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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Incidence and Mortality
Estimated new cases and deaths from CML in the United States in 2023:
CML is one of a group of diseases called the myeloproliferative disorders. Other related entities include the following:
For more information, see Chronic Myeloproliferative Neoplasms Treatment.
CML is identified by too many myeloblasts in the blood and bone marrow, and the disease worsens as the number of myeloblasts increase.
Figure 1. Hematopoietic tree, expanded lymphoid line.
CML is a clonal disorder that is easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph).
Figure 2. The Philadelphia chromosome is a translocation between the ABL1 oncogene (on the long arm of chromosome 9) and the BCR gene (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL1 encodes an oncogenic protein with tyrosine kinase activity.
The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, and it is demonstrable in all hematopoietic precursors. This translocation results in the transfer of the ABL oncogene on chromosome 9 to an area of chromosome 22 termed the breakpoint cluster region (within the BCR gene). This, in turn, results in a fused BCR-ABL gene and in the production of an abnormal tyrosine kinase protein that causes the disordered myelopoiesis found in CML. Using peripheral blood, molecular techniques can detect the presence of the 9;22 translocation.
Although CML may present without symptoms, splenomegaly is the most common finding during physical examination at the time of diagnosis. The spleen may be enormous, filling most of the abdomen, causing pain or a feeling of fullness 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 computed tomography (CT) scan.
Patients may also present with the following symptoms:
Transition between the chronic, accelerated, and blastic phases may occur gradually over 1 year or more, or it may occur abruptly (blast crisis). Patients with accelerated-phase CML show signs of progression without meeting the criteria for blast crisis (acute leukemia). Signs and symptoms that indicate a change to accelerated-phase CML include the following:
Signs and symptoms that indicate a change to a blast crisis, in addition to the accelerated-phase CML symptoms, include the following:
In the accelerated phase, differentiated cells persist, although they often show increasing morphologic abnormalities. The patient experiences increased anemia, thrombocytopenia, and marrow fibrosis.
Risk factors for CML include the following:
In addition to a health history and physical examination, the initial workup may include the following:
Prognosis and Survival
The median age of patients with Ph chromosome–positive CML is 67 years. With the advent of the oral tyrosine kinase inhibitors (TKIs) , the median survival is projected to approach normal life expectancy for most patients.
Ph chromosome–negative CML is a poorly defined entity that is less clearly distinguished from other myeloproliferative syndromes. Patients with Ph chromosome–negative CML generally have a poorer response to treatment and shorter survival than Ph chromosome–positive patients. Ph chromosome–negative patients who have BCR-ABL gene rearrangements detectable by Southern blot analysis, however, have prognoses equivalent to Ph chromosome–positive patients.[6,12]
Histopathological examination of the bone marrow aspirate of patients with chronic myelogenous leukemia (CML) 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 like that found in normal marrow. Increased numbers of eosinophils or basophils are often present, and monocytosis is sometimes 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 compared with normal samples. 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 CML.
Most patients do not require bone marrow examination. However, bone marrow testing is appropriate for patients with fever, malaise, rapidly enlarging splenomegaly, and more than 10% circulating blast. In patients with CML, bone marrow sampling is performed to assess cellularity, fibrosis, and cytogenetics. Reverse transcription–polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) analyses using blood or marrow aspirates demonstrate the 9;22 translocation.
Chronic-phase CML is characterized by bone marrow and cytogenetic findings as listed below with less than 10% blasts and promyelocytes in the peripheral blood and bone marrow. The following factors are predictive of a shorter chronic phase after treatment with tyrosine kinase inhibitors:
Predictive models using multivariate analysis have been derived.[5,6,7]
The rate of progression from chronic phase to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent years.
For more information, see the Treatment of Chronic-Phase CML section.
Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.
For more information, see the Treatment of Accelerated-Phase CML section.
Blastic-phase CML is characterized by 20% or more blasts in the peripheral blood or bone marrow.
When 20% or more blasts are present along with fever, malaise, and progressive splenomegaly, the patient has entered blast crisis.
For more information, see the Treatment of Blastic-Phase CML section.
Treatment of patients with chronic myelogenous leukemia (CML) is usually initiated at diagnosis, which is based on the presence of an elevated white blood cell count, splenomegaly, thrombocytosis, and identification of the BCR-ABL translocation.
Targeted Therapy With Tyrosine Kinase Inhibitors (TKIs)
The optimal front-line treatment for patients with chronic-phase CML involves specific inhibitors of the BCR-ABL tyrosine kinase. Although imatinib mesylate has been extensively studied in patients with CML, TKIs with greater potency and selectivity for BCR-ABL than imatinib have also been evaluated.
Allogeneic Bone Marrow Transplantation (BMT) or Stem Cell Transplantation (SCT)
Allogeneic BMT or SCT has also been used with curative intent. Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the BCR-ABL translocation by any available test (e.g., cytogenetics, reverse transcription–polymerase chain reaction, or fluorescence in situ hybridization). Some patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 5% to 10% treatment-related mortality can be expected, depending on whether a donor is related and the presence of mismatched antigens.
Evidence (allogeneic SCT vs. drug treatment):
Similar outcomes were seen in patients who underwent allogeneic SCT because of TKI intolerance or nonadherence.
Long-term data are also available for patients treated with interferon alfa.[5,6,7] Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of BCR-ABL translocation by any available test, and most of these patients are disease-free beyond 10 years. Maintenance therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
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 mg/kg 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 × 109 /L, the hydroxyurea is often reduced and titrated to maintain a WBC count between 5 × 109 /L and 20 × 109 /L.
Hydroxyurea is used primarily to stabilize patients with hyperleukocytosis or as palliative therapy for patients who have not responded to other therapies.
Treatment options for chronic-phase chronic myelogenous leukemia (CML) include the following:
Targeted Therapy With TKIs
The preferred initial treatment for patients with newly diagnosed chronic-phase CML could be any of the specific inhibitors of the BCR-ABL tyrosine kinase (including nilotinib, dasatinib, bosutinib, or imatinib). With any of these agents, the 10-year event-free survival and overall survival (OS) rates exceed 80%.[2,3,4]
CML response rate abbreviations used in this section include the following:
A BCR-ABL transcript level of 10% or less in patients after 3 months of treatment with a specific TKI (deemed EMR) is associated with the best prognosis in terms of failure-free survival, progression-free survival (PFS), and OS.[5,6,7,8,9,10] However, in a retrospective analysis, even patients with a BCR-ABL transcript level greater than 10% after 3 months of therapy did well when the halving time was less than 76 days.
Mandating a change of therapy based on this 10% transcript level at 3 to 6 months is problematic because 75% of patients do well even with a suboptimal response. After 1 year, the preferred response target is an MMR, which is defined as a BCR/ABL level of less than or equal to 0.1%. The optimal target is a DMR, which is defined as under 4 logs (BCR-ABL ≤ 0.01%) or undetectable, which is usually a BCR-ABL level of ≤ 0.001% (MR 5).
Evidence (targeted therapy with TKIs):
In randomized prospective trials, nilotinib, dasatinib, and bosutinib showed higher rates of earlier MMR compared with imatinib. It is unclear whether this will translate to improved long-term outcomes.[8,9,16][Level of evidence B3] A dose-ranging phase II study of dasatinib in patients over age 70 showed optimal response and reduction of toxicity starting at 20 mg once daily with dose escalation if needed, versus the standard dose of 100 mg daily.[Level of evidence C3]
Can TKIs be discontinued?
For patients who obtain a DMR (deep molecular response), it is unclear if TKI therapy can be discontinued. Several nonrandomized reports can be summarized as follows:[18,19,20,21,22][Level of evidence C3]
However, after the reinduction of a previous TKI, the duration of remissions or the depth of responses are not known. There are insufficient data to recommend routinely discontinuing TKIs, even in this select group of patients. Follow-up (i.e., at least every 3 months initially, although the precise interval is not well-defined) is required after stopping therapy because relapses have been noted even after 2 to 3 years.
Allogeneic BMT or SCT
The only consistently successful curative treatment of patients with CML has been allogeneic BMT or SCT.[23,24,25] Patients younger than 60 years with an identical twin or with human leukocyte antigen (HLA)-matched siblings can be considered for BMT early in the chronic phase. Although the procedure is associated with considerable acute morbidity and mortality, 50% to 70% of patients who undergo transplantation in the chronic phase appear to be cured. The results are better in younger patients, especially for those younger than 20 years. The outcomes of patients who undergo transplantation in the accelerated and blastic phases of the disease are progressively worse.[26,27] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[28,29,30][Level of evidence C1] The data supporting early transplant, however, have never been confirmed in controlled trials.
Evidence (allogeneic SCT):
Although most relapses occur within 5 years of transplantation, relapses have occurred as late as 15 years after a BMT. In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable BCR-ABL transcript by PCR analysis. The risk of relapse appears to be less in patients who underwent transplantation early in disease and in patients who develop chronic GVHD.[27,36]
With the advent of imatinib, dasatinib, bosutinib, and nilotinib therapy, the timing and sequence of allogeneic BMT or SCT has been questioned. Allogeneic SCT is the preferred choice for some patients presenting with blastic-phase disease, some patients with a T315I mutation resistant to ponatinib (an oral TKI), and for patients with complete intolerance to the pharmacological options. Similar outcomes were seen in patients who underwent allogeneic SCT because of TKI intolerance or nonadherence.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for accelerated-phase chronic myelogenous leukemia (CML) include the following:
The U.S. Food and Drug Administration approved bosutinib as a first-line treatment for patients with accelerated-phase CML. These patients were included in the initial phase I/II trial that showed improved efficacy versus imatinib, on the basis of response rates and major molecular response at 5 years of follow-up.[Level of evidence C3]
Induction of remission using a tyrosine kinase inhibitor (TKI) and consideration of an allogeneic SCT for patients with poor responses, when feasible, is a standard approach for patients with accelerated-phase CML.
Evidence (imatinib vs. allogeneic SCT):
Treatment options for blastic-phase chronic myelogenous leukemia (CML) include the following:
Bosutinib, imatinib mesylate, dasatinib, and nilotinib have demonstrated activity in patients with myeloid blast crisis and lymphoid blast crisis or Philadelphia chromosome–positive acute lymphoblastic leukemia.[1,2,3]
Allogeneic BMT or SCT should be considered when feasible, depending on response and durability of response.[7,8,9,10,11]
Treatment options for relapsed chronic myelogenous leukemia (CML) include the following:
Overt treatment failure is defined as a loss of hematologic remission or progression to accelerated-phase or blast crisis-phase CML as previously defined. A consistently rising quantitative reverse–transcription polymerase chain reaction (RT-PCR) BCR-ABL level suggests relapsed disease.
Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:
Detection of the BCR-ABL translocation by RT-PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT-PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT-PCR measurements that are closely connected with clinical relapse.
In case of treatment failure or suboptimal response, patients should undergo BCR-ABL kinase domain mutation analysis to help guide therapy with the newer TKIs or with allogeneic transplantation.[2,3]
Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate. Alternative TKIs such as dasatinib, nilotinib, or bosutinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) have been studied in this setting.[4,5,6,7,8,9,10,11,12,13,14,15,16] In particular, the T315I mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib.
Ponatinib has activity in patients with T315I mutation or in patients for whom another TKI failed.[17,18,19] A dose-ranging phase II study concluded that the optimal response (≤ 1% BCR-ABL) and least toxicity occurred at 45 mg starting dose, with a decrease to 15 mg upon achieving the aforementioned response.[Level of evidence C3]
These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic myelogenous leukemia (CML) treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for CML. Listed after each reference are the sections within this summary where the reference is cited.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and reformatted.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Chronic Myelogenous Leukemia Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Chronic Myelogenous Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389354]
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Last Revised: 2023-03-21
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