> Table of Contents > Leukemia, Chronic Myelogenous
Leukemia, Chronic Myelogenous
Jan Cerny, MD, PhD
image BASICS
DESCRIPTION
  • Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm 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 three clinical phases: a chronic phase, an accelerated phase, and blast phase or crisis (transformation to acute leukemia).
EPIDEMIOLOGY
Incidence
  • Per year, 1.6 cases/100,000 persons
  • Predominant age: 50 to 60 years
  • Predominant sex: male > female (1.3:1)
Prevalence
Accounts for 15-20% of adult leukemias
ETIOLOGY AND PATHOPHYSIOLOGY
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.
Genetics
Acquired genomic changes
RISK FACTORS
Ionizing radiation exposure (uncommon)
GENERAL PREVENTION
None currently identified
image DIAGNOSIS
85-90% of patients present in the chronic phase, and the disease can be found accidentally during routine screening.
PHYSICAL EXAM
  • Splenomegaly (50-90%), hepatomegaly (up to 50%)
  • Less common: splenic friction rub, lymphadenopathy
DIFFERENTIAL DIAGNOSIS
  • 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 it lacks Philadelphia chromosome and BCR-ABL rearrangement.
DIAGNOSTIC TESTS & INTERPRETATION
  • CBC
    • Hematocrit: may be normal, slightly increased, or decreased
    • WBC count: markedly increased (50,000 to 100,000/&mgr;L), 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, fluorescence in situ hybridization (FISH), or reverse transcriptionpolymerase chain reaction (RT-PCR)
    • Additional cytogenetic abnormalities occur in the accelerated and blast phases (monosomy 7, t[3;21], trisomies 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; e.g., imatinib). Further molecular testing (mutations within BCR-ABL) is suggested in case of loss of response to therapy.
  • Others:
    • Low or absent leukocyte alkaline phosphatase in neutrophils
    • High lactate dehydrogenase (LDH)
    • Elevated uric acid
Initial Tests (lab, imaging)
  • CBC, LDH, uric acid, bone marrow biopsy and aspiration, cytogenetics on bone marrow, and FISH for BCR-ABL, RT-PCR, LFTs
  • Abdominal ultrasound or CT scan shows splenomegaly; not mandatory.
Follow-Up Tests & Special Considerations
  • Mutation analysis of tyrosine kinase domain of ABL kinase, as they may cause resistance to therapy with TKIs
  • HLA-A*02 positive is associated with CML, and a protective effect is seen with the HLA-B*35 allele (pooled odds ratio 0.64, 95% confidence interval 0.48 to 0.86).
Diagnostic Procedures/Other
Bone marrow aspiration and biopsy
Test Interpretation
Myeloid hyperplasia with elevated myeloid: erythroid ratio, normal maturation, marrow basophilia, and increased reticulin fibrosis
image TREATMENT
MEDICATION
  • TKIs (e.g., imatinib) provide durable, long-term control of 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): 1-34%, 35-90%, 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
  • Imatinib mesylate (Gleevec), an oral TKI, 400 mg/day
  • Side effects: thrombocytopenia, anemia, elevated liver enzymes, edema, GI disturbances, rash
  • International Randomized Study of Interferon versus STI571 (IRIS) established imatinib as first-line therapy (1)[A].
  • Imatinib dose can be increased to 600 and 800 mg/day if only suboptimal response is achieved with standard dose.
  • 2nd-generation TKIs have shown higher efficacy and fewer side effects and are approved for first-line therapy of chronic phase CML: nilotinib (Tasigna) and dasatinib (Sprycel) (2,3)[A].
Second Line
  • Dasatinib, 2nd-generation TKI; active against most of BRC-ABL mutants; not active in T3151 mutation
    • 100 mg/day in patients resistant or intolerant to imatinib and 70 mg BID for patients in accelerated or blastic phase
    • Side effects: pleural effusions, cytopenias
  • Nilotinib, also 2nd-generation TKI; highly selective and more potent BCR-ABL TKI; active against most BRC-ABL mutants; not active in T3151 mutation
    • 400 mg PO BID in patients resistant or intolerant to imatinib in chronic or accelerated phase
    • Side effects: cytopenias, QTc prolongation, pancreatitis
  • Bosutinib and omacetaxine are now approved for patient who failed or did not tolerate two TKIs previously. Ponatinib has now more restricted approval, but together with omacetaxine, they are the only effective agents in patients with T3151 mutation. Agents targeting leukemic stem cells are being developed for clinical use.
P.605

ISSUES FOR REFERRAL
All patients with CML should be referred to a hematologist. Patients with inadequate response to TKIs or with T315I mutation should consult with a bone marrow transplant physician.
SURGERY/OTHER PROCEDURES
Allogenic bone marrow transplant (BMT)
  • It is the only known cure; however, 71% of patients who achieve CCR with imatinib maintain that response for 7 years, and no patient progressed on the trial between years 5 and 6 of treatment.
  • 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-TKI era.
  • Significant improvement in transplant techniques leading to better outcomes, such as alternative sources of stem cells; nonmyeloablative regimens have shown improvements in transplant-related mortality.
  • Transplant option should be thoroughly discussed with young patients in chronic phase and considered an alternative to TKIs especially if the patient does not tolerate TKIs or disease is not responding.
  • Can be considered in patients who fail to achieve CHR by 3 months, have no cytogenetic response or cytogenetic relapse, or have T315I mutation
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Acute abdominal symptoms (infarcted or ruptured spleen); tumor lysis syndrome owing to initial therapy; complications of BMT
  • Hydroxyurea might be given, with the goal of reduction of the WBC count, but it has minimal impact on patient response to TKIs.
  • Induction chemotherapy (for acute leukemia) in setting of blastic phase
  • Allopurinol to prevent tumor lysis syndrome in patients with very high counts; however, probably not necessary when TKIs are used
Discharge Criteria
Abatement of acute symptoms
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Frequency depends on stage at presentation and response to first-line therapy
  • Although splenomegaly persists, avoid contact sports or trauma to abdomen.
Patient Monitoring
  • CBC with differential: weekly until blood counts stable, then every 2 to 4 weeks during CHR; 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 to 18 months while in complete cytogenic response, MMR, CMR
  • Quantitative RT-PCR every 3 months (peripheral blood)
  • ECGs (concern for QT prolongation), LFTs while on TKIs. Nilotinib, bosutinib, and ponatinib can cause pancreatitis.
PROGNOSIS
  • With treatment and good response, the survival is similar to the normal population.
  • Without treatment: CML invariably will progress to accelerated phase within 2 to 5 years and blast phase within several months of the accelerated phase.
  • Poor prognosis: patients presenting in accelerated or blastic phase or presenting with very large spleen size, platelets >700,000/&mgr;L, and patients resistant to TKIs (T3151 mutation)
REFERENCES
1. O'Brien SG, Guilhot F, Goldman JM, et al. 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 (CML-CP) treated with imatinib (IM). ASH Ann Meeting Abstracts. 2008;112:186.
2. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259.
3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270.
Additional Reading
&NA;
  • Kantarjian HM, Baccarani M, Jabbour E, et al. Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy. Clin Cancer Res. 2011;17(7):1674-1683.
  • 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(12):5143-5150.
  • Naugler C, Liwski R. Human leukocyte antigen class I alleles and the risk of chronic myelogenous leukemia: a meta-analysis. Leuk Lymphoma. 2010;51(7):1288-1292.
Codes
&NA;
ICD10
  • C92.10 Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
  • C92.11 Chronic myeloid leukemia, BCR/ABL-positive, in remission
  • C92.12 Chronic myeloid leukemia, BCR/ABL-positive, in relapse
Clinical Pearls
&NA;
  • 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.
  • TKIs 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.