PDQ® Treatment Health Professionals
Chronic myelogenous leukemia (CML) is one of a group of diseases called the myeloproliferative disorders. CML is not currently curable with conventional chemotherapy or immunotherapy. Allogeneic bone marrow transplantation from related or unrelated donors is the only known curative therapy. Survival after development of an accelerated phase is usually less than 1 year and after blastic transformation is only a few months, although patients with lymphoblastic transformation may live longer with appropriate treatment.
Other related entities include polycythemia vera, myelofibrosis, and essential thrombocythemia. CML is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia (Ph) chromosome. The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors. This translocation results in the transfer of the Abelson (abl) oncogene to an area of chromosome 22 termed the breakpoint cluster region (bcr). This in turn results in a fused bcr-abl gene and in the production of an abnormal tyrosine kinase protein that may be related to the disordered myelopoiesis found in CML. Furthermore, these molecular techniques can now be used to supplement cytogenetic studies to detect the presence of the 9;22 translocation in patients without a visible Ph chromosome (Ph-). Ph- CML is a poorly defined entity that is less clearly distinguished from other myeloproliferative syndromes. Patients with Ph- CML generally have a poorer response to treatment and shorter survival than Ph+ patients. However, Ph- patients who have bcr-abl gene rearrangement detectable by Southern blot analysis have prognoses equivalent to Ph+ patients.[5,6] A small subset of patients have bcr-abl detectable only by reverse transcription-polymerase chain reaction (RT-PCR), which is the most sensitive technique currently available. Patients with RT- PCR evidence of the bcr-abl fusion gene appear clinically and prognostically identical to patients with a classic Ph chromosome. However, patients who are bcr-abl-negative by RT-PCR have a clinical course more consistent with chronic myelomonocytic leukemia, a distinct clinical entity related to myelodysplastic syndrome.[5,7]
The median age of patients with Ph+ CML is 67 years of age. Median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years.
CML can occur in children (2%-3% of all childhood leukemias are CML), but if Ph+, the prognosis for children may be better than that for adults.
Bone marrow sampling is done to assess cellularity, fibrosis, and cytogenetics. The Philadelphia (Ph) chromosome is usually more readily apparent in marrow metaphases than in peripheral blood metaphases; in some cases, it may be "mashed" and molecular studies are necessary to demonstrate the 9;22 translocation. Quantitative Southern blot analysis of blood samples for breakpoint cluster region gene rearrangement may substitute for bone marrow sampling to monitor response to therapy.
The most common finding on physical examination at diagnosis is splenomegaly. The spleen may be enormous, filling most of the abdomen and presenting a significant clinical problem, or the spleen may be only minimally enlarged. In about 10% of patients, the spleen is neither palpable nor enlarged on splenic scan.
Histopathologic examination of bone marrow aspirate demonstrates a shift in the myeloid series to immature forms that increase in number as patients progress to the blastic phase of the disease. The marrow is hypercellular, and differential counts of both marrow and blood show a spectrum of mature and immature granulocytes similar to that found in normal marrow. Increased numbers of eosinophils or basophils are often present, and sometimes monocytosis is seen. Increased megakaryocytes are often found in the marrow, and sometimes fragments of megakaryocytic nuclei are present in the blood, especially when the platelet count is very high. The percentage of lymphocytes is reduced in both the marrow and blood in comparison with normal subjects, and the myeloid/erythroid ratio in the marrow is usually greatly elevated. The leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in the neutrophils of patients with chronic myelogenous leukemia.
Transition from the chronic phase to the accelerated and later the blastic phase may occur gradually over a period of 1 year or more, or it may appear abruptly ("blast crisis"). The annual rate of progression from chronic phase to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent years.[3,4] Signs and symptoms commonly heralding such a change are progressive leukocytosis, thrombocytosis or thrombocytopenia, anemia, increasing and painful splenomegaly or hepatomegaly, fever, bone pain, development of destructive bone lesions, and thrombotic or bleeding complications. In the accelerated phase, differentiated cells persist, although they often show increasing morphologic abnormalities, and increasing anemia and thrombocytopenia and marrow fibrosis are apparent.[2,5,6]
Studies have suggested that certain presenting features have prognostic significance and may help in identifying patients in whom bone marrow transplantation should be considered earlier in the course of the disease. Increased splenomegaly, older age, male sex, elevated serum lactate dehydrogenase, cytogenetic abnormalities in addition to the Ph chromosome, a higher proportion of marrow or peripheral blood blasts, basophilia, eosinophilia, thrombocytosis, and anemia predicted for a shorter chronic phase. Predictive models using multivariate analysis have been derived.[3,7,4,8,9] It should be noted that transplant centers performing 5 or fewer transplants annually usually have poorer results than larger centers.
Chronic phase: bone marrow and cytogenetic findings as described above with less than 5% blasts and promyelocytes in the peripheral blood and bone marrow.
Accelerated phase: greater than 5% in either the peripheral blood or bone marrow but less than 30% blasts in both the peripheral blood and bone marrow.
Blastic phase: greater than 30% blasts in the peripheral blood or bone marrow.
Treatment of chronic myelogenous leukemia (CML) is usually initiated when the diagnosis is established, which is done by the presence of an elevated white blood cell (WBC) count, thrombocytosis, Philadelphia (Ph) chromosome, and splenomegaly. At initial diagnosis, consideration should be given to referral of patients younger than age 60 years to centers exploring potentially curative therapy with bone marrow transplantation when appropriate donors are available. Many patients will not be young or healthy enough to tolerate transplantation; those who can are likely to find a histocompatible related donor 30% of the time and a suitable unrelated donor 50% of the time. Interferon alfa may produce partial or complete remissions in chronic phase CML. Cytogenetic responses have been reported in up to 20% of patients, with delay of disease progression and prolongation of overall survival. Standard drug therapy is administered to diminish WBC count to approximately 10,000 per cubic millimeter without producing marrow hypoplasia. Before chemotherapy, early deaths occurred in patients left with extremely high WBC and platelet counts. Leukapheresis and platelet pheresis can also be used to rapidly lower these counts although this is only of temporary benefit and is rarely required in adults in chronic phase.
When blast crisis supervenes (as evidenced by fever, progressive splenomegaly, and increased blast cells in the peripheral blood), minimally satisfactory remission-induction treatment appears to be available only to a group of patients whose cells are positive for the enzyme terminal deoxynucleotidyl transferase (TdT). In these patients survival can be extended 4 to 8 months using simple treatment with combinations of drugs including vincristine and prednisone, usually given in the treatment of acute lymphocytic leukemia. In addition intensive chemotherapy/radiation therapy followed by reinfusion of marrow or peripheral blood or both collected and frozen during the chronic phase has also been used regardless of TdT status.[5,4,6-9] However, in most patients early relapse of blast crisis has developed. Intensive combination chemotherapy for juvenile CML may be more effective in producing long-term disease-free survivors.
Allogeneic bone marrow transplantation in the chronic phase is the only therapy known to cure CML. Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[Level of evidence: 3iiiA];[Level of evidence: 3iiiA];[Level of evidence: 3iiiA] However, the data supporting early transplant have never been confirmed in controlled trials. Other treatment of CML does not cure the disease. Thus, all newly diagnosed patients should be considered appropriate candidates for clinical trials exploring new therapeutic approaches, including bone marrow transplantation, biologic response modifiers, and combination chemotherapy.
It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Ph chromosome. In typical Ph+ CML or CML presenting de novo in blast crisis without a recognizable preceding chronic phase, the breakpoints in chromosome 22 occur either between the second and third or between the third and fourth exon of the breakpoint cluster region (bcr). This results in the 2 common variants of the fused bcr-Abelson (abl) gene seen typically in Ph+ CML, both of which are associated with the expression of a p210 bcr-abl hybrid protein.[3,15,16]
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.
The choice of initial therapy for patients with chronic phase chronic myelogenous leukemia (CML) is complicated. Allogeneic transplantation offers the only prospect of cure, but the morbidity and mortality are high. For patients younger than 40 years of age, allogeneic transplantation with a related or unrelated donor is the highest priority and should be considered within the first year following diagnosis.[1-3] Patients older than 40 years of age who have a related donor should strongly consider allogeneic transplantation, although morbidity and mortality of the procedure rise with increased age. Because of the increased morbidity and mortality from unrelated donors in patients over 40 years of age, a trial of interferon with or without cytarabine is recommended. Patients without a major cytogenetic response would then proceed to transplantation when feasible.
Treatment options for chronic phase:
About 20% of otherwise eligible CML patients lack a suitably matched sibling donor. HLA-matched unrelated donors or donors mismatched at 1 HLA antigen can be found for about 50% of eligible participants through the National Marrow Donor Program. However, there are still major obstacles in using unrelated donors, especially in older patients. Two retrospective series following allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate of 3% to 10% and a 5-year overall survival rate of 31% to 57% (most deaths were treatment-related).[Level of evidence: 3iiiA]; Patients with unrelated donor transplants were generally younger and had a longer interval from diagnosis to transplant. While the majority of relapses occur within 5 years of transplantation, relapses have occurred as long as 9 years following BMT. The risk of relapse appears to be less in patients transplanted early in disease, and in patients who develop chronic graft-versus host disease.[9,11] BMT from an unrelated donor is associated with a higher risk of post-transplant graft failure and infection (viral and fungal). The incidence of relapse is lower with BMT from unrelated donors than it is from sibling donors. Interferon alfa, hydroxyurea, or both, are standard treatments used to stabilize patients prior to BMT. Some investigators report a worse outcome when interferon is applied for over 6 months prior to unrelated donor marrow transplantation, based on retrospective series.[12,13] There is contradictory evidence about interferon having an adverse effect on transplant outcomes.[14,15] Some transplant centers avoid using interferon while a transplant donor is selected.
2. Patients ineligible for syngeneic or allogeneic transplantation should receive interferon alfa. In 2 trials comparing interferon alfa with conventional chemotherapy (hydroxyurea or busulfan), patients in chronic phase who received interferon alfa had more karyotypic responses, more delay of disease progression, and prolonged overall survival.[16,17] Another randomized study confirmed the advantage of interferon (median survival 5.5 years) over busulfan (median survival 3.8 years), but it did not detect a significant difference between interferon and hydroxyurea (median survival 4.7 years). About 20% of the chronic-phase patients treated with interferon alfa have complete cytogenetic remissions with temporary disappearance of Ph+ cells in the marrow, and in about 10% of the patients these cytogenetic responses are quite long-lasting.[19,20] However, using molecular methods of analysis, small numbers of Ph+ cells can still be detected in the majority of patients having long-term cytogenetic remissions, and longer follow-up will be required to ascertain whether the disease will recur. Patients older than 60 years with chronic phase CML have a hematologic and cytogenetic response rate and duration of cytogenetic response similar to that in younger patients; however, the incidence of complications is greater in elderly patients. Interferon alfa has significant toxic effects that can result in dosage modification or discontinuation of therapy in many cases. Common side effects include influenza-like syndrome, nausea, anorexia, and weight loss. Immune -mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment. Interferon alfa is quite costly, and daily subcutaneous injections can be troublesome. Patients who achieve cytogenetic remission should continue therapy (3-5 million units per meter squared daily) for at least 2 to 3 years beyond remission, and perhaps indefinitely, as suggested by some investigators. Partially responding patients (<35% Philadelphia chromosome) should continue taking interferon until loss of response unless a suitable transplant donor can be found (if applicable). The French Chronic Myeloid Leukemia Study Group randomized 721 patients to interferon and cytarabine versus interferon alone.[Level of evidence: 1iiA] Patients who received the combination had significantly more major cytogenetic responses (41% versus 24%, p<.001) and improved 3-year survival (86% versus 80%). All patients initially received hydroxyurea until complete hematologic remission was attained; many clinicians use hydroxyurea to normalize the leukocytosis when starting interferon. The improved efficacy of this combination of interferon and cytarabine must be balanced against the increased toxic effects. For patients who have adequate performance status, yet are not candidates for transplantation, this combination is a reasonable option. Interferon alfa is also effective for patients who have relapsed after allogeneic bone marrow transplantation.[25,26]
3. Hydroxyurea is given daily by mouth (1-3 grams per day as a single dose on an empty stomach). Hydroxyurea is superior to busulfan in the chronic phase of CML, with significantly longer median survival and significantly fewer severe adverse effects. A dose of 40 milligrams per kilogram per day is often used initially and frequently results in a rapid reduction of the white blood cell (WBC) count. When the WBC count drops below 20,000 per cubic millimeter, the hydroxyurea is often reduced and titrated to maintain a WBC count between 5,000 and 20,000. However, in a randomized trial in which the hydroxyurea dose was adjusted to normalize the WBC count, no difference in survival was seen between a group treated with hydroxyurea and a group treated with interferon alfa, suggesting that a more aggressive application of hydroxyurea may lead to additional benefits. This finding requires confirmation. Because of its lower toxic effects, hydroxyurea is the drug of choice for patients who are candidates for bone marrow transplantation.
4. Busulfan (Myleran), which is rarely used, is given orally, either daily (4-8 milligrams per day) or in 2-week courses. Busulfan is associated with unpredictable prolonged myelosuppression, pulmonary fibrosis, and Addison's-like disease. A dose of 0.1 milligrams per kilogram per day is often used initially. The dose is halved as the WBC count drops by one half and is discontinued when the WBC count drops below 20,000.
5. Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.
6. The possibility of eradicating the leukemic cell population during the chronic phase by intensive treatment followed by rescue with autologous marrow or peripheral blood stem cells has also been considered.[28,29] Various methods have been tried to eliminate or reduce residual leukemic cells in the autografts, including ex vivo treatment with cytotoxic drugs and various immunologic or biologic purging methods. While some of the early reports appear promising, they are based on relatively small numbers of selected patients, and the follow-up period is too short to be sure late relapses will not occur.
Treatment options for accelerated phase:
2. Interferon alfa. Although the response rate is lower for accelerated phase disease than it is for chronic phase disease, durable responses and suppression of cytogenetic clonal evolution have been reported.[5,6]
3. High-dose cytarabine.
6. Supportive transfusion therapy.
Treatment options for blastic phase:
2. Vincristine and prednisone with or without an anthracycline (for the approximately 25% of patients with terminal deoxynucleotidyl transferase- positive cells and lymphoblastic transformation).[2,3]
3. Allogeneic bone marrow transplantation is successful in less than 10% of patients because of complications of transplantation and recurrent leukemia.[4,5] If available, this represents the only potentially curative approach in such patients.
4. Hydroxyurea (palliative).
5. Radiation therapy to lytic bone lesions.
Treatment options for meningeal chronic myelogenous leukemia:
2. Intrathecal cytarabine.
3. Cranial irradiation.
The prognosis for any treated cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. The question and selection of further treatment depends on many factors, including the specific cancer, previous treatment, and site of recurrence, as well as individual patient considerations. Because of the extremely poor results with standard therapy of blast crisis, clinical trials are particularly appropriate and should be considered when possible.[2-5] After relapse from allogeneic bone marrow transplantation, some patients will respond to interferon alfa.
Infusions of buffy coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant. The efficacy of this treatment is thought to be due to an immunologic graft-versus-leukemia effect. This treatment is most effective for patients whose relapse is detectable only by cytogenetics or molecular studies and is associated with significant graft-versus-host disease.[7-11]
Date Last Modified: 11/1999