for three to five years are considered cured and no longer need routine bone marrow examination.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at: www.cancer.gov/clinical_trials/ http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-6]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schiffer, CA, Dodge, R, Larson, RA. Long-term followup of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997; 80:2210.
2. Estey, EH. Therapeutic options for acute myelogenous leukemia. Cancer 2001; 92:1059.
3. Benjamin, S, Kroll, ME, Cartwright, RA, et al. Haematologists' approaches to the management of adolescents and young adults with acute leukaemia. Br J Haematol 2000; 111:1045.
4. Cassileth, PA, Harrington, DP, Appelbaum, FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649.
5. Estey, EH. How I treat older patients with AML. Blood 2000; 96:1670.
6. Wahlin, A, Markevarn, B, Golovleva, I, Nilsson, M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115:25.
Friday, October 12, 2007
Treatment of acute lymphoblastic leukemia (ALL) in adults
INTRODUCTION — Acute lymphoblastic leukemia (ALL), also known as lymphoblastic lymphoma when the disease primarily involves lymph nodes rather than the blood and bone marrow, is a cancer of blood cells. It involves a type of white blood cell called a lymphocyte. Acute means that it develops and advances quickly, requiring immediate treatment.
Normally, lymphocytes and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with ALL, this production process is abnormal. Large numbers of immature and abnormal lymphocytes (lymphoblasts) are produced and released into the blood stream. In their immature state, they cannot perform their usual functions, leaving the person vulnerable to anemia, infection and bleeding.
The overproduction of lymphoblasts prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells (especially neutrophils, sometimes called "polys"), and platelets. The lymphoblasts can collect in certain areas of the body, such as the brain, spinal cord, and lymph nodes (glands).
GENERAL INFORMATION ABOUT TREATMENT — A number of medications, or chemotherapy agents, are known to be effective against ALL. However, the best combination of medicines or the best treatment schedule is still not known. Because there are so many different medicines, dosing schedules, and combinations, it has been difficult to study any one component of treatment thoroughly. Still, general principles of treatment have emerged and are followed in most cancer treatment centers, although the exact regimens given may vary from one center to another. Regimens can also vary based on characteristics such as the age of the patient, the total number of white blood cells, or characteristics of the acquired genetic changes in the leukemia cells, found in some patients with ALL.
Side effects of treatment will depend on the actual medicines being used, the schedule of treatment, and other factors. Many of the chemotherapy medicines used to treat ALL share common side effects such as loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is generally recommended. For example, anti-nausea medicines can be very effective in preventing nausea and vomiting, and mouth care can reduce the discomfort associated with sores in the mouth.
The usual treatment for ALL can be divided into three phases: induction of remission, consolidation/intensification of therapy, and maintenance. A summary of the entire treatment process is available in table 1 (show table 1). Patients with high risk disease (examples include those with Philadelphia chromosome positive (Ph+) ALL and Burkitts leukemia) require special treatment programs that use medications and doses different from those used in patients with standard risk ALL. In addition, allogeneic stem cell transplantation is more frequently recommended in these patients.
INDUCTION OF REMISSION — This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. Treatment includes: vincristine (Oncovin) and an anthracycline (such as daunorubicin or doxorubicin) along with prednisone, dexamethasone, or another steroid hormone (show table 1).
Vincristine and the anthracycline drugs are anti-cancer chemotherapy drugs. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Vincristine and the anthracycline drugs are given through an intravenous (IV) line. Prednisone can be given either by mouth or IV. Other medicines such as cyclophosphamide (Cytoxan, given IV) or L-asparaginase (Elspar, given as a subcutaneous, intramuscular or IV injection) may also be given. In one study of 204 patients treated with cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (abbreviated as Hyper-CVAD), complete remission was obtained in 91 percent, with 42 percent of patients still in remission after an average of 40 months.
Approximately 80 percent of newly diagnosed adults with ALL enter complete remission, meaning that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional chemotherapy is given. Additional phases of treatment are described in the following sections.
CONSOLIDATION/INTENSIFICATION THERAPY — Once remission is achieved, additional therapy is needed to avoid relapse. Relapse is thought to occur because minimal residual disease is still present, even though it cannot be detected by routine examination of the blood or bone marrow.
Chemotherapy — Some of the same medicines given during induction are also used during remission consolidation therapy, which may last for several months. Most of this treatment can take place without staying overnight in the hospital (show table 1).
In addition to scheduled doses of chemotherapy, many treatment programs call for preventive treatment of the central nervous system (the brain and spinal cord). Abnormal lymphoblasts in the brain often do not respond to chemotherapy given only into a vein, but must be treated directly with radiation to the head and/or injection of chemotherapy, such as methotrexate, into the fluid surrounding the spinal cord and brain, through a lumbar puncture (also called a spinal tap).
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or total body radiation, called myeloablative treatment. This kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (the bone marrow) is no longer functional.
Attempts have been made to reduce the dose of chemotherapy or radiation for some patients, especially those who are older. This is called a non-myeloablative transplantation regimen. The hope with this regimen is that it would reduce early transplant related illness and death. However, the value of this regimen, as compared to its risks and expense, remains to be determined.
After the treatment, the patient requires a supply of healthy young blood cells (called stem cells) to be reintroduced, or transplanted. The transplanted cells reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
The current data indicate that there is no clear advantage to stem cell transplantation as compared to chemotherapy during consolidation therapy for standard risk patients during the first complete remission, although it may shorten the overall treatment course. However, allogeneic stem cell transplantation is recommended following a second complete remission, if necessary, and for subsets of patients with more aggressive forms of ALL in first remission. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor, or MRD). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor, or MUD). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or total body radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. Autologous transplantation, which uses the patient's own stem cells collected while the patient is in complete remission, is of no greater benefit than chemotherapy for adults with ALL. Thus, it is not recommended.
MAINTENANCE THERAPY — Remission maintenance therapy or remission continuation therapy is a standard part of ALL treatment, although research studies have not clearly shown its benefit for adults. It is also unclear how long therapy should continue. Depending upon the program chosen, treatment is often continued for two to two and one-half years (show table 1).
During maintenance treatment, oral medications (pills) are taken on certain days of the month and intravenous (IV) chemotherapy may be given into a vein once per month. Side effects during this phase of treatment are less frequent and less severe than those experienced during earlier stages of treatment. Most people are able to return to full activity during their maintenance treatment period.
RESIDUAL DISEASE AND RELAPSE RISK — Following the standard two to three years of treatment, patients in complete clinical remission should have a bone marrow aspiration and biopsy repeated every three to six months for at least the next two years. This allows for early detection and treatment if relapse were to occur. Patients with ALL who maintain complete, continuous remission for four to five years are considered cured and no longer need routine bone marrow examination. However, relapses of ALL as long as 21 years after diagnosis have been reported.
Unfortunately, up to 25 percent of adults with ALL are resistant to the initial induction of remission. In addition, many adults with ALL who do attain an initial complete remission will ultimately suffer a relapse. Although a second remission can often be achieved, retreatment of such patients is generally unsuccessful in the long run, and most will die of their disease or of complications of treatment. In patients with ALL who received hematopoietic cell transplantation and were in complete remission at two years, the overall chance of being alive in complete remission at nine years was 82 percent [1]. The latest relapses in this group occurred at four to seven years.
Treatment of relapse or resistant disease — A second remission may be attained using a similar induction regimen if the relapse occurs more than two years following initial treatment. However, this approach is not recommended if a patient has primary resistant disease (complete remission was never attained) or for those who relapse while receiving induction or maintenance therapy.
Salvage regimens are treatments used after all other available treatments have failed. They are intended to reduce symptoms and prolong survival, but may not be able to cure the disease. Optimally, such patients should enroll onto a clinical trial specifically designed for treatment of resistant ALL with new agents alone or in combination. Allogeneic stem cell transplantation is also a reasonable option for selected patients with resistant or relapsed disease.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked to enroll in a clinical research trial. A clinical trial is a controlled way to study the effectiveness of new treatments or new combinations of known therapies. They are carefully designed and reviewed by experts in the field to provide state-of-the-art care for individual patients as well as to improve the outcomes of patients overall. Additional information concerning clinical trials for ALL can be obtained from the treatment team or the following websites: www.cancer.gov/clinical_trials http://clinicaltrials.gov
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Frassoni, F, Labopin, M, Gluckman, E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 1994; 8:924.
2. Brincker, H, Christensen, BE. Long-term survival and late relapses in acute leukaemia in adults. Br J Haematol 1990; 74:156.
3. Laport, GF, Larson, RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24:70.
4. Hoelzer, D. Gokbuget, N New approaches to acute lymphoblastic leukemia in adults: Where do we go? Semin Oncol 2000; 27:540.
5. Weisdorf, DJ, Woods, WG, Nesbit, ME Jr, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcomes. Br J Haematol 1994; 86:62.
Normally, lymphocytes and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with ALL, this production process is abnormal. Large numbers of immature and abnormal lymphocytes (lymphoblasts) are produced and released into the blood stream. In their immature state, they cannot perform their usual functions, leaving the person vulnerable to anemia, infection and bleeding.
The overproduction of lymphoblasts prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells (especially neutrophils, sometimes called "polys"), and platelets. The lymphoblasts can collect in certain areas of the body, such as the brain, spinal cord, and lymph nodes (glands).
GENERAL INFORMATION ABOUT TREATMENT — A number of medications, or chemotherapy agents, are known to be effective against ALL. However, the best combination of medicines or the best treatment schedule is still not known. Because there are so many different medicines, dosing schedules, and combinations, it has been difficult to study any one component of treatment thoroughly. Still, general principles of treatment have emerged and are followed in most cancer treatment centers, although the exact regimens given may vary from one center to another. Regimens can also vary based on characteristics such as the age of the patient, the total number of white blood cells, or characteristics of the acquired genetic changes in the leukemia cells, found in some patients with ALL.
Side effects of treatment will depend on the actual medicines being used, the schedule of treatment, and other factors. Many of the chemotherapy medicines used to treat ALL share common side effects such as loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is generally recommended. For example, anti-nausea medicines can be very effective in preventing nausea and vomiting, and mouth care can reduce the discomfort associated with sores in the mouth.
The usual treatment for ALL can be divided into three phases: induction of remission, consolidation/intensification of therapy, and maintenance. A summary of the entire treatment process is available in table 1 (show table 1). Patients with high risk disease (examples include those with Philadelphia chromosome positive (Ph+) ALL and Burkitts leukemia) require special treatment programs that use medications and doses different from those used in patients with standard risk ALL. In addition, allogeneic stem cell transplantation is more frequently recommended in these patients.
INDUCTION OF REMISSION — This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. Treatment includes: vincristine (Oncovin) and an anthracycline (such as daunorubicin or doxorubicin) along with prednisone, dexamethasone, or another steroid hormone (show table 1).
Vincristine and the anthracycline drugs are anti-cancer chemotherapy drugs. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Vincristine and the anthracycline drugs are given through an intravenous (IV) line. Prednisone can be given either by mouth or IV. Other medicines such as cyclophosphamide (Cytoxan, given IV) or L-asparaginase (Elspar, given as a subcutaneous, intramuscular or IV injection) may also be given. In one study of 204 patients treated with cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (abbreviated as Hyper-CVAD), complete remission was obtained in 91 percent, with 42 percent of patients still in remission after an average of 40 months.
Approximately 80 percent of newly diagnosed adults with ALL enter complete remission, meaning that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional chemotherapy is given. Additional phases of treatment are described in the following sections.
CONSOLIDATION/INTENSIFICATION THERAPY — Once remission is achieved, additional therapy is needed to avoid relapse. Relapse is thought to occur because minimal residual disease is still present, even though it cannot be detected by routine examination of the blood or bone marrow.
Chemotherapy — Some of the same medicines given during induction are also used during remission consolidation therapy, which may last for several months. Most of this treatment can take place without staying overnight in the hospital (show table 1).
In addition to scheduled doses of chemotherapy, many treatment programs call for preventive treatment of the central nervous system (the brain and spinal cord). Abnormal lymphoblasts in the brain often do not respond to chemotherapy given only into a vein, but must be treated directly with radiation to the head and/or injection of chemotherapy, such as methotrexate, into the fluid surrounding the spinal cord and brain, through a lumbar puncture (also called a spinal tap).
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or total body radiation, called myeloablative treatment. This kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (the bone marrow) is no longer functional.
Attempts have been made to reduce the dose of chemotherapy or radiation for some patients, especially those who are older. This is called a non-myeloablative transplantation regimen. The hope with this regimen is that it would reduce early transplant related illness and death. However, the value of this regimen, as compared to its risks and expense, remains to be determined.
After the treatment, the patient requires a supply of healthy young blood cells (called stem cells) to be reintroduced, or transplanted. The transplanted cells reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
The current data indicate that there is no clear advantage to stem cell transplantation as compared to chemotherapy during consolidation therapy for standard risk patients during the first complete remission, although it may shorten the overall treatment course. However, allogeneic stem cell transplantation is recommended following a second complete remission, if necessary, and for subsets of patients with more aggressive forms of ALL in first remission. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor, or MRD). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor, or MUD). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or total body radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. Autologous transplantation, which uses the patient's own stem cells collected while the patient is in complete remission, is of no greater benefit than chemotherapy for adults with ALL. Thus, it is not recommended.
MAINTENANCE THERAPY — Remission maintenance therapy or remission continuation therapy is a standard part of ALL treatment, although research studies have not clearly shown its benefit for adults. It is also unclear how long therapy should continue. Depending upon the program chosen, treatment is often continued for two to two and one-half years (show table 1).
During maintenance treatment, oral medications (pills) are taken on certain days of the month and intravenous (IV) chemotherapy may be given into a vein once per month. Side effects during this phase of treatment are less frequent and less severe than those experienced during earlier stages of treatment. Most people are able to return to full activity during their maintenance treatment period.
RESIDUAL DISEASE AND RELAPSE RISK — Following the standard two to three years of treatment, patients in complete clinical remission should have a bone marrow aspiration and biopsy repeated every three to six months for at least the next two years. This allows for early detection and treatment if relapse were to occur. Patients with ALL who maintain complete, continuous remission for four to five years are considered cured and no longer need routine bone marrow examination. However, relapses of ALL as long as 21 years after diagnosis have been reported.
Unfortunately, up to 25 percent of adults with ALL are resistant to the initial induction of remission. In addition, many adults with ALL who do attain an initial complete remission will ultimately suffer a relapse. Although a second remission can often be achieved, retreatment of such patients is generally unsuccessful in the long run, and most will die of their disease or of complications of treatment. In patients with ALL who received hematopoietic cell transplantation and were in complete remission at two years, the overall chance of being alive in complete remission at nine years was 82 percent [1]. The latest relapses in this group occurred at four to seven years.
Treatment of relapse or resistant disease — A second remission may be attained using a similar induction regimen if the relapse occurs more than two years following initial treatment. However, this approach is not recommended if a patient has primary resistant disease (complete remission was never attained) or for those who relapse while receiving induction or maintenance therapy.
Salvage regimens are treatments used after all other available treatments have failed. They are intended to reduce symptoms and prolong survival, but may not be able to cure the disease. Optimally, such patients should enroll onto a clinical trial specifically designed for treatment of resistant ALL with new agents alone or in combination. Allogeneic stem cell transplantation is also a reasonable option for selected patients with resistant or relapsed disease.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked to enroll in a clinical research trial. A clinical trial is a controlled way to study the effectiveness of new treatments or new combinations of known therapies. They are carefully designed and reviewed by experts in the field to provide state-of-the-art care for individual patients as well as to improve the outcomes of patients overall. Additional information concerning clinical trials for ALL can be obtained from the treatment team or the following websites: www.cancer.gov/clinical_trials http://clinicaltrials.gov
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Frassoni, F, Labopin, M, Gluckman, E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 1994; 8:924.
2. Brincker, H, Christensen, BE. Long-term survival and late relapses in acute leukaemia in adults. Br J Haematol 1990; 74:156.
3. Laport, GF, Larson, RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24:70.
4. Hoelzer, D. Gokbuget, N New approaches to acute lymphoblastic leukemia in adults: Where do we go? Semin Oncol 2000; 27:540.
5. Weisdorf, DJ, Woods, WG, Nesbit, ME Jr, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcomes. Br J Haematol 1994; 86:62.
Treatment of acute lymphoblastic leukemia (ALL) in adults
INTRODUCTION — Acute lymphoblastic leukemia (ALL), also known as lymphoblastic lymphoma when the disease primarily involves lymph nodes rather than the blood and bone marrow, is a cancer of blood cells. It involves a type of white blood cell called a lymphocyte. Acute means that it develops and advances quickly, requiring immediate treatment.
Normally, lymphocytes and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with ALL, this production process is abnormal. Large numbers of immature and abnormal lymphocytes (lymphoblasts) are produced and released into the blood stream. In their immature state, they cannot perform their usual functions, leaving the person vulnerable to anemia, infection and bleeding.
The overproduction of lymphoblasts prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells (especially neutrophils, sometimes called "polys"), and platelets. The lymphoblasts can collect in certain areas of the body, such as the brain, spinal cord, and lymph nodes (glands).
GENERAL INFORMATION ABOUT TREATMENT — A number of medications, or chemotherapy agents, are known to be effective against ALL. However, the best combination of medicines or the best treatment schedule is still not known. Because there are so many different medicines, dosing schedules, and combinations, it has been difficult to study any one component of treatment thoroughly. Still, general principles of treatment have emerged and are followed in most cancer treatment centers, although the exact regimens given may vary from one center to another. Regimens can also vary based on characteristics such as the age of the patient, the total number of white blood cells, or characteristics of the acquired genetic changes in the leukemia cells, found in some patients with ALL.
Side effects of treatment will depend on the actual medicines being used, the schedule of treatment, and other factors. Many of the chemotherapy medicines used to treat ALL share common side effects such as loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is generally recommended. For example, anti-nausea medicines can be very effective in preventing nausea and vomiting, and mouth care can reduce the discomfort associated with sores in the mouth.
The usual treatment for ALL can be divided into three phases: induction of remission, consolidation/intensification of therapy, and maintenance. A summary of the entire treatment process is available in table 1 (show table 1). Patients with high risk disease (examples include those with Philadelphia chromosome positive (Ph+) ALL and Burkitts leukemia) require special treatment programs that use medications and doses different from those used in patients with standard risk ALL. In addition, allogeneic stem cell transplantation is more frequently recommended in these patients.
INDUCTION OF REMISSION — This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. Treatment includes: vincristine (Oncovin) and an anthracycline (such as daunorubicin or doxorubicin) along with prednisone, dexamethasone, or another steroid hormone (show table 1).
Vincristine and the anthracycline drugs are anti-cancer chemotherapy drugs. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Vincristine and the anthracycline drugs are given through an intravenous (IV) line. Prednisone can be given either by mouth or IV. Other medicines such as cyclophosphamide (Cytoxan, given IV) or L-asparaginase (Elspar, given as a subcutaneous, intramuscular or IV injection) may also be given. In one study of 204 patients treated with cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (abbreviated as Hyper-CVAD), complete remission was obtained in 91 percent, with 42 percent of patients still in remission after an average of 40 months.
Approximately 80 percent of newly diagnosed adults with ALL enter complete remission, meaning that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional chemotherapy is given. Additional phases of treatment are described in the following sections.
CONSOLIDATION/INTENSIFICATION THERAPY — Once remission is achieved, additional therapy is needed to avoid relapse. Relapse is thought to occur because minimal residual disease is still present, even though it cannot be detected by routine examination of the blood or bone marrow.
Chemotherapy — Some of the same medicines given during induction are also used during remission consolidation therapy, which may last for several months. Most of this treatment can take place without staying overnight in the hospital (show table 1).
In addition to scheduled doses of chemotherapy, many treatment programs call for preventive treatment of the central nervous system (the brain and spinal cord). Abnormal lymphoblasts in the brain often do not respond to chemotherapy given only into a vein, but must be treated directly with radiation to the head and/or injection of chemotherapy, such as methotrexate, into the fluid surrounding the spinal cord and brain, through a lumbar puncture (also called a spinal tap).
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or total body radiation, called myeloablative treatment. This kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (the bone marrow) is no longer functional.
Attempts have been made to reduce the dose of chemotherapy or radiation for some patients, especially those who are older. This is called a non-myeloablative transplantation regimen. The hope with this regimen is that it would reduce early transplant related illness and death. However, the value of this regimen, as compared to its risks and expense, remains to be determined.
After the treatment, the patient requires a supply of healthy young blood cells (called stem cells) to be reintroduced, or transplanted. The transplanted cells reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
The current data indicate that there is no clear advantage to stem cell transplantation as compared to chemotherapy during consolidation therapy for standard risk patients during the first complete remission, although it may shorten the overall treatment course. However, allogeneic stem cell transplantation is recommended following a second complete remission, if necessary, and for subsets of patients with more aggressive forms of ALL in first remission. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor, or MRD). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor, or MUD). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or total body radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. Autologous transplantation, which uses the patient's own stem cells collected while the patient is in complete remission, is of no greater benefit than chemotherapy for adults with ALL. Thus, it is not recommended.
MAINTENANCE THERAPY — Remission maintenance therapy or remission continuation therapy is a standard part of ALL treatment, although research studies have not clearly shown its benefit for adults. It is also unclear how long therapy should continue. Depending upon the program chosen, treatment is often continued for two to two and one-half years (show table 1).
During maintenance treatment, oral medications (pills) are taken on certain days of the month and intravenous (IV) chemotherapy may be given into a vein once per month. Side effects during this phase of treatment are less frequent and less severe than those experienced during earlier stages of treatment. Most people are able to return to full activity during their maintenance treatment period.
RESIDUAL DISEASE AND RELAPSE RISK — Following the standard two to three years of treatment, patients in complete clinical remission should have a bone marrow aspiration and biopsy repeated every three to six months for at least the next two years. This allows for early detection and treatment if relapse were to occur. Patients with ALL who maintain complete, continuous remission for four to five years are considered cured and no longer need routine bone marrow examination. However, relapses of ALL as long as 21 years after diagnosis have been reported.
Unfortunately, up to 25 percent of adults with ALL are resistant to the initial induction of remission. In addition, many adults with ALL who do attain an initial complete remission will ultimately suffer a relapse. Although a second remission can often be achieved, retreatment of such patients is generally unsuccessful in the long run, and most will die of their disease or of complications of treatment. In patients with ALL who received hematopoietic cell transplantation and were in complete remission at two years, the overall chance of being alive in complete remission at nine years was 82 percent [1]. The latest relapses in this group occurred at four to seven years.
Treatment of relapse or resistant disease — A second remission may be attained using a similar induction regimen if the relapse occurs more than two years following initial treatment. However, this approach is not recommended if a patient has primary resistant disease (complete remission was never attained) or for those who relapse while receiving induction or maintenance therapy.
Salvage regimens are treatments used after all other available treatments have failed. They are intended to reduce symptoms and prolong survival, but may not be able to cure the disease. Optimally, such patients should enroll onto a clinical trial specifically designed for treatment of resistant ALL with new agents alone or in combination. Allogeneic stem cell transplantation is also a reasonable option for selected patients with resistant or relapsed disease.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked to enroll in a clinical research trial. A clinical trial is a controlled way to study the effectiveness of new treatments or new combinations of known therapies. They are carefully designed and reviewed by experts in the field to provide state-of-the-art care for individual patients as well as to improve the outcomes of patients overall. Additional information concerning clinical trials for ALL can be obtained from the treatment team or the following websites: www.cancer.gov/clinical_trials http://clinicaltrials.gov
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Frassoni, F, Labopin, M, Gluckman, E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 1994; 8:924.
2. Brincker, H, Christensen, BE. Long-term survival and late relapses in acute leukaemia in adults. Br J Haematol 1990; 74:156.
3. Laport, GF, Larson, RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24:70.
4. Hoelzer, D. Gokbuget, N New approaches to acute lymphoblastic leukemia in adults: Where do we go? Semin Oncol 2000; 27:540.
5. Weisdorf, DJ, Woods, WG, Nesbit, ME Jr, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcomes. Br J Haematol 1994; 86:62.
Normally, lymphocytes and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with ALL, this production process is abnormal. Large numbers of immature and abnormal lymphocytes (lymphoblasts) are produced and released into the blood stream. In their immature state, they cannot perform their usual functions, leaving the person vulnerable to anemia, infection and bleeding.
The overproduction of lymphoblasts prevents the bone marrow from producing other important blood cells, including red blood cells, other types of white blood cells (especially neutrophils, sometimes called "polys"), and platelets. The lymphoblasts can collect in certain areas of the body, such as the brain, spinal cord, and lymph nodes (glands).
GENERAL INFORMATION ABOUT TREATMENT — A number of medications, or chemotherapy agents, are known to be effective against ALL. However, the best combination of medicines or the best treatment schedule is still not known. Because there are so many different medicines, dosing schedules, and combinations, it has been difficult to study any one component of treatment thoroughly. Still, general principles of treatment have emerged and are followed in most cancer treatment centers, although the exact regimens given may vary from one center to another. Regimens can also vary based on characteristics such as the age of the patient, the total number of white blood cells, or characteristics of the acquired genetic changes in the leukemia cells, found in some patients with ALL.
Side effects of treatment will depend on the actual medicines being used, the schedule of treatment, and other factors. Many of the chemotherapy medicines used to treat ALL share common side effects such as loss of hair (which is temporary), nausea and vomiting, mouth sores, and an increased risk of infections and bleeding. Treatment to minimize these side effects is generally recommended. For example, anti-nausea medicines can be very effective in preventing nausea and vomiting, and mouth care can reduce the discomfort associated with sores in the mouth.
The usual treatment for ALL can be divided into three phases: induction of remission, consolidation/intensification of therapy, and maintenance. A summary of the entire treatment process is available in table 1 (show table 1). Patients with high risk disease (examples include those with Philadelphia chromosome positive (Ph+) ALL and Burkitts leukemia) require special treatment programs that use medications and doses different from those used in patients with standard risk ALL. In addition, allogeneic stem cell transplantation is more frequently recommended in these patients.
INDUCTION OF REMISSION — This phase of treatment takes about four weeks and is almost always performed while the patient remains in the hospital. Treatment includes: vincristine (Oncovin) and an anthracycline (such as daunorubicin or doxorubicin) along with prednisone, dexamethasone, or another steroid hormone (show table 1).
Vincristine and the anthracycline drugs are anti-cancer chemotherapy drugs. These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including anemia (lowered red blood cell count), susceptibility to infection (lowered white blood cell count) and bleeding (lowered platelet count).
Vincristine and the anthracycline drugs are given through an intravenous (IV) line. Prednisone can be given either by mouth or IV. Other medicines such as cyclophosphamide (Cytoxan, given IV) or L-asparaginase (Elspar, given as a subcutaneous, intramuscular or IV injection) may also be given. In one study of 204 patients treated with cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (abbreviated as Hyper-CVAD), complete remission was obtained in 91 percent, with 42 percent of patients still in remission after an average of 40 months.
Approximately 80 percent of newly diagnosed adults with ALL enter complete remission, meaning that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional chemotherapy is given. Additional phases of treatment are described in the following sections.
CONSOLIDATION/INTENSIFICATION THERAPY — Once remission is achieved, additional therapy is needed to avoid relapse. Relapse is thought to occur because minimal residual disease is still present, even though it cannot be detected by routine examination of the blood or bone marrow.
Chemotherapy — Some of the same medicines given during induction are also used during remission consolidation therapy, which may last for several months. Most of this treatment can take place without staying overnight in the hospital (show table 1).
In addition to scheduled doses of chemotherapy, many treatment programs call for preventive treatment of the central nervous system (the brain and spinal cord). Abnormal lymphoblasts in the brain often do not respond to chemotherapy given only into a vein, but must be treated directly with radiation to the head and/or injection of chemotherapy, such as methotrexate, into the fluid surrounding the spinal cord and brain, through a lumbar puncture (also called a spinal tap).
Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic cell transplantation, is a treatment in which the patient is given very high doses of chemotherapy or total body radiation, called myeloablative treatment. This kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal source of critical blood components (the bone marrow) is no longer functional.
Attempts have been made to reduce the dose of chemotherapy or radiation for some patients, especially those who are older. This is called a non-myeloablative transplantation regimen. The hope with this regimen is that it would reduce early transplant related illness and death. However, the value of this regimen, as compared to its risks and expense, remains to be determined.
After the treatment, the patient requires a supply of healthy young blood cells (called stem cells) to be reintroduced, or transplanted. The transplanted cells reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
The current data indicate that there is no clear advantage to stem cell transplantation as compared to chemotherapy during consolidation therapy for standard risk patients during the first complete remission, although it may shorten the overall treatment course. However, allogeneic stem cell transplantation is recommended following a second complete remission, if necessary, and for subsets of patients with more aggressive forms of ALL in first remission. Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor, or MRD). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor, or MUD). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.
Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or total body radiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are injected, the donor stem cells undergo an immune response that helps destroy any remaining leukemia cells. This is called the "graft versus leukemia" or "graft versus tumor" effect. Unfortunately, this response is closely associated with a complication called "graft versus host disease", in which the immune response includes an attack on some of the patient's own organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems. Still, allogeneic transplant is preferred over autologous transplantation in patients with ALL. Autologous transplantation, which uses the patient's own stem cells collected while the patient is in complete remission, is of no greater benefit than chemotherapy for adults with ALL. Thus, it is not recommended.
MAINTENANCE THERAPY — Remission maintenance therapy or remission continuation therapy is a standard part of ALL treatment, although research studies have not clearly shown its benefit for adults. It is also unclear how long therapy should continue. Depending upon the program chosen, treatment is often continued for two to two and one-half years (show table 1).
During maintenance treatment, oral medications (pills) are taken on certain days of the month and intravenous (IV) chemotherapy may be given into a vein once per month. Side effects during this phase of treatment are less frequent and less severe than those experienced during earlier stages of treatment. Most people are able to return to full activity during their maintenance treatment period.
RESIDUAL DISEASE AND RELAPSE RISK — Following the standard two to three years of treatment, patients in complete clinical remission should have a bone marrow aspiration and biopsy repeated every three to six months for at least the next two years. This allows for early detection and treatment if relapse were to occur. Patients with ALL who maintain complete, continuous remission for four to five years are considered cured and no longer need routine bone marrow examination. However, relapses of ALL as long as 21 years after diagnosis have been reported.
Unfortunately, up to 25 percent of adults with ALL are resistant to the initial induction of remission. In addition, many adults with ALL who do attain an initial complete remission will ultimately suffer a relapse. Although a second remission can often be achieved, retreatment of such patients is generally unsuccessful in the long run, and most will die of their disease or of complications of treatment. In patients with ALL who received hematopoietic cell transplantation and were in complete remission at two years, the overall chance of being alive in complete remission at nine years was 82 percent [1]. The latest relapses in this group occurred at four to seven years.
Treatment of relapse or resistant disease — A second remission may be attained using a similar induction regimen if the relapse occurs more than two years following initial treatment. However, this approach is not recommended if a patient has primary resistant disease (complete remission was never attained) or for those who relapse while receiving induction or maintenance therapy.
Salvage regimens are treatments used after all other available treatments have failed. They are intended to reduce symptoms and prolong survival, but may not be able to cure the disease. Optimally, such patients should enroll onto a clinical trial specifically designed for treatment of resistant ALL with new agents alone or in combination. Allogeneic stem cell transplantation is also a reasonable option for selected patients with resistant or relapsed disease.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked to enroll in a clinical research trial. A clinical trial is a controlled way to study the effectiveness of new treatments or new combinations of known therapies. They are carefully designed and reviewed by experts in the field to provide state-of-the-art care for individual patients as well as to improve the outcomes of patients overall. Additional information concerning clinical trials for ALL can be obtained from the treatment team or the following websites: www.cancer.gov/clinical_trials http://clinicaltrials.gov
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Frassoni, F, Labopin, M, Gluckman, E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 1994; 8:924.
2. Brincker, H, Christensen, BE. Long-term survival and late relapses in acute leukaemia in adults. Br J Haematol 1990; 74:156.
3. Laport, GF, Larson, RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24:70.
4. Hoelzer, D. Gokbuget, N New approaches to acute lymphoblastic leukemia in adults: Where do we go? Semin Oncol 2000; 27:540.
5. Weisdorf, DJ, Woods, WG, Nesbit, ME Jr, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcomes. Br J Haematol 1994; 86:62.
Chronic myelogenous leukemia (CML)
INTRODUCTION — Chronic myelogenous leukemia (also called CML, chronic myelocytic leukemia, or chronic myeloid leukemia) is a chronic (long-term) disorder of the bone marrow. Bone marrow is the spongy, red tissue that fills the large bones.
Patients with CML have acquired an abnormality that causes one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.
The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme; this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease can transform into an acute leukemia, with an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which results in difficulty fighting infection and which limits production of other vital blood cells, including red blood cells and platelets.
PHASES OF CML — There are three phases of CML:
Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells circulating in the blood and in the bone marrow. Approximately 85 percent of patients are in the chronic phase when initially diagnosed. This phase generally lasts several years and is readily controllable with oral chemotherapy medications.
Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 5 and 30 percent blast cells in the blood and bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.
Blast phase — In blast crisis (blast phase), there are more than 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.
TREATMENT OPTIONS — Treatment decisions for patients with CML are complex due to the variety of available options and the lack of long term follow-up results for the newer, simpler options. Currently, the most frequently used treatment options include: Stem cell transplantation (also called bone marrow transplantation), which may be considered in younger patients with stable disease who have a suitable donor Oral tyrosine kinase inhibitors such as imatinib (Gleevec®) or dasatinib (Sprycel®) Injections of interferon alpha with or without cytarabine, now used infrequently in newly diagnosed patients.
The primary goal of treatment is to markedly reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood count to normal. This is measured as the hematologic response. While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved.
The "best" form of response, however, is seen when sensitive molecular testing shows no evidence of the BCR-ABL gene. This is called a molecular response. It is the goal of bone marrow transplantation to achieve this level of response. Longer term follow up of patients treated with imatinib indicate that some of these patients have a molecular response as well. Chemotherapy, on the other hand, only occasionally produces such a response.
TYROSINE KINASE INHIBITORS — The consequence of the Philadelphia chromosome is the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. As a result, researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme. Tyrosine kinase inhibitors slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the Philadelphia chromosomes. Normal cells suffer less toxic effects from tyrosine kinase inhibitors as compared to traditional chemotherapy treatments.
Imatinib (Gleevec®) — Imatinib mesylate is a tyrosine kinase inhibitor that can be used in patients with all phases of CML. It is proven to have significant benefits; one study comparing imatinib to interferon plus cytarabine (a form of chemotherapy) for patients with newly diagnosed, chronic phase CML found that 97 percent of patients receiving imatinib had a complete hematological response rate, and 76 percent achieved a complete cytogenetic response [1]. Treatment with interferon plus cytarabine was less effective.
Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in patients followed for six or more years who achieved a complete cytogenic response. At the current time, experts recommend continuing Gleevec® treatment indefinitely as the disease will recur, often within months, in the majority of patients who stop taking it. Progression to blast crisis can occur despite Gleevec® treatment in patients with advanced disease and in those who acquire new genetic mutations.
The recommended initial starting dose of Gleevec® is 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase or blast crisis. A higher dose of Gleevec® (400 mg twice a day) may be associated with a faster or better response, defined as more patients achieving a cytogenetic response. This dose should currently be reserved for patients enrolled in clinical trials.
The medication should be taken by mouth once daily, with a meal and a large glass of water.
Side effects — Gleevec® is generally very well tolerated; most side effects are mild to moderate and do not cause patients to stop taking it. Common side effects include: Nausea and vomiting, although this is not usually a problem when the drug is taken with meals. Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with immodium. Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting calves, feet, and hands. There is no definitive treatment, although some patients benefit from treatment with calcium or magnesium supplements, or the use of quinine. Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment. Breast enlargement (gynecomastia) may occur in a small number of men. Mild anemia is not uncommon in patients who use Gleevec® for long periods.
Acetaminophen (Tylenol®) and St. John's wort (hypericum perforatum) should be avoided while taking Gleevec® due to the risk of a drug interaction.
Pregnancy — Women and men who take Gleevec® usually have no increased difficulty achieving pregnancy. However, the risk of miscarriage and birth defects while taking Gleevec® is uncertain. It is strongly recommended that patients with CML use a birth control method during Gleevec® treatment. It should not be used by patients who are pregnant or breastfeeding.
Dasatinib (Sprycel®) — For patients who cannot tolerate, fail to respond, or stop responding to imatinib, alternative tyrosine kinase inhibitors are being developed. Dasatinib is now available for these patients, and both hematologic and cytogenetic responses have been seen in all stages of the disease.
However, more information about the long-term effectiveness and side effects of this medication are needed. Clinical trials are being planned to determine whether dasatinib and other alternative tyrosine kinase inhibitors can be used, either alone or in combination with Gleevec® or other agents, as initial therapy. Combinations of drugs should be not be used by patients unless they are enrolled in a well-designed clinical trial.
INTERFERON ALPHA — Interferon alpha (IFNa, Roferon-A®) and the recombinant form, IFNa-2a, were commonly used in the past for treatment of patients with CML. However, studies comparing IFNa to Gleevec® show clear superiority for Gleevec®. This, combined with the higher frequency of side effects with IFNa, has limited its use. A patient who cannot tolerate Gleevec or any other tyrosine kinase inhibitor could be offered IFNa with or without another chemotherapy medication, cytarabine.
Side effects — Side effects are a major problem with IFNa-2a, and include fever, chills, and flu-like symptoms. Typically, the drug is started at a relatively low dose three days per week and then slowly increased. IFNa must be injected, and many patients prefer to take their injection at night along with acetaminophen (Tylenol) and an antihistamine such as diphenhydramine (Benadryl) to minimize the side effects.
STEM CELL TRANSPLANTATION — In stem cell transplantation, also referred to as bone marrow transplantation or hematopoietic cell transplantation, the patient's diseased bone marrow (hematopoietic) cells are replaced with healthy ones from a donor. (See "Patient information: Overview of bone marrow transplantation").
A number of options are available when transplantation is considered: Hematopoietic stem (or progenitor) cells can be obtained from a patient or donor's bone marrow or blood, or from blood taken from the umbilical cord of an infant immediately after birth. The donor may be the patient (autologous transplant) or an identical twin (syngeneic transplant). Autologous hematopoietic cell transplantation uses the patient's own blood cells or bone marrow for transplantation. The patient's own hematopoietic cells are removed from the body, chemotherapy is given to reduce the number of abnormal cells, and then the stored cells are retransplanted into the patient. This type of transplantation has been explored in a limited number of patients with CML. However, autologous transplantation is not generally effective in CML and most patients do not have an identical twin. In addition, in CML, the use of an identical twin has been associated with a higher risk of disease relapse compared to a matched related or unrelated donor. More commonly, the donor is a person other than the patient or an identical twin; this is called an allogeneic transplant. Allogeneic transplants can come from a relative (eg, sibling) or from an unrelated donor. It is important to find a donor whose stem cells closely match those of the patient, but this may not always be necessary. Doctors look for matching proteins (human leukocyte antigen or HLA) on stem cells from the donor. The goal is for the donated hematopoietic stem cells (the graft) to be accepted (engrafted) by the patient's body (the host) and begin producing normal mature blood cells. Related or unrelated donors are preferred to be fully HLA-matched. Under some circumstances, half-matched (haploidentical) or mismatched donors can be used. Preparative treatments with chemotherapy and/or radiation that fully destroy (myeloablative) or do not fully destroy (nonmyeloablative) bone marrow activity must be used in order for the transplant to be effective.
In CML, the results obtained with hematopoietic cell transplantation (HCT) are directly related to the phase of disease at the time of the transplant. In the past, among patients in chronic phase, transplantation within the first year resulted in the best outcomes. It is not clear in patients treated with imatinib if longer delays to transplantation compromise the outcome.
Related donors — If a matched sibling donor can be found, 50 to 75 percent of patients with CML transplanted in the first or second chronic phase of their disease achieve long-term remissions. Disease-free survival falls to 30 to 40 percent in patients transplanted in the accelerated phase, and to 10 to 20 percent in patients transplanted in blastic phase.
For patients in blast phase, giving chemotherapy or Gleevec® prior to transplantation to achieve a second chronic phase may be preferable to transplanting during the blast phase.
Patient age has a major influence on the outcome after transplantation with cells from a sibling donor. In the subgroup of patients under age 50 who undergo this procedure during the first year of diagnosis, 70 to 85 percent will be alive and free of disease five years later. However, patients up to 60 years of age have successfully undergone allogeneic transplantation with treatments that completely destroy bone marrow. The development of regimens that do not completely destroy the bone and have reduced toxicity has permitted even older patients to be successfully transplanted.
Matched unrelated donors — For patients without an HLA-matched sibling donor, matched unrelated donor (URD) transplantation has been explored. An important advance with this procedure has been the development of techniques that permit tissue matching using molecular typing.
Because of the relatively slow pace of CML, there is usually adequate time to perform a search for a matched unrelated donor through the National Marrow Donor Program and other donor agencies. This search may take up to three to six months to complete; it may be less successful in certain minority populations that are under-represented within the donor programs.
In a 1998 report involving 196 patients receiving a matched unrelated donor (URD) transplant, estimated five year survival was 74 percent in patients who were 50 years of age or younger and transplanted within one year after diagnosis; this value is similar to that achieved with matched sibling donors (70 to 80 percent).
Other donor sources — For patients without a matched sibling or matched unrelated donor, other donor sources have been used. Among the options are transplants using hematopoietic cells from haploidentical (partially HLA-matched) donors or those found in blood taken from the umbilical cord of healthy unrelated newborn infants.
Risks — There are a number of serious risks following allogeneic transplantation. These include: Toxicity of the treatment (eg, chemotherapy, radiation therapy) used to prepare the patient for the transplant. These include life-threatening bacterial, viral, or fungal infection, anemia, and bleeding. When the transplant donor is not the patient or an identical twin, cells of the immune system within the graft may attack the new host (patient), causing what is called graft-versus-host disease (GVHD). GVHD is the major cause of death following transplantation. GVHD requires treatment with anti-rejection medications, such as tacrolimus, cyclosporine, and prednisone. These medications may be given to prevent or treat GVHD. The graft may fail to take (engraft), leaving the patient with reduced immunity and reduced numbers of bone marrow cells unless and until the patient's own bone marrow recovers or the patient receives a second transplant. However, this is an uncommon problem when matched donors are used.
Relapse after transplant — Relapse, or recurrence, of CML may occur if sufficient numbers of Philadelphia chromosomes remain after the transplant procedure. However, finding residual disease with sensitive molecular tests in the first 6 months following transplantation is not associated with eventual relapse because the anti-tumor effects of the graft may eventually prevail.
Relapse can be treated with imatinib or dasatinib or with infusions of leukocytes from the original donor, with the hope of mounting a graft-versus-tumor effect. Donor leukocyte infusions (DLIs) can be extremely effective, and remissions attained after DLI appear to be quite durable. However, graft-versus-host disease, and in some instances graft failure, may complicate DLI
Deciding between transplantation and imatinib — The major decision facing newly diagnosed patients is whether to proceed with transplantation or to be treated initially with imatinib, reserving transplantation if imatinib not produce a complete cytogenetic response. There have not been any randomized clinical trials directly comparing chemotherapy (eg, interferon, Gleevec®) to hematopoietic stem cell transplantation in newly diagnosed patients. From analyses comparing transplantation with the use of interferon, the following general results can be noted: There was a higher mortality for the first 18 months in those treated with transplantation. Thus, an unsuccessful transplant can actually shorten a patient's life. The mortality was similar in the two groups between 18 and 56 months After 56 months, mortality was significantly lower in the transplanted patients and the probability of being alive at seven years was also higher in the transplant group (58 versus 32 percent). Thus, successful allogeneic transplantation can produce long term suppression of disease with a very low chance of relapse because such patients have a molecular, cytogenetic, and hematologic response) as assessed by even the most sensitive of testing procedures (ie, the polymerase chain reaction technique).
RECOMMENDATIONS — The treatment of CML is complex, and the optimal treatment is a source of considerable debate. Therefore, consultation with a physician familiar with the latest data is critical. Allogeneic HCT remains the only treatment approach that is known to cure CML. Younger patients in the chronic phase who have a suitably matched sibling donor should discuss this option in detail. The results with matched unrelated donor transplantation continue to improve, which can increase the number of possible donors. Imatinib (Gleevec®) therapy is preferred by most patients, and an expert panel has recommended the use of imatinib as the initial treatment for most patients with newly diagnosed chronic phase CML. Careful evaluation of the quality and duration of the response to Gleevec® is very important in deciding whether and when to proceed to transplantation. It is critically important that the depth and quality of the response be frequently evaluated using sensitive cytogenetic and molecular techniques in a laboratory qualified to perform these tests.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[2-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. O'Brien, SG, Guilhot, F, Larson, RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
2. Lee, SJ. Chronic myelogenous leukemia. Br J Haematol 2000; 111:993.
3. McGlave, PB, Shu, XO, Wen, W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program. Blood 2000; 95:2219.
4. Kantarjian, HM, Giles, FL, O'Brien, S, et al. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer 2000; 89:1647.
5. Goldman, JM, Druker, BJ. Chronic myeloid leukemia: current treatment options. Blood 2001; 98:2039.
6. El-Zimaity, MM, Kantarjian, H, Talpaz, M, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004; 125:187.
7. Copland, M, Hamilton, A, Elrick, LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532.
Patients with CML have acquired an abnormality that causes one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.
The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme; this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease can transform into an acute leukemia, with an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which results in difficulty fighting infection and which limits production of other vital blood cells, including red blood cells and platelets.
PHASES OF CML — There are three phases of CML:
Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells circulating in the blood and in the bone marrow. Approximately 85 percent of patients are in the chronic phase when initially diagnosed. This phase generally lasts several years and is readily controllable with oral chemotherapy medications.
Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 5 and 30 percent blast cells in the blood and bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.
Blast phase — In blast crisis (blast phase), there are more than 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.
TREATMENT OPTIONS — Treatment decisions for patients with CML are complex due to the variety of available options and the lack of long term follow-up results for the newer, simpler options. Currently, the most frequently used treatment options include: Stem cell transplantation (also called bone marrow transplantation), which may be considered in younger patients with stable disease who have a suitable donor Oral tyrosine kinase inhibitors such as imatinib (Gleevec®) or dasatinib (Sprycel®) Injections of interferon alpha with or without cytarabine, now used infrequently in newly diagnosed patients.
The primary goal of treatment is to markedly reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood count to normal. This is measured as the hematologic response. While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved.
The "best" form of response, however, is seen when sensitive molecular testing shows no evidence of the BCR-ABL gene. This is called a molecular response. It is the goal of bone marrow transplantation to achieve this level of response. Longer term follow up of patients treated with imatinib indicate that some of these patients have a molecular response as well. Chemotherapy, on the other hand, only occasionally produces such a response.
TYROSINE KINASE INHIBITORS — The consequence of the Philadelphia chromosome is the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. As a result, researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme. Tyrosine kinase inhibitors slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the Philadelphia chromosomes. Normal cells suffer less toxic effects from tyrosine kinase inhibitors as compared to traditional chemotherapy treatments.
Imatinib (Gleevec®) — Imatinib mesylate is a tyrosine kinase inhibitor that can be used in patients with all phases of CML. It is proven to have significant benefits; one study comparing imatinib to interferon plus cytarabine (a form of chemotherapy) for patients with newly diagnosed, chronic phase CML found that 97 percent of patients receiving imatinib had a complete hematological response rate, and 76 percent achieved a complete cytogenetic response [1]. Treatment with interferon plus cytarabine was less effective.
Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in patients followed for six or more years who achieved a complete cytogenic response. At the current time, experts recommend continuing Gleevec® treatment indefinitely as the disease will recur, often within months, in the majority of patients who stop taking it. Progression to blast crisis can occur despite Gleevec® treatment in patients with advanced disease and in those who acquire new genetic mutations.
The recommended initial starting dose of Gleevec® is 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase or blast crisis. A higher dose of Gleevec® (400 mg twice a day) may be associated with a faster or better response, defined as more patients achieving a cytogenetic response. This dose should currently be reserved for patients enrolled in clinical trials.
The medication should be taken by mouth once daily, with a meal and a large glass of water.
Side effects — Gleevec® is generally very well tolerated; most side effects are mild to moderate and do not cause patients to stop taking it. Common side effects include: Nausea and vomiting, although this is not usually a problem when the drug is taken with meals. Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with immodium. Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting calves, feet, and hands. There is no definitive treatment, although some patients benefit from treatment with calcium or magnesium supplements, or the use of quinine. Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment. Breast enlargement (gynecomastia) may occur in a small number of men. Mild anemia is not uncommon in patients who use Gleevec® for long periods.
Acetaminophen (Tylenol®) and St. John's wort (hypericum perforatum) should be avoided while taking Gleevec® due to the risk of a drug interaction.
Pregnancy — Women and men who take Gleevec® usually have no increased difficulty achieving pregnancy. However, the risk of miscarriage and birth defects while taking Gleevec® is uncertain. It is strongly recommended that patients with CML use a birth control method during Gleevec® treatment. It should not be used by patients who are pregnant or breastfeeding.
Dasatinib (Sprycel®) — For patients who cannot tolerate, fail to respond, or stop responding to imatinib, alternative tyrosine kinase inhibitors are being developed. Dasatinib is now available for these patients, and both hematologic and cytogenetic responses have been seen in all stages of the disease.
However, more information about the long-term effectiveness and side effects of this medication are needed. Clinical trials are being planned to determine whether dasatinib and other alternative tyrosine kinase inhibitors can be used, either alone or in combination with Gleevec® or other agents, as initial therapy. Combinations of drugs should be not be used by patients unless they are enrolled in a well-designed clinical trial.
INTERFERON ALPHA — Interferon alpha (IFNa, Roferon-A®) and the recombinant form, IFNa-2a, were commonly used in the past for treatment of patients with CML. However, studies comparing IFNa to Gleevec® show clear superiority for Gleevec®. This, combined with the higher frequency of side effects with IFNa, has limited its use. A patient who cannot tolerate Gleevec or any other tyrosine kinase inhibitor could be offered IFNa with or without another chemotherapy medication, cytarabine.
Side effects — Side effects are a major problem with IFNa-2a, and include fever, chills, and flu-like symptoms. Typically, the drug is started at a relatively low dose three days per week and then slowly increased. IFNa must be injected, and many patients prefer to take their injection at night along with acetaminophen (Tylenol) and an antihistamine such as diphenhydramine (Benadryl) to minimize the side effects.
STEM CELL TRANSPLANTATION — In stem cell transplantation, also referred to as bone marrow transplantation or hematopoietic cell transplantation, the patient's diseased bone marrow (hematopoietic) cells are replaced with healthy ones from a donor. (See "Patient information: Overview of bone marrow transplantation").
A number of options are available when transplantation is considered: Hematopoietic stem (or progenitor) cells can be obtained from a patient or donor's bone marrow or blood, or from blood taken from the umbilical cord of an infant immediately after birth. The donor may be the patient (autologous transplant) or an identical twin (syngeneic transplant). Autologous hematopoietic cell transplantation uses the patient's own blood cells or bone marrow for transplantation. The patient's own hematopoietic cells are removed from the body, chemotherapy is given to reduce the number of abnormal cells, and then the stored cells are retransplanted into the patient. This type of transplantation has been explored in a limited number of patients with CML. However, autologous transplantation is not generally effective in CML and most patients do not have an identical twin. In addition, in CML, the use of an identical twin has been associated with a higher risk of disease relapse compared to a matched related or unrelated donor. More commonly, the donor is a person other than the patient or an identical twin; this is called an allogeneic transplant. Allogeneic transplants can come from a relative (eg, sibling) or from an unrelated donor. It is important to find a donor whose stem cells closely match those of the patient, but this may not always be necessary. Doctors look for matching proteins (human leukocyte antigen or HLA) on stem cells from the donor. The goal is for the donated hematopoietic stem cells (the graft) to be accepted (engrafted) by the patient's body (the host) and begin producing normal mature blood cells. Related or unrelated donors are preferred to be fully HLA-matched. Under some circumstances, half-matched (haploidentical) or mismatched donors can be used. Preparative treatments with chemotherapy and/or radiation that fully destroy (myeloablative) or do not fully destroy (nonmyeloablative) bone marrow activity must be used in order for the transplant to be effective.
In CML, the results obtained with hematopoietic cell transplantation (HCT) are directly related to the phase of disease at the time of the transplant. In the past, among patients in chronic phase, transplantation within the first year resulted in the best outcomes. It is not clear in patients treated with imatinib if longer delays to transplantation compromise the outcome.
Related donors — If a matched sibling donor can be found, 50 to 75 percent of patients with CML transplanted in the first or second chronic phase of their disease achieve long-term remissions. Disease-free survival falls to 30 to 40 percent in patients transplanted in the accelerated phase, and to 10 to 20 percent in patients transplanted in blastic phase.
For patients in blast phase, giving chemotherapy or Gleevec® prior to transplantation to achieve a second chronic phase may be preferable to transplanting during the blast phase.
Patient age has a major influence on the outcome after transplantation with cells from a sibling donor. In the subgroup of patients under age 50 who undergo this procedure during the first year of diagnosis, 70 to 85 percent will be alive and free of disease five years later. However, patients up to 60 years of age have successfully undergone allogeneic transplantation with treatments that completely destroy bone marrow. The development of regimens that do not completely destroy the bone and have reduced toxicity has permitted even older patients to be successfully transplanted.
Matched unrelated donors — For patients without an HLA-matched sibling donor, matched unrelated donor (URD) transplantation has been explored. An important advance with this procedure has been the development of techniques that permit tissue matching using molecular typing.
Because of the relatively slow pace of CML, there is usually adequate time to perform a search for a matched unrelated donor through the National Marrow Donor Program and other donor agencies. This search may take up to three to six months to complete; it may be less successful in certain minority populations that are under-represented within the donor programs.
In a 1998 report involving 196 patients receiving a matched unrelated donor (URD) transplant, estimated five year survival was 74 percent in patients who were 50 years of age or younger and transplanted within one year after diagnosis; this value is similar to that achieved with matched sibling donors (70 to 80 percent).
Other donor sources — For patients without a matched sibling or matched unrelated donor, other donor sources have been used. Among the options are transplants using hematopoietic cells from haploidentical (partially HLA-matched) donors or those found in blood taken from the umbilical cord of healthy unrelated newborn infants.
Risks — There are a number of serious risks following allogeneic transplantation. These include: Toxicity of the treatment (eg, chemotherapy, radiation therapy) used to prepare the patient for the transplant. These include life-threatening bacterial, viral, or fungal infection, anemia, and bleeding. When the transplant donor is not the patient or an identical twin, cells of the immune system within the graft may attack the new host (patient), causing what is called graft-versus-host disease (GVHD). GVHD is the major cause of death following transplantation. GVHD requires treatment with anti-rejection medications, such as tacrolimus, cyclosporine, and prednisone. These medications may be given to prevent or treat GVHD. The graft may fail to take (engraft), leaving the patient with reduced immunity and reduced numbers of bone marrow cells unless and until the patient's own bone marrow recovers or the patient receives a second transplant. However, this is an uncommon problem when matched donors are used.
Relapse after transplant — Relapse, or recurrence, of CML may occur if sufficient numbers of Philadelphia chromosomes remain after the transplant procedure. However, finding residual disease with sensitive molecular tests in the first 6 months following transplantation is not associated with eventual relapse because the anti-tumor effects of the graft may eventually prevail.
Relapse can be treated with imatinib or dasatinib or with infusions of leukocytes from the original donor, with the hope of mounting a graft-versus-tumor effect. Donor leukocyte infusions (DLIs) can be extremely effective, and remissions attained after DLI appear to be quite durable. However, graft-versus-host disease, and in some instances graft failure, may complicate DLI
Deciding between transplantation and imatinib — The major decision facing newly diagnosed patients is whether to proceed with transplantation or to be treated initially with imatinib, reserving transplantation if imatinib not produce a complete cytogenetic response. There have not been any randomized clinical trials directly comparing chemotherapy (eg, interferon, Gleevec®) to hematopoietic stem cell transplantation in newly diagnosed patients. From analyses comparing transplantation with the use of interferon, the following general results can be noted: There was a higher mortality for the first 18 months in those treated with transplantation. Thus, an unsuccessful transplant can actually shorten a patient's life. The mortality was similar in the two groups between 18 and 56 months After 56 months, mortality was significantly lower in the transplanted patients and the probability of being alive at seven years was also higher in the transplant group (58 versus 32 percent). Thus, successful allogeneic transplantation can produce long term suppression of disease with a very low chance of relapse because such patients have a molecular, cytogenetic, and hematologic response) as assessed by even the most sensitive of testing procedures (ie, the polymerase chain reaction technique).
RECOMMENDATIONS — The treatment of CML is complex, and the optimal treatment is a source of considerable debate. Therefore, consultation with a physician familiar with the latest data is critical. Allogeneic HCT remains the only treatment approach that is known to cure CML. Younger patients in the chronic phase who have a suitably matched sibling donor should discuss this option in detail. The results with matched unrelated donor transplantation continue to improve, which can increase the number of possible donors. Imatinib (Gleevec®) therapy is preferred by most patients, and an expert panel has recommended the use of imatinib as the initial treatment for most patients with newly diagnosed chronic phase CML. Careful evaluation of the quality and duration of the response to Gleevec® is very important in deciding whether and when to proceed to transplantation. It is critically important that the depth and quality of the response be frequently evaluated using sensitive cytogenetic and molecular techniques in a laboratory qualified to perform these tests.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[2-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. O'Brien, SG, Guilhot, F, Larson, RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
2. Lee, SJ. Chronic myelogenous leukemia. Br J Haematol 2000; 111:993.
3. McGlave, PB, Shu, XO, Wen, W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program. Blood 2000; 95:2219.
4. Kantarjian, HM, Giles, FL, O'Brien, S, et al. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer 2000; 89:1647.
5. Goldman, JM, Druker, BJ. Chronic myeloid leukemia: current treatment options. Blood 2001; 98:2039.
6. El-Zimaity, MM, Kantarjian, H, Talpaz, M, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004; 125:187.
7. Copland, M, Hamilton, A, Elrick, LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532.
Chronic myelogenous leukemia (CML)
INTRODUCTION — Chronic myelogenous leukemia (also called CML, chronic myelocytic leukemia, or chronic myeloid leukemia) is a chronic (long-term) disorder of the bone marrow. Bone marrow is the spongy, red tissue that fills the large bones.
Patients with CML have acquired an abnormality that causes one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.
The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme; this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease can transform into an acute leukemia, with an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which results in difficulty fighting infection and which limits production of other vital blood cells, including red blood cells and platelets.
PHASES OF CML — There are three phases of CML:
Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells circulating in the blood and in the bone marrow. Approximately 85 percent of patients are in the chronic phase when initially diagnosed. This phase generally lasts several years and is readily controllable with oral chemotherapy medications.
Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 5 and 30 percent blast cells in the blood and bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.
Blast phase — In blast crisis (blast phase), there are more than 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.
TREATMENT OPTIONS — Treatment decisions for patients with CML are complex due to the variety of available options and the lack of long term follow-up results for the newer, simpler options. Currently, the most frequently used treatment options include: Stem cell transplantation (also called bone marrow transplantation), which may be considered in younger patients with stable disease who have a suitable donor Oral tyrosine kinase inhibitors such as imatinib (Gleevec®) or dasatinib (Sprycel®) Injections of interferon alpha with or without cytarabine, now used infrequently in newly diagnosed patients.
The primary goal of treatment is to markedly reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood count to normal. This is measured as the hematologic response. While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved.
The "best" form of response, however, is seen when sensitive molecular testing shows no evidence of the BCR-ABL gene. This is called a molecular response. It is the goal of bone marrow transplantation to achieve this level of response. Longer term follow up of patients treated with imatinib indicate that some of these patients have a molecular response as well. Chemotherapy, on the other hand, only occasionally produces such a response.
TYROSINE KINASE INHIBITORS — The consequence of the Philadelphia chromosome is the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. As a result, researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme. Tyrosine kinase inhibitors slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the Philadelphia chromosomes. Normal cells suffer less toxic effects from tyrosine kinase inhibitors as compared to traditional chemotherapy treatments.
Imatinib (Gleevec®) — Imatinib mesylate is a tyrosine kinase inhibitor that can be used in patients with all phases of CML. It is proven to have significant benefits; one study comparing imatinib to interferon plus cytarabine (a form of chemotherapy) for patients with newly diagnosed, chronic phase CML found that 97 percent of patients receiving imatinib had a complete hematological response rate, and 76 percent achieved a complete cytogenetic response [1]. Treatment with interferon plus cytarabine was less effective.
Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in patients followed for six or more years who achieved a complete cytogenic response. At the current time, experts recommend continuing Gleevec® treatment indefinitely as the disease will recur, often within months, in the majority of patients who stop taking it. Progression to blast crisis can occur despite Gleevec® treatment in patients with advanced disease and in those who acquire new genetic mutations.
The recommended initial starting dose of Gleevec® is 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase or blast crisis. A higher dose of Gleevec® (400 mg twice a day) may be associated with a faster or better response, defined as more patients achieving a cytogenetic response. This dose should currently be reserved for patients enrolled in clinical trials.
The medication should be taken by mouth once daily, with a meal and a large glass of water.
Side effects — Gleevec® is generally very well tolerated; most side effects are mild to moderate and do not cause patients to stop taking it. Common side effects include: Nausea and vomiting, although this is not usually a problem when the drug is taken with meals. Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with immodium. Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting calves, feet, and hands. There is no definitive treatment, although some patients benefit from treatment with calcium or magnesium supplements, or the use of quinine. Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment. Breast enlargement (gynecomastia) may occur in a small number of men. Mild anemia is not uncommon in patients who use Gleevec® for long periods.
Acetaminophen (Tylenol®) and St. John's wort (hypericum perforatum) should be avoided while taking Gleevec® due to the risk of a drug interaction.
Pregnancy — Women and men who take Gleevec® usually have no increased difficulty achieving pregnancy. However, the risk of miscarriage and birth defects while taking Gleevec® is uncertain. It is strongly recommended that patients with CML use a birth control method during Gleevec® treatment. It should not be used by patients who are pregnant or breastfeeding.
Dasatinib (Sprycel®) — For patients who cannot tolerate, fail to respond, or stop responding to imatinib, alternative tyrosine kinase inhibitors are being developed. Dasatinib is now available for these patients, and both hematologic and cytogenetic responses have been seen in all stages of the disease.
However, more information about the long-term effectiveness and side effects of this medication are needed. Clinical trials are being planned to determine whether dasatinib and other alternative tyrosine kinase inhibitors can be used, either alone or in combination with Gleevec® or other agents, as initial therapy. Combinations of drugs should be not be used by patients unless they are enrolled in a well-designed clinical trial.
INTERFERON ALPHA — Interferon alpha (IFNa, Roferon-A®) and the recombinant form, IFNa-2a, were commonly used in the past for treatment of patients with CML. However, studies comparing IFNa to Gleevec® show clear superiority for Gleevec®. This, combined with the higher frequency of side effects with IFNa, has limited its use. A patient who cannot tolerate Gleevec or any other tyrosine kinase inhibitor could be offered IFNa with or without another chemotherapy medication, cytarabine.
Side effects — Side effects are a major problem with IFNa-2a, and include fever, chills, and flu-like symptoms. Typically, the drug is started at a relatively low dose three days per week and then slowly increased. IFNa must be injected, and many patients prefer to take their injection at night along with acetaminophen (Tylenol) and an antihistamine such as diphenhydramine (Benadryl) to minimize the side effects.
STEM CELL TRANSPLANTATION — In stem cell transplantation, also referred to as bone marrow transplantation or hematopoietic cell transplantation, the patient's diseased bone marrow (hematopoietic) cells are replaced with healthy ones from a donor. (See "Patient information: Overview of bone marrow transplantation").
A number of options are available when transplantation is considered: Hematopoietic stem (or progenitor) cells can be obtained from a patient or donor's bone marrow or blood, or from blood taken from the umbilical cord of an infant immediately after birth. The donor may be the patient (autologous transplant) or an identical twin (syngeneic transplant). Autologous hematopoietic cell transplantation uses the patient's own blood cells or bone marrow for transplantation. The patient's own hematopoietic cells are removed from the body, chemotherapy is given to reduce the number of abnormal cells, and then the stored cells are retransplanted into the patient. This type of transplantation has been explored in a limited number of patients with CML. However, autologous transplantation is not generally effective in CML and most patients do not have an identical twin. In addition, in CML, the use of an identical twin has been associated with a higher risk of disease relapse compared to a matched related or unrelated donor. More commonly, the donor is a person other than the patient or an identical twin; this is called an allogeneic transplant. Allogeneic transplants can come from a relative (eg, sibling) or from an unrelated donor. It is important to find a donor whose stem cells closely match those of the patient, but this may not always be necessary. Doctors look for matching proteins (human leukocyte antigen or HLA) on stem cells from the donor. The goal is for the donated hematopoietic stem cells (the graft) to be accepted (engrafted) by the patient's body (the host) and begin producing normal mature blood cells. Related or unrelated donors are preferred to be fully HLA-matched. Under some circumstances, half-matched (haploidentical) or mismatched donors can be used. Preparative treatments with chemotherapy and/or radiation that fully destroy (myeloablative) or do not fully destroy (nonmyeloablative) bone marrow activity must be used in order for the transplant to be effective.
In CML, the results obtained with hematopoietic cell transplantation (HCT) are directly related to the phase of disease at the time of the transplant. In the past, among patients in chronic phase, transplantation within the first year resulted in the best outcomes. It is not clear in patients treated with imatinib if longer delays to transplantation compromise the outcome.
Related donors — If a matched sibling donor can be found, 50 to 75 percent of patients with CML transplanted in the first or second chronic phase of their disease achieve long-term remissions. Disease-free survival falls to 30 to 40 percent in patients transplanted in the accelerated phase, and to 10 to 20 percent in patients transplanted in blastic phase.
For patients in blast phase, giving chemotherapy or Gleevec® prior to transplantation to achieve a second chronic phase may be preferable to transplanting during the blast phase.
Patient age has a major influence on the outcome after transplantation with cells from a sibling donor. In the subgroup of patients under age 50 who undergo this procedure during the first year of diagnosis, 70 to 85 percent will be alive and free of disease five years later. However, patients up to 60 years of age have successfully undergone allogeneic transplantation with treatments that completely destroy bone marrow. The development of regimens that do not completely destroy the bone and have reduced toxicity has permitted even older patients to be successfully transplanted.
Matched unrelated donors — For patients without an HLA-matched sibling donor, matched unrelated donor (URD) transplantation has been explored. An important advance with this procedure has been the development of techniques that permit tissue matching using molecular typing.
Because of the relatively slow pace of CML, there is usually adequate time to perform a search for a matched unrelated donor through the National Marrow Donor Program and other donor agencies. This search may take up to three to six months to complete; it may be less successful in certain minority populations that are under-represented within the donor programs.
In a 1998 report involving 196 patients receiving a matched unrelated donor (URD) transplant, estimated five year survival was 74 percent in patients who were 50 years of age or younger and transplanted within one year after diagnosis; this value is similar to that achieved with matched sibling donors (70 to 80 percent).
Other donor sources — For patients without a matched sibling or matched unrelated donor, other donor sources have been used. Among the options are transplants using hematopoietic cells from haploidentical (partially HLA-matched) donors or those found in blood taken from the umbilical cord of healthy unrelated newborn infants.
Risks — There are a number of serious risks following allogeneic transplantation. These include: Toxicity of the treatment (eg, chemotherapy, radiation therapy) used to prepare the patient for the transplant. These include life-threatening bacterial, viral, or fungal infection, anemia, and bleeding. When the transplant donor is not the patient or an identical twin, cells of the immune system within the graft may attack the new host (patient), causing what is called graft-versus-host disease (GVHD). GVHD is the major cause of death following transplantation. GVHD requires treatment with anti-rejection medications, such as tacrolimus, cyclosporine, and prednisone. These medications may be given to prevent or treat GVHD. The graft may fail to take (engraft), leaving the patient with reduced immunity and reduced numbers of bone marrow cells unless and until the patient's own bone marrow recovers or the patient receives a second transplant. However, this is an uncommon problem when matched donors are used.
Relapse after transplant — Relapse, or recurrence, of CML may occur if sufficient numbers of Philadelphia chromosomes remain after the transplant procedure. However, finding residual disease with sensitive molecular tests in the first 6 months following transplantation is not associated with eventual relapse because the anti-tumor effects of the graft may eventually prevail.
Relapse can be treated with imatinib or dasatinib or with infusions of leukocytes from the original donor, with the hope of mounting a graft-versus-tumor effect. Donor leukocyte infusions (DLIs) can be extremely effective, and remissions attained after DLI appear to be quite durable. However, graft-versus-host disease, and in some instances graft failure, may complicate DLI
Deciding between transplantation and imatinib — The major decision facing newly diagnosed patients is whether to proceed with transplantation or to be treated initially with imatinib, reserving transplantation if imatinib not produce a complete cytogenetic response. There have not been any randomized clinical trials directly comparing chemotherapy (eg, interferon, Gleevec®) to hematopoietic stem cell transplantation in newly diagnosed patients. From analyses comparing transplantation with the use of interferon, the following general results can be noted: There was a higher mortality for the first 18 months in those treated with transplantation. Thus, an unsuccessful transplant can actually shorten a patient's life. The mortality was similar in the two groups between 18 and 56 months After 56 months, mortality was significantly lower in the transplanted patients and the probability of being alive at seven years was also higher in the transplant group (58 versus 32 percent). Thus, successful allogeneic transplantation can produce long term suppression of disease with a very low chance of relapse because such patients have a molecular, cytogenetic, and hematologic response) as assessed by even the most sensitive of testing procedures (ie, the polymerase chain reaction technique).
RECOMMENDATIONS — The treatment of CML is complex, and the optimal treatment is a source of considerable debate. Therefore, consultation with a physician familiar with the latest data is critical. Allogeneic HCT remains the only treatment approach that is known to cure CML. Younger patients in the chronic phase who have a suitably matched sibling donor should discuss this option in detail. The results with matched unrelated donor transplantation continue to improve, which can increase the number of possible donors. Imatinib (Gleevec®) therapy is preferred by most patients, and an expert panel has recommended the use of imatinib as the initial treatment for most patients with newly diagnosed chronic phase CML. Careful evaluation of the quality and duration of the response to Gleevec® is very important in deciding whether and when to proceed to transplantation. It is critically important that the depth and quality of the response be frequently evaluated using sensitive cytogenetic and molecular techniques in a laboratory qualified to perform these tests.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[2-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. O'Brien, SG, Guilhot, F, Larson, RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
2. Lee, SJ. Chronic myelogenous leukemia. Br J Haematol 2000; 111:993.
3. McGlave, PB, Shu, XO, Wen, W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program. Blood 2000; 95:2219.
4. Kantarjian, HM, Giles, FL, O'Brien, S, et al. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer 2000; 89:1647.
5. Goldman, JM, Druker, BJ. Chronic myeloid leukemia: current treatment options. Blood 2001; 98:2039.
6. El-Zimaity, MM, Kantarjian, H, Talpaz, M, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004; 125:187.
7. Copland, M, Hamilton, A, Elrick, LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532.
Patients with CML have acquired an abnormality that causes one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.
The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme; this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease can transform into an acute leukemia, with an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which results in difficulty fighting infection and which limits production of other vital blood cells, including red blood cells and platelets.
PHASES OF CML — There are three phases of CML:
Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells circulating in the blood and in the bone marrow. Approximately 85 percent of patients are in the chronic phase when initially diagnosed. This phase generally lasts several years and is readily controllable with oral chemotherapy medications.
Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 5 and 30 percent blast cells in the blood and bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.
Blast phase — In blast crisis (blast phase), there are more than 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.
TREATMENT OPTIONS — Treatment decisions for patients with CML are complex due to the variety of available options and the lack of long term follow-up results for the newer, simpler options. Currently, the most frequently used treatment options include: Stem cell transplantation (also called bone marrow transplantation), which may be considered in younger patients with stable disease who have a suitable donor Oral tyrosine kinase inhibitors such as imatinib (Gleevec®) or dasatinib (Sprycel®) Injections of interferon alpha with or without cytarabine, now used infrequently in newly diagnosed patients.
The primary goal of treatment is to markedly reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood count to normal. This is measured as the hematologic response. While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved.
The "best" form of response, however, is seen when sensitive molecular testing shows no evidence of the BCR-ABL gene. This is called a molecular response. It is the goal of bone marrow transplantation to achieve this level of response. Longer term follow up of patients treated with imatinib indicate that some of these patients have a molecular response as well. Chemotherapy, on the other hand, only occasionally produces such a response.
TYROSINE KINASE INHIBITORS — The consequence of the Philadelphia chromosome is the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. As a result, researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme. Tyrosine kinase inhibitors slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the Philadelphia chromosomes. Normal cells suffer less toxic effects from tyrosine kinase inhibitors as compared to traditional chemotherapy treatments.
Imatinib (Gleevec®) — Imatinib mesylate is a tyrosine kinase inhibitor that can be used in patients with all phases of CML. It is proven to have significant benefits; one study comparing imatinib to interferon plus cytarabine (a form of chemotherapy) for patients with newly diagnosed, chronic phase CML found that 97 percent of patients receiving imatinib had a complete hematological response rate, and 76 percent achieved a complete cytogenetic response [1]. Treatment with interferon plus cytarabine was less effective.
Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in patients followed for six or more years who achieved a complete cytogenic response. At the current time, experts recommend continuing Gleevec® treatment indefinitely as the disease will recur, often within months, in the majority of patients who stop taking it. Progression to blast crisis can occur despite Gleevec® treatment in patients with advanced disease and in those who acquire new genetic mutations.
The recommended initial starting dose of Gleevec® is 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase or blast crisis. A higher dose of Gleevec® (400 mg twice a day) may be associated with a faster or better response, defined as more patients achieving a cytogenetic response. This dose should currently be reserved for patients enrolled in clinical trials.
The medication should be taken by mouth once daily, with a meal and a large glass of water.
Side effects — Gleevec® is generally very well tolerated; most side effects are mild to moderate and do not cause patients to stop taking it. Common side effects include: Nausea and vomiting, although this is not usually a problem when the drug is taken with meals. Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with immodium. Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting calves, feet, and hands. There is no definitive treatment, although some patients benefit from treatment with calcium or magnesium supplements, or the use of quinine. Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment. Breast enlargement (gynecomastia) may occur in a small number of men. Mild anemia is not uncommon in patients who use Gleevec® for long periods.
Acetaminophen (Tylenol®) and St. John's wort (hypericum perforatum) should be avoided while taking Gleevec® due to the risk of a drug interaction.
Pregnancy — Women and men who take Gleevec® usually have no increased difficulty achieving pregnancy. However, the risk of miscarriage and birth defects while taking Gleevec® is uncertain. It is strongly recommended that patients with CML use a birth control method during Gleevec® treatment. It should not be used by patients who are pregnant or breastfeeding.
Dasatinib (Sprycel®) — For patients who cannot tolerate, fail to respond, or stop responding to imatinib, alternative tyrosine kinase inhibitors are being developed. Dasatinib is now available for these patients, and both hematologic and cytogenetic responses have been seen in all stages of the disease.
However, more information about the long-term effectiveness and side effects of this medication are needed. Clinical trials are being planned to determine whether dasatinib and other alternative tyrosine kinase inhibitors can be used, either alone or in combination with Gleevec® or other agents, as initial therapy. Combinations of drugs should be not be used by patients unless they are enrolled in a well-designed clinical trial.
INTERFERON ALPHA — Interferon alpha (IFNa, Roferon-A®) and the recombinant form, IFNa-2a, were commonly used in the past for treatment of patients with CML. However, studies comparing IFNa to Gleevec® show clear superiority for Gleevec®. This, combined with the higher frequency of side effects with IFNa, has limited its use. A patient who cannot tolerate Gleevec or any other tyrosine kinase inhibitor could be offered IFNa with or without another chemotherapy medication, cytarabine.
Side effects — Side effects are a major problem with IFNa-2a, and include fever, chills, and flu-like symptoms. Typically, the drug is started at a relatively low dose three days per week and then slowly increased. IFNa must be injected, and many patients prefer to take their injection at night along with acetaminophen (Tylenol) and an antihistamine such as diphenhydramine (Benadryl) to minimize the side effects.
STEM CELL TRANSPLANTATION — In stem cell transplantation, also referred to as bone marrow transplantation or hematopoietic cell transplantation, the patient's diseased bone marrow (hematopoietic) cells are replaced with healthy ones from a donor. (See "Patient information: Overview of bone marrow transplantation").
A number of options are available when transplantation is considered: Hematopoietic stem (or progenitor) cells can be obtained from a patient or donor's bone marrow or blood, or from blood taken from the umbilical cord of an infant immediately after birth. The donor may be the patient (autologous transplant) or an identical twin (syngeneic transplant). Autologous hematopoietic cell transplantation uses the patient's own blood cells or bone marrow for transplantation. The patient's own hematopoietic cells are removed from the body, chemotherapy is given to reduce the number of abnormal cells, and then the stored cells are retransplanted into the patient. This type of transplantation has been explored in a limited number of patients with CML. However, autologous transplantation is not generally effective in CML and most patients do not have an identical twin. In addition, in CML, the use of an identical twin has been associated with a higher risk of disease relapse compared to a matched related or unrelated donor. More commonly, the donor is a person other than the patient or an identical twin; this is called an allogeneic transplant. Allogeneic transplants can come from a relative (eg, sibling) or from an unrelated donor. It is important to find a donor whose stem cells closely match those of the patient, but this may not always be necessary. Doctors look for matching proteins (human leukocyte antigen or HLA) on stem cells from the donor. The goal is for the donated hematopoietic stem cells (the graft) to be accepted (engrafted) by the patient's body (the host) and begin producing normal mature blood cells. Related or unrelated donors are preferred to be fully HLA-matched. Under some circumstances, half-matched (haploidentical) or mismatched donors can be used. Preparative treatments with chemotherapy and/or radiation that fully destroy (myeloablative) or do not fully destroy (nonmyeloablative) bone marrow activity must be used in order for the transplant to be effective.
In CML, the results obtained with hematopoietic cell transplantation (HCT) are directly related to the phase of disease at the time of the transplant. In the past, among patients in chronic phase, transplantation within the first year resulted in the best outcomes. It is not clear in patients treated with imatinib if longer delays to transplantation compromise the outcome.
Related donors — If a matched sibling donor can be found, 50 to 75 percent of patients with CML transplanted in the first or second chronic phase of their disease achieve long-term remissions. Disease-free survival falls to 30 to 40 percent in patients transplanted in the accelerated phase, and to 10 to 20 percent in patients transplanted in blastic phase.
For patients in blast phase, giving chemotherapy or Gleevec® prior to transplantation to achieve a second chronic phase may be preferable to transplanting during the blast phase.
Patient age has a major influence on the outcome after transplantation with cells from a sibling donor. In the subgroup of patients under age 50 who undergo this procedure during the first year of diagnosis, 70 to 85 percent will be alive and free of disease five years later. However, patients up to 60 years of age have successfully undergone allogeneic transplantation with treatments that completely destroy bone marrow. The development of regimens that do not completely destroy the bone and have reduced toxicity has permitted even older patients to be successfully transplanted.
Matched unrelated donors — For patients without an HLA-matched sibling donor, matched unrelated donor (URD) transplantation has been explored. An important advance with this procedure has been the development of techniques that permit tissue matching using molecular typing.
Because of the relatively slow pace of CML, there is usually adequate time to perform a search for a matched unrelated donor through the National Marrow Donor Program and other donor agencies. This search may take up to three to six months to complete; it may be less successful in certain minority populations that are under-represented within the donor programs.
In a 1998 report involving 196 patients receiving a matched unrelated donor (URD) transplant, estimated five year survival was 74 percent in patients who were 50 years of age or younger and transplanted within one year after diagnosis; this value is similar to that achieved with matched sibling donors (70 to 80 percent).
Other donor sources — For patients without a matched sibling or matched unrelated donor, other donor sources have been used. Among the options are transplants using hematopoietic cells from haploidentical (partially HLA-matched) donors or those found in blood taken from the umbilical cord of healthy unrelated newborn infants.
Risks — There are a number of serious risks following allogeneic transplantation. These include: Toxicity of the treatment (eg, chemotherapy, radiation therapy) used to prepare the patient for the transplant. These include life-threatening bacterial, viral, or fungal infection, anemia, and bleeding. When the transplant donor is not the patient or an identical twin, cells of the immune system within the graft may attack the new host (patient), causing what is called graft-versus-host disease (GVHD). GVHD is the major cause of death following transplantation. GVHD requires treatment with anti-rejection medications, such as tacrolimus, cyclosporine, and prednisone. These medications may be given to prevent or treat GVHD. The graft may fail to take (engraft), leaving the patient with reduced immunity and reduced numbers of bone marrow cells unless and until the patient's own bone marrow recovers or the patient receives a second transplant. However, this is an uncommon problem when matched donors are used.
Relapse after transplant — Relapse, or recurrence, of CML may occur if sufficient numbers of Philadelphia chromosomes remain after the transplant procedure. However, finding residual disease with sensitive molecular tests in the first 6 months following transplantation is not associated with eventual relapse because the anti-tumor effects of the graft may eventually prevail.
Relapse can be treated with imatinib or dasatinib or with infusions of leukocytes from the original donor, with the hope of mounting a graft-versus-tumor effect. Donor leukocyte infusions (DLIs) can be extremely effective, and remissions attained after DLI appear to be quite durable. However, graft-versus-host disease, and in some instances graft failure, may complicate DLI
Deciding between transplantation and imatinib — The major decision facing newly diagnosed patients is whether to proceed with transplantation or to be treated initially with imatinib, reserving transplantation if imatinib not produce a complete cytogenetic response. There have not been any randomized clinical trials directly comparing chemotherapy (eg, interferon, Gleevec®) to hematopoietic stem cell transplantation in newly diagnosed patients. From analyses comparing transplantation with the use of interferon, the following general results can be noted: There was a higher mortality for the first 18 months in those treated with transplantation. Thus, an unsuccessful transplant can actually shorten a patient's life. The mortality was similar in the two groups between 18 and 56 months After 56 months, mortality was significantly lower in the transplanted patients and the probability of being alive at seven years was also higher in the transplant group (58 versus 32 percent). Thus, successful allogeneic transplantation can produce long term suppression of disease with a very low chance of relapse because such patients have a molecular, cytogenetic, and hematologic response) as assessed by even the most sensitive of testing procedures (ie, the polymerase chain reaction technique).
RECOMMENDATIONS — The treatment of CML is complex, and the optimal treatment is a source of considerable debate. Therefore, consultation with a physician familiar with the latest data is critical. Allogeneic HCT remains the only treatment approach that is known to cure CML. Younger patients in the chronic phase who have a suitably matched sibling donor should discuss this option in detail. The results with matched unrelated donor transplantation continue to improve, which can increase the number of possible donors. Imatinib (Gleevec®) therapy is preferred by most patients, and an expert panel has recommended the use of imatinib as the initial treatment for most patients with newly diagnosed chronic phase CML. Careful evaluation of the quality and duration of the response to Gleevec® is very important in deciding whether and when to proceed to transplantation. It is critically important that the depth and quality of the response be frequently evaluated using sensitive cytogenetic and molecular techniques in a laboratory qualified to perform these tests.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[2-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. O'Brien, SG, Guilhot, F, Larson, RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
2. Lee, SJ. Chronic myelogenous leukemia. Br J Haematol 2000; 111:993.
3. McGlave, PB, Shu, XO, Wen, W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program. Blood 2000; 95:2219.
4. Kantarjian, HM, Giles, FL, O'Brien, S, et al. Therapeutic choices in younger patients with chronic myelogenous leukemia. Cancer 2000; 89:1647.
5. Goldman, JM, Druker, BJ. Chronic myeloid leukemia: current treatment options. Blood 2001; 98:2039.
6. El-Zimaity, MM, Kantarjian, H, Talpaz, M, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 2004; 125:187.
7. Copland, M, Hamilton, A, Elrick, LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532.
Chronic lymphocytic leukemia (CLL)
INTRODUCTION — Chronic lymphocytic leukemia, often referred to as CLL, is a type of cancer of the blood. It is one of a group of diseases that affects a type of white blood cell called a lymphocyte. The lymphocytes help the body fight infection.
In CLL, abnormally high numbers of ineffective lymphocytes are found in the blood and/or bone marrow (the spongy area in the middle of large bones where blood cells are formed). They cannot fight infection as normal lymphocytes do, and collect in increased numbers in lymph nodes and other areas, such as the liver and spleen. Their high numbers can cause them to interfere with the proper production of other blood cells, such as red cells and platelets.
Unlike acute lymphoblastic leukemia, which is fatal if left untreated, CLL is usually characterized by a slow progression of the disease and related symptoms. In many cases, it causes the patient little, if any, problems in its early stages. Patients may live with CLL for decades. Many times, it is diagnosed by blood tests that are performed during a routine physical exam. In other cases, symptoms may bring the patient to the doctor.
Careful analysis of the patient's blood and physical condition help the doctor determine the stage of the disease - a crucial first step in deciding on the proper course of treatment. Unlike patients with many other types of cancer, some patients with CLL may not benefit from early, aggressive treatment, but rather, may do better with careful long-term monitoring of the disease without treatment.
STAGING OF CLL — The natural history of CLL may vary considerably from person to person. Some patients may become sick within a short time of diagnosis; others live comfortably for years without problems. Determining which patients are most likely to get sick, and therefore are most likely to benefit from treatment of the disease, has been a challenge for doctors.
Two systems for staging CLL are now in use. They are used as a way to help identify patients with more serious versus "smoldering" disease, and as a way to help identify which patients are most likely to develop serious problems in the near term.
The Rai system — The Rai system is based on an analysis of how the body is affected by the abnormal lymphocytes. There are five stages. The higher numbers indicate a more advanced stage of disease: Stage 0: Increased numbers of abnormal lymphocytes are found in the blood or bone marrow; lymph nodes/organs are not swollen, and production of red cells and platelets is normal Stage I: Increased abnormal lymphocytes and enlarged lymph nodes Stage II: Increased abnormal lymphocytes with enlarged liver or spleen, with or without enlarged lymph nodes Stage III: Increased abnormal lymphocytes with anemia (low red blood cell count), with or without an enlarged spleen, liver, or lymph nodes Stage IV: Increased abnormal lymphocytes with a low platelet count, with or without anemia, enlarged liver, spleen, or lymph nodes
The Binet system — This system considers the five possible sites where lymphocytes can collect (lymph nodes in the neck, armpit, and groin, and lymphocyte-containing channels in the spleen and liver), and also on whether or not anemia or low platelet counts are present. There are three stages: Stage A: Fewer than three involved sites Stage B: Three or more involved sites Stage C: Presence of anemia or low platelet counts
Experts have recommended that these two systems be used together to define the stage of leukemia, for example, stage A0, A1, AII, BI, and so on. However, many clinicians still use either the Rai or Binet method.
What the stages mean — Staging helps doctors decide how likely it is that the person is soon to develop serious problems related to the CLL. Patients at Rai stage 0 are considered at low risk, those at stages I or II are at intermediate risk, and those at stage III or IV are at high risk. Similarly, patients characterized according to the Binet system have progressively increasing risk, with Stage A as the lowest and Stage C as the highest risk group. Average survivals for these three risk categories are: Low risk — 12 years Intermediate risk — 7.5 years High risk — 1.5 years
In general, doctors are more certain about expected disease progression in the higher versus the lower risk groups. That is, it is more difficult to tell which patients in the lower risk groups are most likely to go on to develop more serious disease. Research is underway to identify factors associated with a more aggressive course. For example, analysis of certain aspects of bone marrow cells and comparison of the patient's blood test results over time may prove helpful in identifying which patients in the lower risk groups are more likely to become ill with CLL.
Indications for treatment — As noted above, treatment is not always required for CLL. Some studies have shown that patients with so-called "smoldering" CLL are no more likely to die than a normal person of similar age and sex. Although treatment can be effective in controlling progression of the disease and alleviating symptoms, it usually does not produce a cure. This means that doctors and patients must carefully weigh the risks and discomforts of treatment against expected benefits to be gained.
However, there are certain groups of patients in whom some type of treatment is generally indicated. This includes patients with: Anemia and/or low platelets (Rai stages III or IV, or Binet stage C) Disease-related symptoms such as weakness, night sweats, weight loss, painful lymph node swelling, or fever Progressive disease, as demonstrated by rapidly increasing white cells in the blood, and/or rapidly enlarging lymph nodes, spleen, or liver Repeated infections
In some cases, especially in younger patients, doctors may recommend treating patients who do not have symptoms and/or those with low risk disease. Patients and doctors may choose to aggressively treat these milder forms of the disease in the hopes of obtaining long-term benefits and possibly a cure. Such aggressive treatments, such as bone marrow transplantation, may have serious side effects, and are generally part of a formal research study.
In other cases, detailed examination of the leukemic cells may be able to determine the future clinical course of the disease (ie, the prognosis), as well as the suitability of one or more treatment options. Such studies are the subject of a large number of ongoing research trials.
A number of different forms of treatment may be proposed. These are outlined in the following sections.
CHEMOTHERAPY — Chemotherapy, or the use of medications to kill cancer cells, can be effective in treating CLL. Depending on factors such as the stage of illness, the patient's age, and symptoms, the goals of chemotherapy may vary. For example, in some cases the goal is to halt the progression of the disease and relieve symptoms. In other cases, medicines will be chosen that are designed to help induce a remission of the disease. A patient undergoing chemotherapy for CLL should talk with the doctor about the goals for treatment.
Some of the medicines that may be used are listed here. Ask your doctor for complete information about the specific medicines you will receive, whether or not you will need to be admitted to the hospital for therapy, and what side effects you should watch for.
Historical agents — The following three agents were among the first to be successfully used for the treatment of CLL:
Chlorambucil (Leukeran) — This is taken by mouth either daily or in a single dose given every three to four weeks. The most common side effects are anemia, low white blood cell counts (leading to risk for infection), and low platelet counts (increasing the risk for bleeding).
Cyclophosphamide (Cytoxan) — This medicine can be given by mouth or through an intravenous (IV) line. Side effects include low blood counts, nausea and vomiting, hair loss, and irritation of the urinary bladder.
Steroids — Some treatment programs call for the use of steroids such as prednisone to treat CLL. Side effects include increased susceptibility to infections, high blood glucose, gastrointestinal problems, muscle weakness, and psychiatric symptoms.
Newer agents — The following two agents have been shown to be clearly superior to the historical agents noted above. Fludarabine, in combination with cyclophosphamide, is the most potent combination regimen developed to date.
Fludarabine — This medicine is showing promise as a way to induce a partial or complete remission of the disease. It must be given intravenously. Major side effects are low blood counts and fever. Older patients seem to be more prone to serious side effects from this medicine, including an increased risk of severe infections.
Cladribine (2-CdA) — This is a medicine similar to fludarabine, with similar side effects.
BIOLOGIC THERAPIES
Monoclonal antibodies — Medicines called monoclonal antibodies may help treat CLL by attacking specific substances (antigens) on the surface of the leukemic cells. Examples include rituximab and alemtuzumab. Combinations of antibodies with such chemotherapeutic agents as prednisone, cytoxan, and/or fludarabine are achieving very high complete remission rates of long duration.
Immunotherapy — The availability of agents known as biologic response modifiers has led to investigation of these agents in the treatment of CLL. Examples include recombinant interferon alfa or interleukin-2. These medicines may boost the patient's immune response so that it can more effectively fight the cancer.
RADIATION THERAPY — Radiation therapy may be used to shrink large, bulky masses of lymphoid tissue that occur because of accumulation of leukemic cells. These cells are very responsive to radiation and usually shrink considerably, although the swelling may return. The spleen or other areas of the body may be treated.
REMOVAL OF THE SPLEEN — Patients with CLL who have significant enlargement of the spleen often respond well to chemotherapy. In patients with persistent enlargement of the spleen, radiation therapy may be prescribed, but removal of the spleen is more likely to provide longer lasting benefits, including improvement in low red cell and platelet counts. If the patient is well enough to withstand surgery, removal of the spleen may be recommended.
BONE MARROW TRANSPLANTATION — Bone marrow transplantation (also called hematopoietic stem cell transplantation) is being more seriously considered as a therapy for CLL, especially for patients below the age of 55. Bone marrow transplant is a treatment in which the patient is given very high doses of chemotherapy or radiation, which kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal pipeline for replenishing critical blood components, the bone marrow, is no longer functional. After the treatment, the patient needs to have a healthy supply of very young blood cells, called stem cells, reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
There are two main types of stem cell transplant: allogeneic and autologous.
Allogeneic transplant — In allogeneic transplant, the healthy cells that the patient receives following the high dose chemotherapy or radiation come from a donor, ideally a brother or sister with a similar genetic make-up. If the patient doesn't have a "matched" sibling, an unrelated person with a partially similar genetic makeup may be used.
Patients whose disease has become life-threatening but who are unable to tolerate high dose chemotherapy may be candidates for a reduced intensity transplant (called a mini-transplant or non-ablative transplant) from a relative or a matched unrelated donor, and may achieve long term control of their CLL.
Autologous transplant — In autologous transplant, the patient's own stem cells are removed before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemic cells that may be present, then they are frozen for storage. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient.
POSTPONING TREATMENT — As noted above, treatment of CLL is not appropriate for all patients. In a patient whose disease is not progressing rapidly, or in whom there are no troubling symptoms, the risks and discomforts of treatment may be greater than any possible benefit. In these cases, doctors will advise the patient to return for blood tests and a physical exam every three months. At the end of a year, it should be clear whether or not the patient has an aggressive form of the disease that requires treatment.
TREATMENT OF COMPLICATIONS — The major complications of CLL are caused by the low blood counts and immune system problems that either arise from the disease itself or the treatment. They include infection, anemia, and low platelets.
Infection — Episodes of infection are major complications that occur during the treatment of CLL. Infection is often related to low levels of important infection fighting proteins called gamma globulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) to decrease the chance of infection. Infections of the upper respiratory tract are common, but usually respond to antibiotics. Some patients may develop chronic sinusitis.
Patients treated with certain chemotherapy agents may develop low white blood cells counts, and an increased risk of other infections. Early treatment with antibiotics is recommended, and, in some cases, medications that promote the growth of new blood cells may be given to boost the white cell count and decrease the infection risk.
Anemia — Anemia, or low red blood cell counts, is common in CLL. Red blood cells are needed to carry oxygen to all the cells in the body. Patients with anemia may experience fatigue, weakness, and chest pain. Treatment includes blood transfusion and, in some cases, administration of a medicine called erythropoietin, which can boost the red cell count in patients with certain types of anemia. Other forms of anemia may be treated with steroids.
Low platelet counts — Platelets are important components of the blood's clotting mechanism. Without adequate numbers of platelets, internal and external bleeding can occur. Patients with CLL and low platelet counts may see their counts improve with treatment of the CLL. In some cases, platelet transfusions are needed. Removal of the spleen, use of steroids, or agents which suppress the immune response as part of the treatment for CLL usually results in improved platelet counts.
Psychological aspects — Patients with CLL are forced to live with the uncertainties associated with a chronic illness. In some cases, it is puzzling and frightening to hear that there is a diagnosis of leukemia and that no treatment is recommended. Patients and their healthcare providers must speak frequently and honestly to deal with fears and clarify any misunderstandings about this sometimes confusing disease. Some patients and families benefit from psychological counseling to help them cope with the strong emotions that can accompany this diagnosis.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at:
http://cancernet.nci.nih.gov/clinicaltrials
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-8]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Call, TG, Phyliky, RL, Noel, P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc 1994; 69:323.
2. Rai, KR, Sawitsky, A, Cronkite, EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219.
3. Binet, L-L, Auquier, A, Dighiero, G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48:198.
4. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 1989; 110:236.
5. Keating, MJ, Kantarjian, H, Talpaz, M, et al. Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74:19.
6. Seymour, JF, Cusack, JD, Lerner, SA, et al. Case/control study of the role of splenectomy in chronic lymphocytic leukemia. J Clin Oncol 1997; 15:52.
7. Khouri, IF, Keating, MJ, Vriesendorp, HM, et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia. J Clin Oncol 1994; 12:748.
8. Johnson, S, Smith, AG, Loffler, H, et al. Multicenter prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 1996; 347:1432.
In CLL, abnormally high numbers of ineffective lymphocytes are found in the blood and/or bone marrow (the spongy area in the middle of large bones where blood cells are formed). They cannot fight infection as normal lymphocytes do, and collect in increased numbers in lymph nodes and other areas, such as the liver and spleen. Their high numbers can cause them to interfere with the proper production of other blood cells, such as red cells and platelets.
Unlike acute lymphoblastic leukemia, which is fatal if left untreated, CLL is usually characterized by a slow progression of the disease and related symptoms. In many cases, it causes the patient little, if any, problems in its early stages. Patients may live with CLL for decades. Many times, it is diagnosed by blood tests that are performed during a routine physical exam. In other cases, symptoms may bring the patient to the doctor.
Careful analysis of the patient's blood and physical condition help the doctor determine the stage of the disease - a crucial first step in deciding on the proper course of treatment. Unlike patients with many other types of cancer, some patients with CLL may not benefit from early, aggressive treatment, but rather, may do better with careful long-term monitoring of the disease without treatment.
STAGING OF CLL — The natural history of CLL may vary considerably from person to person. Some patients may become sick within a short time of diagnosis; others live comfortably for years without problems. Determining which patients are most likely to get sick, and therefore are most likely to benefit from treatment of the disease, has been a challenge for doctors.
Two systems for staging CLL are now in use. They are used as a way to help identify patients with more serious versus "smoldering" disease, and as a way to help identify which patients are most likely to develop serious problems in the near term.
The Rai system — The Rai system is based on an analysis of how the body is affected by the abnormal lymphocytes. There are five stages. The higher numbers indicate a more advanced stage of disease: Stage 0: Increased numbers of abnormal lymphocytes are found in the blood or bone marrow; lymph nodes/organs are not swollen, and production of red cells and platelets is normal Stage I: Increased abnormal lymphocytes and enlarged lymph nodes Stage II: Increased abnormal lymphocytes with enlarged liver or spleen, with or without enlarged lymph nodes Stage III: Increased abnormal lymphocytes with anemia (low red blood cell count), with or without an enlarged spleen, liver, or lymph nodes Stage IV: Increased abnormal lymphocytes with a low platelet count, with or without anemia, enlarged liver, spleen, or lymph nodes
The Binet system — This system considers the five possible sites where lymphocytes can collect (lymph nodes in the neck, armpit, and groin, and lymphocyte-containing channels in the spleen and liver), and also on whether or not anemia or low platelet counts are present. There are three stages: Stage A: Fewer than three involved sites Stage B: Three or more involved sites Stage C: Presence of anemia or low platelet counts
Experts have recommended that these two systems be used together to define the stage of leukemia, for example, stage A0, A1, AII, BI, and so on. However, many clinicians still use either the Rai or Binet method.
What the stages mean — Staging helps doctors decide how likely it is that the person is soon to develop serious problems related to the CLL. Patients at Rai stage 0 are considered at low risk, those at stages I or II are at intermediate risk, and those at stage III or IV are at high risk. Similarly, patients characterized according to the Binet system have progressively increasing risk, with Stage A as the lowest and Stage C as the highest risk group. Average survivals for these three risk categories are: Low risk — 12 years Intermediate risk — 7.5 years High risk — 1.5 years
In general, doctors are more certain about expected disease progression in the higher versus the lower risk groups. That is, it is more difficult to tell which patients in the lower risk groups are most likely to go on to develop more serious disease. Research is underway to identify factors associated with a more aggressive course. For example, analysis of certain aspects of bone marrow cells and comparison of the patient's blood test results over time may prove helpful in identifying which patients in the lower risk groups are more likely to become ill with CLL.
Indications for treatment — As noted above, treatment is not always required for CLL. Some studies have shown that patients with so-called "smoldering" CLL are no more likely to die than a normal person of similar age and sex. Although treatment can be effective in controlling progression of the disease and alleviating symptoms, it usually does not produce a cure. This means that doctors and patients must carefully weigh the risks and discomforts of treatment against expected benefits to be gained.
However, there are certain groups of patients in whom some type of treatment is generally indicated. This includes patients with: Anemia and/or low platelets (Rai stages III or IV, or Binet stage C) Disease-related symptoms such as weakness, night sweats, weight loss, painful lymph node swelling, or fever Progressive disease, as demonstrated by rapidly increasing white cells in the blood, and/or rapidly enlarging lymph nodes, spleen, or liver Repeated infections
In some cases, especially in younger patients, doctors may recommend treating patients who do not have symptoms and/or those with low risk disease. Patients and doctors may choose to aggressively treat these milder forms of the disease in the hopes of obtaining long-term benefits and possibly a cure. Such aggressive treatments, such as bone marrow transplantation, may have serious side effects, and are generally part of a formal research study.
In other cases, detailed examination of the leukemic cells may be able to determine the future clinical course of the disease (ie, the prognosis), as well as the suitability of one or more treatment options. Such studies are the subject of a large number of ongoing research trials.
A number of different forms of treatment may be proposed. These are outlined in the following sections.
CHEMOTHERAPY — Chemotherapy, or the use of medications to kill cancer cells, can be effective in treating CLL. Depending on factors such as the stage of illness, the patient's age, and symptoms, the goals of chemotherapy may vary. For example, in some cases the goal is to halt the progression of the disease and relieve symptoms. In other cases, medicines will be chosen that are designed to help induce a remission of the disease. A patient undergoing chemotherapy for CLL should talk with the doctor about the goals for treatment.
Some of the medicines that may be used are listed here. Ask your doctor for complete information about the specific medicines you will receive, whether or not you will need to be admitted to the hospital for therapy, and what side effects you should watch for.
Historical agents — The following three agents were among the first to be successfully used for the treatment of CLL:
Chlorambucil (Leukeran) — This is taken by mouth either daily or in a single dose given every three to four weeks. The most common side effects are anemia, low white blood cell counts (leading to risk for infection), and low platelet counts (increasing the risk for bleeding).
Cyclophosphamide (Cytoxan) — This medicine can be given by mouth or through an intravenous (IV) line. Side effects include low blood counts, nausea and vomiting, hair loss, and irritation of the urinary bladder.
Steroids — Some treatment programs call for the use of steroids such as prednisone to treat CLL. Side effects include increased susceptibility to infections, high blood glucose, gastrointestinal problems, muscle weakness, and psychiatric symptoms.
Newer agents — The following two agents have been shown to be clearly superior to the historical agents noted above. Fludarabine, in combination with cyclophosphamide, is the most potent combination regimen developed to date.
Fludarabine — This medicine is showing promise as a way to induce a partial or complete remission of the disease. It must be given intravenously. Major side effects are low blood counts and fever. Older patients seem to be more prone to serious side effects from this medicine, including an increased risk of severe infections.
Cladribine (2-CdA) — This is a medicine similar to fludarabine, with similar side effects.
BIOLOGIC THERAPIES
Monoclonal antibodies — Medicines called monoclonal antibodies may help treat CLL by attacking specific substances (antigens) on the surface of the leukemic cells. Examples include rituximab and alemtuzumab. Combinations of antibodies with such chemotherapeutic agents as prednisone, cytoxan, and/or fludarabine are achieving very high complete remission rates of long duration.
Immunotherapy — The availability of agents known as biologic response modifiers has led to investigation of these agents in the treatment of CLL. Examples include recombinant interferon alfa or interleukin-2. These medicines may boost the patient's immune response so that it can more effectively fight the cancer.
RADIATION THERAPY — Radiation therapy may be used to shrink large, bulky masses of lymphoid tissue that occur because of accumulation of leukemic cells. These cells are very responsive to radiation and usually shrink considerably, although the swelling may return. The spleen or other areas of the body may be treated.
REMOVAL OF THE SPLEEN — Patients with CLL who have significant enlargement of the spleen often respond well to chemotherapy. In patients with persistent enlargement of the spleen, radiation therapy may be prescribed, but removal of the spleen is more likely to provide longer lasting benefits, including improvement in low red cell and platelet counts. If the patient is well enough to withstand surgery, removal of the spleen may be recommended.
BONE MARROW TRANSPLANTATION — Bone marrow transplantation (also called hematopoietic stem cell transplantation) is being more seriously considered as a therapy for CLL, especially for patients below the age of 55. Bone marrow transplant is a treatment in which the patient is given very high doses of chemotherapy or radiation, which kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal pipeline for replenishing critical blood components, the bone marrow, is no longer functional. After the treatment, the patient needs to have a healthy supply of very young blood cells, called stem cells, reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
There are two main types of stem cell transplant: allogeneic and autologous.
Allogeneic transplant — In allogeneic transplant, the healthy cells that the patient receives following the high dose chemotherapy or radiation come from a donor, ideally a brother or sister with a similar genetic make-up. If the patient doesn't have a "matched" sibling, an unrelated person with a partially similar genetic makeup may be used.
Patients whose disease has become life-threatening but who are unable to tolerate high dose chemotherapy may be candidates for a reduced intensity transplant (called a mini-transplant or non-ablative transplant) from a relative or a matched unrelated donor, and may achieve long term control of their CLL.
Autologous transplant — In autologous transplant, the patient's own stem cells are removed before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemic cells that may be present, then they are frozen for storage. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient.
POSTPONING TREATMENT — As noted above, treatment of CLL is not appropriate for all patients. In a patient whose disease is not progressing rapidly, or in whom there are no troubling symptoms, the risks and discomforts of treatment may be greater than any possible benefit. In these cases, doctors will advise the patient to return for blood tests and a physical exam every three months. At the end of a year, it should be clear whether or not the patient has an aggressive form of the disease that requires treatment.
TREATMENT OF COMPLICATIONS — The major complications of CLL are caused by the low blood counts and immune system problems that either arise from the disease itself or the treatment. They include infection, anemia, and low platelets.
Infection — Episodes of infection are major complications that occur during the treatment of CLL. Infection is often related to low levels of important infection fighting proteins called gamma globulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) to decrease the chance of infection. Infections of the upper respiratory tract are common, but usually respond to antibiotics. Some patients may develop chronic sinusitis.
Patients treated with certain chemotherapy agents may develop low white blood cells counts, and an increased risk of other infections. Early treatment with antibiotics is recommended, and, in some cases, medications that promote the growth of new blood cells may be given to boost the white cell count and decrease the infection risk.
Anemia — Anemia, or low red blood cell counts, is common in CLL. Red blood cells are needed to carry oxygen to all the cells in the body. Patients with anemia may experience fatigue, weakness, and chest pain. Treatment includes blood transfusion and, in some cases, administration of a medicine called erythropoietin, which can boost the red cell count in patients with certain types of anemia. Other forms of anemia may be treated with steroids.
Low platelet counts — Platelets are important components of the blood's clotting mechanism. Without adequate numbers of platelets, internal and external bleeding can occur. Patients with CLL and low platelet counts may see their counts improve with treatment of the CLL. In some cases, platelet transfusions are needed. Removal of the spleen, use of steroids, or agents which suppress the immune response as part of the treatment for CLL usually results in improved platelet counts.
Psychological aspects — Patients with CLL are forced to live with the uncertainties associated with a chronic illness. In some cases, it is puzzling and frightening to hear that there is a diagnosis of leukemia and that no treatment is recommended. Patients and their healthcare providers must speak frequently and honestly to deal with fears and clarify any misunderstandings about this sometimes confusing disease. Some patients and families benefit from psychological counseling to help them cope with the strong emotions that can accompany this diagnosis.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at:
http://cancernet.nci.nih.gov/clinicaltrials
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-8]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Call, TG, Phyliky, RL, Noel, P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc 1994; 69:323.
2. Rai, KR, Sawitsky, A, Cronkite, EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219.
3. Binet, L-L, Auquier, A, Dighiero, G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48:198.
4. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 1989; 110:236.
5. Keating, MJ, Kantarjian, H, Talpaz, M, et al. Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74:19.
6. Seymour, JF, Cusack, JD, Lerner, SA, et al. Case/control study of the role of splenectomy in chronic lymphocytic leukemia. J Clin Oncol 1997; 15:52.
7. Khouri, IF, Keating, MJ, Vriesendorp, HM, et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia. J Clin Oncol 1994; 12:748.
8. Johnson, S, Smith, AG, Loffler, H, et al. Multicenter prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 1996; 347:1432.
Subscribe to:
Posts (Atom)