Chronic Myelogenous Leukemia (CML)
- Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP more...
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. It accounts for 20% of all leukemias affecting adults. See the image below.
See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.
Signs and symptoms
The clinical manifestations of CML are insidious, changing somewhat as the disease progresses through its 3 phases (chronic, accelerated, and blast). Signs and symptoms in the chronic phase are as follows:
Fatigue, weight loss, loss of energy, decreased exercise tolerance
Low-grade fever and excessive sweating from hypermetabolism
Elevated white blood cell (WBC) count or splenomegaly on routine assessment
Early satiety and decreased food intake from encroachment on stomach by enlarged spleen
Left upper quadrant abdominal pain from spleen infarction
The following are signs and symptoms of progressive disease:
Bleeding, petechiae, and ecchymoses during the acute phase
Bone pain and fever in the blast phase
Increasing anemia, thrombocytopenia, basophilia, and a rapidly enlarging spleen in blast crisis
See Clinical Presentation for more detail.
The diagnosis of CML is based on the following:
Histopathologic findings in the peripheral blood
Philadelphia (Ph) chromosome in bone marrow cells
The workup for CML consists of the following:
CBC with differential
Peripheral blood smear
Bone marrow analysis
Blood count and peripheral smear findings
Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils
Mild to moderate anemia, usually normochromic and normocytic
Platelet counts low, normal, or increased
Leukocyte alkaline phosphatase stains very low to absent in most cells
Leukoerythroblastosis, with circulating immature cells from the bone marrow
Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)
Bone marrow findings
Ph chromosome (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)
Hypercellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells
Megakaryocytes are prominent and may be increased
Mild fibrosis in the reticulin stain
See Workup for more detail.
Goals of treatment of CML include the following:
Hematologic remission (normal CBC and physical examination [ie, no organomegaly])
Cytogenetic remission (normal chromosome returns with 0% Ph-positive cells)
Molecular remission (negative polymerase chain reaction [PCR] result for BCR/ABL mRNA
Tyrosine kinase inhibitors for CML
Imatinib mesylate (Gleevec): For chronic, accelerated, and blastic phases; standard treatment of choice
Dasatinib (Sprycel): For chronic phase
Nilotinib (Tasigna): For chronic phase
Bosutinib (Bosulif): For chronic, accelerated, and blast phases
Ponatinib (Iclusig): For chronic or blast phase T315I -positive cases, or in appropriate patients in whom no other TKI therapy is tolerated or indicated
Other medications for CML
Interferon-alfa: Former first-line agent; now combined with newer drugs for refractory cases
Hydroxyurea (Hydrea): Myelosuppressive agent for inducing hematologic remission
Busulfan: Myelosuppressive agent for inducing hematologic remission
Omacetaxine (Synribo): Protein translation inhibitor indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors
Allogeneic bone marrow transplantation (BMT) or stem cell transplantation
Only proven cure for CML
Ideally performed in the chronic phase
Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available
Overall survival for allogeneic BMT with matched unrelated donors ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients
Currently relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure of second-generation tyrosine kinase inhibitors (eg, dasatinib)
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.
CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome (see Pathophysiology).
CML progresses through three phases: chronic, accelerated, and blast. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate.[1, 2] Approximately 85% of patients are diagnosed in the chronic phase and then progress to the accelerated and blast phases after 3-5 years. The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia chromosome in bone marrow cells (see Workup).
CML accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Uncommonly, the disease occurs in younger individuals. Younger patients may present with a more aggressive form of CML, such as in accelerated phase or blast crisis. Uncommonly, CML may appear as a disease of new onset in elderly individuals.
The goals of treatment are to achieve hematologic, cytogenetic, and molecular remission. Although a variety of medications have been used in CML, including myelosuppressive agents and interferon alfa, the tyrosine kinase inhibitor imatinib mesylate is currently the agent of choice, and other drugs in this category are playing increasingly important roles. However, allogeneic bone marrow transplantation is currently the only proven cure for CML. (See Treatment.)
For more information on CML, see Chronic Myelogenous Leukemia (CML) Guidelines
CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome after the city of discovery. (See the image below.)
This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood.[3, 4, 5, 6, 7, 8, 9, 10, 2]
The presence of BCR/ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.
The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.
Historically, the median survival of patients with CML was 3-5 years from the time of diagnosis. Currently, patients with CML have a median survival of 5 or more years. The 5-year survival rate has doubled from 31% in the early 1990s to 63% for patients diagnosed from 2005 to 2011. The improvement has resulted from earlier diagnosis, improved therapy with targeted drugs and bone marrow transplantation, and better supportive care.
As treatment improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as bone marrow transplantation.
Staging of patients is based on several analyses using multiple variate analysis between the association of pretreatment host and leukemic cell characteristics and corresponding survival rates. The findings from these studies classify patients into the following groups:
Good risk (average survival of 5-6 years)
Intermediate risk (average survival of 3-4 years)
Poor risk (average survival of 2 years)
One widely used prognostic index, the Sokal score, is calculated for patients aged 5-84 years by the following equation:
Hazard ratio = exp 0.0116 (age - 43) + 0 .0345 (spleen size [cm below costal margin] - 7.5 cm) + 0.188 [(platelet count/700)2 - 0.563] + 0.0887 (% blasts in blood - 2.1)
Online calculators for the Sokal score are available.
The three categories of the Sokal score are as follows:
- Low risk: score <0.8
- Intermediate risk: score 0.8-1.2
- High risk: score >1.2
The Sokal score correlates with the likelihood of achieving complete cytogenetic response, as follows:
Low-risk patients: 91%
Intermediate-risk patients: 84%
High-risk patients: 69%
A combined prognostic model, incorporating previous models such as the Sokal score, has been devised using the number of poor-prognosis characteristics. Stages in this model are as follows:
Stage 1: 0 or 1 characteristic
Stage 2: 2 characteristics
Stage 3: 3 or more characteristics
Stage 4: diagnosis at blast phase
Poor-prognosis characteristics include the following clinical and laboratory factors:
Poor performance status
Negative Ph chromosome or BCR/ABL
Myelofibrosis (increased reticulin or collagen)
The following therapy-associated factors may indicate a poor prognosis in patients with CML:
Longer time to hematologic remission with myelosuppression therapy
Short duration of remission
High total dose of hydroxyurea or busulfan
Poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy
A German study of 139 low-risk patients with CML, according to the Sokal score, indicated that new therapeutic agents have brought improvement in survival. Median survival according to treatment used was as follows:
Busulfan: 6 years (50 patients)
Hydroxyurea: 6.5 years (55 patients)
Interferon alfa: approximately 9.5 years (34 patients)
Some patients with molecular remissions from interferon alfa may be cured, but this can only be established over time.
The tyrosine kinase inhibitor imatinib has replaced interferon as a first-line therapy, as it is associated with a higher response rate and better tolerance of adverse effects. Long-term follow-up of patients who received imatinib in the treatment of CML and achieved a complete cytogenic response 2 years after the start of treatment demonstrated that their survival was not statistically significantly different from that of the general population.
Patients who develop blast crisis, which has manifestations similar to those of acute leukemia, have a very poor prognosis. Treatment results are unsatisfactory, and most of these patients succumb to the disease. Survival is 3-6 months.
A study by Wang et al addressed the prognostic impact of specific additional chromosomal abnormalities (ACAs) in CML. The concurrent presence of two or more ACAs conferred inferior survival. In patients with a single chromosomal change at the time of ACA emergence, the following three were associated with a relatively good prognosis :
An extra copy of Philadelphia chromosome
In contrast, the following three ACAs were associated with a relatively poor prognosis:
The American Cancer Society (ACS) estimates that 8220 new cases of CML will be diagnosed in 2016, 4610 in males and 3610 in females. The ACS estimates that 1070 deaths from CML will occur in 2016, 570 in males and 500 in females. The ACS notes that over the past few decades, overall leukemia incidence rates have been slowly increasing. From 2003 to 2012, rates increased by 1.3% per year.
Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999 Apr 29. 340(17):1330-40. [Medline].
Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001 Apr 5. 344(14):1038-42. [Medline]. [Full Text].
Kantarjian H, Sawyers C, Hochhaus A, et al, for the International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002 Feb 28. 346(9):645-52. [Medline]. [Full Text].
Merx K, Muller MC, Kreil S, et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia. 2002 Sep. 16(9):1579-83. [Medline]. [Full Text].
Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002 Mar 15. 99(6):1928-37. [Medline]. [Full Text].
Kantarjian HM, Cortes JE, O'Brien S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003 Jan 1. 101(1):97-100. [Medline]. [Full Text].
Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004 Jul 16. 305(5682):399-401. [Medline].
Volpe G, Panuzzo C, Ulisciani S, Cilloni D. Imatinib resistance in CML. Cancer Lett. 2009 Feb 8. 274(1):1-9. [Medline].
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999 Jul 15. 341(3):164-72. [Medline].
Cancer Facts & Figures 2016. American Cancer Society. Available at http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed: April 14, 2016.
Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M al et. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011 Apr 6. 103(7):553-61. [Medline].
Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016 Mar 22. [Medline].
Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015 May 21. 125 (21):3230-5. [Medline].
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5. 344(14):1031-7. [Medline]. [Full Text].
Santos FP, Alvarado Y, Kantarjian H, Verma D, O'Brien S, Mattiuzzi G, et al. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer. 2011 Mar 1. 117(5):982-91. [Medline].
Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002 May 15. 99(10):3530-9. [Medline].
Tang M, Gonen M, Quintas-Cardama A, et al. Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood. 2011 Aug 11. 118(6):1622-31. [Medline].
Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011 Apr 7. 117(14):3733-6. [Medline].
Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002 Nov. 16(11):2190-6. [Medline].
Marcolino MS, Boersma E, Clementino NC, et al. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann Oncol. 2011 Sep. 22(9):2073-9. [Medline].
FDA Approval for Dasatinib. National Cancer Institute. Available at http://www.cancer.gov/cancertopics/druginfo/fda-dasatinib. Accessed: October 8, 2015.
FDA Approval for Nilotinib. National Cancer Institute. Available at http://www.cancer.gov/cancertopics/druginfo/fda-nilotinib. Accessed: October 8, 2015.
Bosulif (bosutinib) [package insert]. New York, NY: Pfizer, Inc. April 2016. Available at [Full Text].
Jabbour E, Kantarjian H, O'Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011 Oct 27. 118(17):4541-6; quiz 4759. [Medline].
Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda JS, Foroni L, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010 Nov 11. 116(19):3758-65. [Medline].
FDA. Sprycel (dasatinib): Drug Safety Communication – Risk of Pulmonary Arterial Hypertension. US Food and Drug Administration. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm275176.htm. Accessed: October 8, 2015.
Sawyers CL. Even better kinase inhibitors for chronic myeloid leukemia. N Engl J Med. 2010 Jun 17. 362(24):2314-5. [Medline].
Jabbour E, Kantarjian H, O'Brien S, Shan J, Garcia-Manero G, Wierda W, et al. Predictive factors for outcome and response in patients treated with second generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase post imatinib failure. Blood. 2010 Oct 28. [Medline].
Verma D, Kantarjian H, Strom SS, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood. 2011 Oct 20. 118(16):4353-8. [Medline].
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17. 362(24):2260-70. [Medline].
Cortes JE, Jones D, O'Brien S, Jabbour E, Ravandi F, Koller C, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010 Jan 20. 28(3):398-404. [Medline]. [Full Text].
Mulcahy N. FDA updates dasatinib label for chronic myeloid leukemia. Medscape Medical News. June 26, 2013. [Full Text].
Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014 Jan 23. 123 (4):494-500. [Medline]. [Full Text].
Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brümmendorf TH, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of phase 3 study. Blood. 2014 Feb 25. [Medline].
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17. 362(24):2251-9. [Medline].
Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep. 12(9):841-51. [Medline].
Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12. 119(15):3403-12. [Medline].
Chustecka Z. FDA Approves Ponatinib for Rare Leukemias. Medscape Medical News. December 14, 2012. [Full Text].
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29. 367(22):2075-88. [Medline].
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7. 369 (19):1783-96. [Medline].
Mulahy N. Leukemia Drug Ponatinib (Iclusig) Pulled From Market. Medscape Medical News. Available at http://www.medscape.com/viewarticle/813531. Accessed: October 8, 2015.
FDA Drug Safety Communication. FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. US Food and Drug Administration. Available at http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm. Accessed: October 8, 2015.
Nelson R. Ponatinib (Iclusig) Returns to Market, With a Few Caveats. Medscape Medical News. Available at http://www.medscape.com/viewarticle/818183?src=wnl_edit_specol&uac=72886PK. Accessed: October 8, 2015.
FDA Drug Safety Communication: FDA requires multiple new safety measures for leukemia drug Iclusig; company expected to resume marketing. US Food and Drug Administration. Available at http://www.fda.gov/Drugs/DrugSafety/ucm379554.htm. Accessed: October 8, 2015.
Synribo (omacetaxine) [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc. October, 2012. Available at [Full Text].
Simonsson B, Gedde-Dahl T, Markevarn B, et al. Combination of pegylated IFN-a2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011 Sep 22. 118(12):3228-35. [Medline].
Moreb J, Johnson T, Kubilis P, Myers L, Oblon D, Miller A, et al. Improved survival of patients with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation. Am J Hematol. 1995 Dec. 50(4):304-6. [Medline].
McGlave PB, Beatty P, Ash R, Hows JM. Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases. Blood. 1990 Apr 15. 75(8):1728-32. [Medline].
Deininger M, Schleuning M, Greinix H, Sayer HG, Fischer T, Martinez J, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006 Apr. 91(4):452-9. [Medline].
Lima L, Bernal-Mizrachi L, Saxe D, Mann KP, Tighiouart M, Arellano M, et al. Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer. 2011 Mar 15. 117(6):1245-52. [Medline].