Chronic Myelogenous Leukemia

Ritesh Rathore, M.D.

Basic Information

Definition

Chronic myelogenous leukemia (CML) is a malignant clonal stem disease. The hallmark of CML is the Philadelphia chromosome, an acquired cytogenetic abnormality arising out of the reciprocal translocation of long arms of the ABL and BCR genes on chromosomes 9 and 22, resulting in the BCR:ABL fusion oncogene. CML is characterized by abnormal myeloid proliferation and accumulation of immature granulocytes. CML manifests with a chronic phase (CP-CML) lasting months to years, which evolves into an advanced phase (AP-CML) characterized by poor response to therapy, worsening anemia, or thrombocytopenia; this phase then evolves into a terminal blast phase (BP) resulting in acute leukemia (70% myeloid and approximately 30% lymphoid subtype). The WHO criteria for accelerated and blast phases of CML are described in Table 1.

TABLE1 Comparison of Currently Used Classification Systems for CML Phases

	WHO criteria^a	European Leukaemia Net Criteria^b
Accelerated phase
Blasts in peripheral blood or bone marrow	10%-19%	15%-29% or blasts plus promyelocytes in peripheral blood or bone marrow >30% with blasts <30%
Basophils in peripheral blood	≥20%	≥20%
Platelets	<100 × 10⁹/L not attributable to treatment or platelets >1000 × 10⁹/L uncontrolled on treatment	<100 × 10⁹/L not attributable to treatment
Additional chromosomal abnormalities	Occurring on treatment	Occurring on treatment
White cell count and spleen size	Increasing and uncontrolled on treatment	..
Blast crisis
Blasts in peripheral blood or bone marrow	≥20%	≥30%
Blast proliferation	Extramedullary, except spleen	Extramedullary, except spleen
Large foci of blasts	Bone marrow or spleen	..

Synonyms

CML
Chronic granulocytic leukemia
Chronic myeloid leukemia

ICD-10CM CODES
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

Epidemiology & Demographics

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The median age for CML presentation is usually in the mid-50 year range. It accounts for 15% to 20% of adult leukemias.
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Incidence is 1 to 1.5 cases per 100,000 people annually.
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In 2017, nearly 9000 new cases and more than 1000 deaths occurred in the U.S.

Physical Findings & Clinical Presentation

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Up to 50% patients are asymptomatic, with diagnosis based on abnormal blood counts.
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In chronic phase, symptomatic patients can have fatigue, weight loss, early satiety, and left abdomen pain. Examination can reveal splenomegaly. Occasionally, a very high WBC count may lead to hyperviscosity-related symptoms.
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Patients in accelerated phase are usually symptomatic with fevers, sweats, weight loss, abdomen pain, and progressive splenomegaly.
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Patients in blast phase in addition can have bone pain; symptoms of anemia, infectious complications, and bleeding are also present.

Etiology

The etiology of CML is unclear, though radiation exposure has been linked in its development.

Diagnosis

Differential Diagnosis

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Splenic lymphoma.
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Myeloproliferative syndrome.
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Chronic neutrophilic leukemia.
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Essential thrombocythemia.

Laboratory Tests

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CBC showing left-shifted myeloid cells, with the presence of precursor polymorphonuclear cells, basophils, and eosinophils; can be accompanied by thrombocytosis and anemia.
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Bone marrow biopsy demonstrates hypercellularity with granulocytic hyperplasia, increased ratio of myeloid cells to erythroid cells, and increased megakaryocytes (Fig. E1).

FIG.E1

Chronic myelogenous leukemia, chronic phase.

Peripheral smear (A) showing marked leukocytosis due to a granulocytic proliferation of all stages with particularly increased myelocytes and absolute basophilia. Bone core biopsy (B) illustrating markedly hypercellular marrow due to granulocytic proliferation and increased small hypolobated megakaryocytes. Compare with large megakaryocytes (C) from a myeloproliferative disorder other than CML. Bone marrow aspirate (D) showing granulocytic proliferation and small, “dwarf” megakaryocyte, compared with large-sized megakaryocyte (E) and micro-megakaryocytes (F) typical of MDS. Pseudo-Gaucher cells (G) and mild fibrosis (H) as seen on reticulin stain.

From Hoffman R, et al.: Hematology: basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.
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Bone marrow cytogenetics demonstrated the 9:22 translocation (Philadelphia chromosome) in >95% of patients (Fig. 2).

FIG.2

The Philadelphia chromosome, der(22q), results from the reciprocal translocation of a portion of the ABL1 gene on chromosome 9 at band q34 to the region of the BCR gene on chromosome 22 at band q11.2. In turn, a portion of BCR is translocated to chromosome 9 to the region of ABL1. In 5% to 10% of patients with chronic myelogenous leukemia, cryptic or complex rearrangements result in a BCR-ABL1 fusion gene, even though no Philadelphia chromosome is detected cytogenetically.

From Jaffe ES, et al.: Hematopathology, Philadelphia, 2011, Saunders.
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Leukocyte alkaline phosphatase is markedly decreased (unlike other myeloproliferative disorders).
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BCR-ABL fusion transcripts can be measured using quantitative RT-PCR technology using either peripheral blood or bone marrow; serial peripheral blood monitoring of transcript level is utilized at 3-month intervals to determine molecular remission status.

Risk Stratification

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Chronic phase CML patients can be stratified into low-, intermediate-, or high-risk criteria using the Sokal or Hasford criteria; more recently, the EUTOS score has been validated as an effective tool used to stratify patients into low- or high-risk categories.
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Patients developing secondary mutations have variable response to second- or third-line therapies; the T315I mutation is typically associated with resistance and is treated with allogeneic stem cell transplantation (SCT).

Imaging Studies

Ultrasound or CT scan of abdomen can be done.

Treatment

Treatment with a potential to either cure CML or prolong long-term survival should be used according to the phase of the disease.

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Chronic phase: the therapeutic approach involves the use of either a first-generation (imatinib) or second-generation (dasatinib, nilotinib) oral tyrosine kinase inhibitor (TKI). The decision to select a particular TKI is based on patient comorbidities, age, and often formulary restrictions. The large majority of patients obtain hematologic and cytogenetic remissions; major molecular remissions are observed in 25%-60% cases. Patients who lose their initial response, develop secondary mutations, or develop intolerance to therapy can be treated with newer third-generation TKIs (bosutinib, ponatinib). Omacetaxine, a protein synthesis inhibitor, is also effective in patients who have previously received TKI therapy.
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During therapy for chronic phase CML, treatment efficacy is monitored by the use of serial RT-PCR to measure peripheral blood BCR-ABL transcripts every 3 to 6 months.
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Accelerated phase: patients are initially treated with second-generation TKIs but ultimately require allogeneic SCT.
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Blast phase: patients are initially treated with conventional induction chemotherapy as per the type of evolved acute leukemia and then subsequently undergo allogeneic SCT.
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Symptomatic hyperleukocytosis is treated with leukapheresis and hydroxyurea; allopurinol should be started to prevent urate nephropathy after the rapid lysis of the leukemia cells.

Disposition

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Median survival for patients with chronic phase CML undergoing therapy with current TKIs is estimated to last 25+ years.
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Median survivals for patients with accelerated and blast phase CML are 5 years and 7 to 11 months, respectively.
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Discontinuing oral TKI therapy in chronic phase CML patients who have achieved deep molecular remissions is associated with molecular relapses in up to half the cases; as such, indefinite therapy is preferred in all cases.

Referral

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To hematology physician.

Pearls

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Chronic-phase CML patients should be risk-stratified at diagnosis to define prognosis upfront; patients achieving complete cytogenetic remission or major molecular remission by 12 months have consistently superior long-term outcomes.
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Regular monitoring of molecular response using peripheral blood RT-PCR for BCR:ABL transcript levels is done every 3 to 6 months for disease monitoring.
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Allogeneic stem cell transplantation is a useful modality for advanced CML patients and chronic phase CML patients who develop resistance to standard TKI therapy.

Ferri – Chronic Myelogenous Leukemia