Chronic myelogenous leukemia– Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by clonal proliferation of myeloid precursors in the bone marrow with continuing differentiation into mature granulocytes.
  • Hallmark of CML is Philadelphia chromosome [translocation t(9;22)]
  • Natural history of the disease evolves in 3 clinical phases: A chronic phase, an accelerated phase, and blast phase or crisis (transformation to acute leukemia)



  • 1.6 cases/100,000 persons per year
  • Predominant age: 50–60 years
  • Predominant sex: Male > Female (1.3:1)


Accounts for 15–20% of adult leukemias

Risk Factors

Ionizing radiation exposure (uncommon)


Acquired genomic changes

General Prevention

None currently identified


Philadelphia chromosome is a balanced translocation between BCR (on chromosome 22) and ABL (on chromosome 9) genes t(9;22)(q34;q11). This fusion gene, BCR-ABL, codes for an abnormal constitutively active tyrosine kinase that affects numerous signal transduction pathways, resulting in uncontrolled cell proliferation and reduced apoptosis.

Bone marrow examination, Myeloproliferative disease, uncontrolled cell proliferation, chromosome translocation, gouty arthritis, progressive weight loss, ionizing radiation, radiation exposure, abdominal fullness, myeloproliferative disorder,


85–90% of patients present in the chronic phase and can be found accidentally during routine screening.


  • Chronic phase: Fatigue, weight loss, night sweats, abdominal fullness owing to enlarged spleen, early satiety, dyspnea, bleeding; rare: bruising, left upper quadrant abdominal pain, sternal pain (owing to expanding bone marrow), and gouty arthritis; up to 30% of patients are asymptomatic.
  • Accelerated phase: Progressive splenomegaly and left upper quadrant abdominal pain occasionally referred to the left shoulder (owing to splenic infarction or rupture), progressive weight loss and sweats, unexplained fever or bone pain, chloromas (extramedullary tumors)
  • Blast phase: Bleeding, bruising, infections, prominent constitutional symptoms

Physical Exam

  • Splenomegaly (50–90%), hepatomegaly (up to 50%)
  • Less common: Splenic friction rub, lymphadenopathy

Diagnostic Tests & Interpretation


  • Complete blood count (CBC):
    • Hematocrit: May be normal, slightly increased, or decreased
    • White blood cell count: Markedly increased (50,000–100,000/µL) with granulocytes in all stages of development, including occasional blasts <10% in chronic phase, basophilia, eosinophilia
    • Platelets: Normal, elevated (34%), or occasionally low
    • In accelerated phase: Anemia, 10–19% blood or marrow blasts, basophils plus eosinophils >20%, thrombocytopenia
    • Blast phase: Blood or marrow blasts >20%
  • Genetics:
    • Demonstration of the Philadelphia chromosome, t(9,22), by cytogenetic techniques, FISH, or reverse-scriptase polymerase chain reaction (RT-PCR)
    • Additional cytogenetic abnormalities occur in the accelerated and blast phases [monosomy 7, t(3,21), trisomy 8 and 19, Philadelphia chromosome duplication, abnormalities of chromosome 17 such as monosomy, trisomy, and isochromosome mutations]. These may contribute to resistance to tyrosine kinase inhibitors (TKIs; eg, imatinib), and, therefore, bone marrow biopsy with cytogenetics should be performed at least once a year even in patients with disease controlled by therapy.
  • Others:
    • Low or absent leukocyte alkaline phosphatase in neutrophils
    • High lactate dehydrogenase (LDH)
    • Elevated uric acid

Initial lab tests

CBC, LDH, uric acid, bone marrow biopsy and aspirate, cytogenetics on bone marrow and FISH for BCR-ABL, RT-PCR, liver function tests

Follow-Up & Special Considerations

Mutation analysis of tyrosine kinase domain of ABL kinase, as they may cause resistance to therapy with TKIs.


Abdominal ultrasound or computed tomography scan shows splenomegaly; not mandatory

Diagnostic Procedures/Surgery

Bone marrow aspiration and biopsy

Pathological Findings

Myeloid hyperplasia with elevated myeloid: Erythroid ratio, normal maturation, marrow basophilia, and increased reticulin fibrosis

Differential Diagnosis

Support's development and hosting
  • Chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, infectious mononucleosis, leukemoid reaction, polycythemia vera, and treatment with granulocyte-stimulating factors.
  • Acute myelogenous leukemia resembles blast crisis with myeloid blasts, and acute lymphoblastic leukemia resembles blast crisis with lymphoid blasts.
  • Atypical CML is a chronic myeloproliferative disorder with a clinical hematologic picture similar to CML, but lacking Philadelphia chromosome and BCR-ABL rearrangement.



  • TKIs provide durable long-term control of the disease.
  • The response to TKIs is assessed at specific time points from the beginning of treatment, and is categorized as follows:
    • Complete hematologic response (CHR): Normalization of peripheral counts, no disease symptoms, no immature cells
    • Minor/partial/complete cytogenetic response (CCR): 35–90%, 1–34%, no Philadelphia-positive metaphases
    • Major molecular response (MMR): Decreased level of BCR-ABL transcript by PCR 3-log
    • Complete molecular response (CMR): BCR-ABL transcript is undetectable by PCR.

First Line

  • Gleevec (imatinib mesylate), an oral tyrosine kinase inhibitor, 400 mg/d p.o.
  • Side effects: Thrombocytopenia, anemia, elevated liver enzymes, edema, gastrointestinal disturbances, rash
  • Illinois Researcher Information Service trial established imatinib as 1st-line therapy (1).
  • Imatinib dose can be increased to 600 and 800 mg/d if only partial cytogenetic response to 400 mg/d is achieved at 6 months of treatment.

Second Line

  • Dasatinib (Sprycel), 2nd-generation TKI, active against most of BRC-ABL mutants, not active in T315I mutation:
    • 100 mg/d in patients resistant or intolerant to imatinib and 70 mg twice a day for patients in accelerated or blastic phase
    • Side effects: Pleural effusions, cytopenias
  • Nilotinib (Tasigna), also 2nd-generation TKI, highly selective and more potent BCR-ABL tyrosine kinase inhibitor, active against most of BRC-ABL mutants, not active in T315I mutation:
    • 400 mg p.o. b.i.d. in patients resistant or intolerant to imatinib in chronic or accelerated phase
    • Side effects: Cytopenias, QTc prolongation, pancreatitis
  • Recent studies with nilotinib and dasatinib as a 1st-line therapy for chronic phase CML have shown very promising results in terms of high efficacy and low rate of side effects in this patient group (2,3).

Additional Treatment

Issues for Referral

All patients with CML should be referred to a hematologist.

Surgery/Other Procedures

Allogenic bone marrow transplant (BMT):

  • Is the only known cure; however, 71% of patients who achieve complete cytogenetic response with imatinib maintain that response for 7 years, and no patient progressed on the trial between years 5 and 6 of treatment (1)
  • Most effective in patients <50 years of age who are in the chronic phase
  • Initial mortality is higher (related to the use of myeloablative regimens) than medical management but provided higher rates of survival in pre-imatinib era. Matched related donors used to have a better prognosis than matched unrelated donors for allogeneic donation (less graft-versus-host disease); however, transplantation regimens and post-transplant care have evolved, and these differences have been practically eliminated.
  • Significant improvement in transplant techniques leading to better outcomes, such as alternative sources of stem cells; nonmyeloablative regimes have shown improvements in transplant-related mortality.
  • Transplant option should be thoroughly discussed with young patients in chronic phase and considered an alternative to imatinib, dasatinib, or nilotinib, especially if the patient does not tolerate TKIs or disease is not responding.
  • Can be considered in patients who fail to achieve complete hematologic response by 3 months, have no cytogenetic response or cytogenetic relapse, or have T315I mutation

In-Patient Considerations

Initial Stabilization

  • Hydroxyurea to rapidly reduce the white cell count
  • Allopurinol to prevent tumor lysis syndrome in patients with very high counts; to be administered before chemotherapy is instituted; probably not necessary when imatinib is used

Admission Criteria

Acute abdominal symptoms (infarcted or ruptured spleen); tumor lysis syndrome owing to initial therapy; complications of BMT

Discharge Criteria

Abatement of acute symptoms

Ongoing Care

Follow-Up Recommendations

  • Frequency depends on stage at presentation and response to 1st-line therapy.
  • While splenomegaly persists, avoid contact sports or trauma to abdomen.

Patient Monitoring

  • CBC with differential: Weekly until blood counts stable, then every 2–4 weeks during complete hematologic response, once in CCR and stable, patient can be followed less frequently (3-month intervals)
  • Bone marrow cytogenetics (evaluation for clonal evolution) every 6 months while in CHR, every 12–18 months while in complete cytogenic response, MMR, CMR
  • Quantitative RT-PCR every 3 months (peripheral blood)
  • Liver function tests monthly on imatinib


  • Without treatment: CML invariably will progress to accelerated phase within 2–5 years and blast phase within several months of the accelerated phase.
  • Poor prognosis: Patients presenting in accelerated or acute leukemia, or presenting with very large spleen size, platelets >700,000/µL, and patients resistant to current therapies (T315I mutation)


  • Splenic infarct or rupture
  • Progression to accelerated or blast phase
  • Thrombotic events owing to elevated platelets
  • Bleeding owing to low or dysfunctional platelets
  • Sequelae of anemia


1. O’Brien, Stephen G, Guilhot, Francois, Goldman, John M, Hochhaus, Andreas, Hughes, Timothy P, Radich, Jerald P., Rudoltz, Marc, Filian, Jeiry, Gathmann, Insa, Druker, Brian J., Larson, Richard A. International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP) Treated with Imatinib (IM). ASH Annual Meeting Abstracts. 2008;112:186.

2. Cortes J, O’Brien S, Borthakur G, Jones D, Ravandi F, Koller C, Mesina O, Ferrajoli A, Shan J, Kantarjian H. Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP). ASH Annual Meeting Abstracts. 2008;112:182.

3. Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin G, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M, and for the GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia. Blood. 2009;114:4933–4938.

Additional Reading

Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103:4010–22.

Goldman JM, Marin D. Management decisions in chronic myeloid leukemia. Semin Hematol. 2003;40:97–103.

Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–50.

Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol. 1997;96:111–6.



  • 205.10 Myeloid leukemia, chronic, without mention of having achieved remission
  • 205.11 Myeloid leukemia, chronic, in remission


  • 92818009 chronic myeloid leukemia, disease (disorder)
  • 92817004 chronic myeloid leukemia in remission (disorder)

Clinical Pearls

  • CML belongs to the myeloproliferative disorders group.
  • The gold standard for diagnosis of CML is detection of the Philadelphia chromosome or its products, BCR-ABL mRNA, and fusion protein.
  • Tyrosine kinase inhibitors provide durable long-term control of the disease and have dramatically altered treatment.
  • Atypical CML is a form of clinically typical CML but without the presence of the typical BCR-ABL translocation.
  • Blast crisis is a form of acute leukemia that is a possible complication of CML.

About the author

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.