Friday, October 12, 2007

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.

No comments: