Chronic Myeloid Leukemia

Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. The chromosome contains the BCR-ABL1 fusion gene (from ABL1 on chromosome 9 and BCR on chromosome 22), which induces constitutive tyrosine kinase activation and consequently, uncontrolled granulocyte production. Patients with CML can be asymptomatic or have constitutional symptoms, sternal pain, and splenomegaly. Laboratory studies show an elevated WBC, and a peripheral blood smear shows increased numbers of immature cells. Demonstration of Philadelphia translocation using cytogenetic techniques is considered the gold standard diagnostic test. Without treatment, CML generally has a triphasic course progressing from a chronic phase to an accelerated phase and leading to a terminal blast crisis. Management includes therapy with tyrosine kinase inhibitors and palliative agents, as well as allogeneic hematopoietic cell transplantation.

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Overview

Definition

Chronic myeloid leukemia is a chronic myeloproliferative neoplasm characterized by uncontrolled and dysregulated proliferation of the granulocytic lineage (mature and maturing cells), with a maintained capacity for differentiation. Chronic myeloid leukemia is also known as chronic myelocytic leukemia or chronic myelogenous leukemia.

Epidemiology

  • 20% of all leukemia in adults
  • Incidence:
    • In the United States: 1–2 cases per 100,000 inhabitants 
    • Increases with age
  • Median age at presentation: approximately 55 years
  • Slight male predominance
  • No known familial predisposition 
  • Prevalence of CML is increasing in developed countries due to the effect of ABL1 kinase inhibitors.

Etiology

  • Not known in most cases
  • High-dose ionizing radiation is an important risk factor.

Pathophysiology

Hematopoiesis

Hematopoiesis starts with a hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Lymphoid stem cells give rise to lymphocytes.
  • Myeloid stem cells eventually differentiate into platelets, erythrocytes, granulocytes (neutrophils, basophils, eosinophils), and monocytes:
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells.
    • Granulocyte macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes (platelets)
    • EPO → differentiation to erythrocytes (RBCs)
Bone marrow hematopoiesis

Bone marrow hematopoiesis:
Proliferation and differentiation of the formed elements of blood:
In CML, there is sustained proliferation of cells in the granulocytic line (myeloblasts → neutrophils, basophils, eosinophils). Both mature and maturing cells are seen; thus, there are cells that are only partially effective.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
GM-CSF: granulocyte macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer

Image by Lecturio.

Mutation

Chronic myeloid leukemia is an acquired abnormality of the hematopoietic stem cells in the bone marrow.

  • Mutation occurs in the BCR-ABL1 fusion gene:
    • Involves BCR on chromosome 22 and ABL1 on chromosome 9
    • Typically results from a reciprocal (9;22)(q34;q11) translocation giving rise to the Philadelphia (Ph) chromosome:
      • Abnormal chromosome 22
      • Hallmark genetic aberration of CML
    • BCR-ABL1 fusion gene produces a unique product, the BCR-ABL1 fusion protein.
  • BCR-ABL1 protein:
    • Oncogenic protein that induces a persistently enhanced tyrosine kinase activity
    • Deregulated tyrosine kinase activity leads to CML through:
      • Overproliferation of myeloid cells in the bone marrow
      • Discordant maturation of cells
      • ↓ Apoptosis 
  • The clinical hallmark of CML is the uncontrolled production of mature and immature granulocytes:
    • Predominantly neutrophils
    • Some basophils and eosinophils
  • ↑ Division of cells → ↑ expansion of the bone marrow 
Schematic diagram of translocation in Philadelphia chromosome

Schematic diagram of the translocation that forms the Philadelphia chromosome, and schematic representation of the BCR and ABL genes.
ABL1 and BCR genes reside on the long arms of chromosomes 9 and 22, respectively. The fusion BCR-ABL gene is formed with the translocation of the ABL1 gene (from chromosome 9) to the long arm of chromosome 22, creating a changed chromosome 22 (the so-called Philadelphia chromosome).

Image: “Figure 1” by Ewelina Trela, Sylwester Glowacki, and Janusz Błasiak. License: CC BY 3.0

Clinical Presentation

General clinical features

  • From anemia and increased cell turnover:
    • Fever, night sweats
    • Malaise, fatigue
    • Weight loss
  • From splenomegaly and splenic infarction:
    • LUQ pain or fullness
    • Early satiety
  • From platelet dysfunction: 
    • Petechiae
    • Ecchymosis
    • Bleeding
  • From expanding bone marrow: 
    • Sternal pain/tenderness
    • Bone pain
  • From ↑ uric acid production (uric acid released as a result of cell degradation): gouty arthritis
  • From hyperviscosity-related or thrombotic events (due to severe leukocytosis and/or thrombocytosis):
    • Confusion
    • Headache
    • Blurred vision
    • Priapism

Phases of disease

The symptoms discussed above vary in severity depending on the 3 disease phases of CML (based on the immature WBCs or blast cells in the blood or bone marrow).

Chronic stable phase:

  • Blast cells: < 10%
  • Most patients present in the chronic stable phase.
  • Insidious onset with generally mild symptoms:
    • Up to 50% of patients are asymptomatic (diagnosis based on laboratory tests).
    • Fatigue, malaise
    • Weight loss, sweating
    • Abdominal fullness
  • Indolent clinical course with a duration of several years
  • Response to therapy is excellent.

Accelerated phase:

  • Untreated CML usually progresses to the accelerated phase.
  • ≥ 1 of the following features:
    • Blast cells: increase to 10%–19%.
    • Peripheral blood basophils: > 20%
    • Platelet count: < 100,000/µL, not due to therapy
    • Platelets: > 1 million/µL, unresponsive to therapy
    • Progressive splenomegaly and increasing WBC, resistant to therapy
    • New chromosome changes (evolution of leukemic cells seen as chromosomal abnormalities in addition to the Philadelphia chromosome)
  • Cells multiply aggressively and cause:
    • Fever
    • Significant weight loss
    • Severe fatigue
    • Significant bone and joint pain
    • Abdominal fullness/pain
    • Bleeding
    • Thrombotic or hyperviscosity symptoms
  • Response to therapy is less favorable.

Blast crisis (or acute phase):

  • Myeloid or lymphoid blasts proliferate in an uncontrolled manner.
  • Presence of ≥ 1 of the following:
    • > 20% of peripheral blood or bone marrow blasts
    • Large clusters of blasts on bone marrow biopsy
    • Extramedullary blast proliferation (other tissues/organs beyond the marrow)
  • Indistinguishable from acute leukemia: fever, bleeding, petechiae, ecchymosis, pallor, and progressive splenomegaly
  • Response to therapy is poor.

Diagnosis

Hematologic and biochemical findings

  • Hematologic tests:
    • CBC: elevated WBC
    • Peripheral smear:
      • Increased numbers of immature cells of the granulocytic series
      • Myelocyte bulge (myelocyte > metamyelocyte)
      • Anemia
      • Thrombocytosis
      • Basophilia, eosinophilia
  • Biochemical findings:
    • Low leukocyte alkaline phosphatase (LAP) score
    • ↑ Uric acid, ↑ LDH

Bone marrow and cytogenetic findings

  • Bone marrow biopsy:
    • Hypercellular (↑ granulocytic precursors)
    • Myeloid hyperplasia with myeloid:erythroid ratio of 15:1–20:1
    • Sea-blue histiocytes (scattered macrophages with increased green-blue cytoplasm)
    • ↑ Reticulin deposition
  • Cytogenetic studies:
    • Test for:
      • Philadelphia chromosome 
      • BCR-ABL1 fusion gene 
      • Fusion mRNA gene product 
    • Techniques:
      • Karyotyping
      • FISH
      • RT-PCR

Comparison with other myeloproliferative neoplasms

Myeloproliferative neoplasms can be compared with the following WHO classification:

Table: Classic types of myeloproliferative neoplasms
DiseaseMutationsKey points
CMLBCR-ABL1 (Philadelphia chromosome)Proliferation of mature and maturing granulocytes
Essential thrombocythemiaJAK2, CALR, or MPLExcessive clonal platelet production
Polycythemia veraJAK2Elevated RBC mass
Primary myelofibrosisJAK2, CALR, or MPLObliterative bone marrow fibrosis
JAK: Janus kinase
CALR: calreticulin

Other types:

  • Chronic neutrophilic leukemia (CNL)
  • Chronic eosinophilic leukemia (CEL), not otherwise specified
  • Myeloproliferative neoplasm, unclassifiable

Management

Treatment goals and options

  • Goals of therapy:
    • Hematologic remission: achieving normal blood counts and spleen size
    • Cytogenetic remission: no Philadelphia chromosome–positive cells
    • Molecular remission: negative BCR-ABL1 fusion gene on PCR
  • Treatment is based on the specific disease phase, and options include:
    • Tyrosine kinase inhibitors (TKIs):
      • Inhibit the constitutively active tyrosine kinase and cause apoptosis of neoplastic cells
      • Preferred initial treatment
      • Imatinib, dasatinib, nilotinib, bosutinib, ponatinib
      • Adverse effects: nausea, diarrhea, fluid retention, myelosuppression, QT prolongation
    • Allogeneic hematopoietic cell transplantation (HCT)
    • Other agents (used if refractory to initial treatment and/or patient is not a transplant candidate):
      • Hydroxyurea: to reduce WBC
      • Interferon alfa (with/without cytarabine)
      • Busulfan
      • Omacetaxine mepesuccinate (inhibitor of protein synthesis)

Treatment approach

Chronic stable phase:

  • TKIs:
    • Treatment of choice for almost all newly diagnosed patients
    • To achieve long-term control in the majority of patients, with cytogenetic and molecular responses
  • The prognosis is good.

Accelerated phase:

  • Tends to be difficult to control
  • TKIs:
    • An initial response may be seen but is generally short-lived.
    • Significant relapse rate even after successful treatment with TKIs
  • Allogeneic HCT: 
    • Potentially curative
    • Referral for transplantation (with search for a donor) is also initiated during TKI treatment for all eligible patients.
  • The prognosis is poor.

Blast crisis:

  • Aggressive disease
  • All therapies discussed thus far are viable options.
  • Manage as acute leukemia.
  • Palliative treatment to relieve symptoms
  • The prognosis is dismal.

Monitoring and supportive management

  • Monitor the following:
    • CBC to determine hematologic response
    • Chromosome banding analysis (percentage of Philadelphia chromosome–positive cell) to determine cytogenetic response
    • BCR-ABL1 by quantitative PCR to determine the molecular response
  • Follow-up of response is critical in predicting when therapies other than TKIs should be considered.
  • Supportive therapies:
    • Blood transfusions for anemia
    • Platelet transfusions for thrombocytopenia
  • Tumor lysis syndrome:
    • Medical emergency caused by metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly
    • Lysis of tumor cells leads to the release of intracellular contents into the bloodstream:
      • Electrolyte imbalances (↑ potassium, ↑ phosphate, ↓ calcium) → neurologic, cardiac, and GI complications
      • Increase in nucleic acid breakdown → hyperuricemia, which can lead to AKI
    • Management:
      • Hydration
      • Allopurinol
      • Rasburicase

Differential Diagnosis

Other chronic myeloproliferative neoplasms

  • Primary myelofibrosis: chronic myeloproliferative neoplasm characterized by fibrosis of the bone marrow and extramedullary hematopoiesis in the spleen and liver: Primary myelofibrosis is linked to mutations in JAK2, CALR, and MPL. There is no BCR-ABL1 fusion gene. Clinical findings are severe fatigue, splenomegaly, hepatomegaly, and anemia. The peripheral blood smear is leukoerythroblastic and contains precursors of WBCs and RBCs, nucleated RBCs, and teardrop cells. Diagnosis is made by bone marrow examination and molecular testing. Management includes allogeneic HCT and therapy with ruxolitinib and fedratinib.
  • Polycythemia vera: unregulated overproduction of hematopoietic stem cells, mainly RBCs, despite low levels of EPO: In polycythemia vera, there is a gain-of-function mutation in the JAK2 gene. The majority of the patients present with hyperviscosity symptoms. Management includes phlebotomy, low-dose aspirin, and myelosuppressive therapies.
  • Essential thrombocythemia: proliferation of megakaryocytes, usually due to JAK2, CALR, and MPL mutations, that results in thrombocytosis: The clinical manifestations of essential thrombocythemia are headaches, visual disturbances, and erythromelalgia. Excessive platelet counts result in both thrombosis and bleeding. Management is aimed at reducing the platelet count (with hydroxyurea) and decreasing the risk of thrombosis (by systemic anticoagulation and/or antiplatelet agents).
  • CNL: rare disorder characterized by the proliferation of mature granulocytes in the blood and marrow: Organ infiltration can occur in CNL, leading to hepatosplenomegaly. There is no Philadelphia chromosome, but an increased LAP score is noted in CNL. Chronic neutrophilic leukemia does not usually progress to AML. Management options are not well defined, but the JAK1/2 inhibitor, ruxolitinib, is an option.
  • CEL, not otherwise specified: rare clonal chronic myeloproliferative disorder characterized by excessive production of eosinophils in the bone marrow leading to proliferation in the blood and organ infiltration (hepatomegaly/splenomegaly): According to cytogenetics in CEL, CEL does not exhibit the Philadelphia chromosome or the BCR-ABL1 fusion gene. Management is supportive and involves imatinib therapy.

Other disorders that resemble CML

  • Leukemoid reaction: condition characterized by WBC > 50,000/µL from causes other than leukemia: Neutrophilia and prominent left shift, usually in response to infection, are typical. Findings include toxic granulation in the neutrophils, a high LAP score, lack of a myelocyte bulge, and most importantly, the presence of an obvious cause for neutrophilia. Cytogenetic or molecular testing is performed to rule out CML if the distinction cannot be made. Management is supportive and involves treatment of the underlying etiology. Leukapheresis is indicated in the case of hyperviscosity.
  • Chronic myelomonocytic leukemia (CMML): rare myelodysplastic/myeloproliferative neoplasm with increased production of maturing monocytic cells and, sometimes, dysplastic neutrophils. Chronic myelomonocytic leukemia is often accompanied by constitutional symptoms, splenomegaly, anemia, and/or thrombocytopenia. Bone marrow morphology shows prominent dysplasia in at least 2 of the 3 myeloid lineages. There is no Philadelphia chromosome or BCR-ABL1 gene. Management includes supportive care, hydroxyurea, a hypomethylating agent, and allogeneic HCT.

References

  1. Chen, Y., Wang, H., Kantarjian, H., Cortes, J. (2013). Trends in chronic myeloid leukemia incidence and survival in the United States from 1975 to 2009. Leuk Lymphoma 54:1411–1417. https://pubmed.ncbi.nlm.nih.gov/23121646/
  2. Cortes, J.E., Talpaz, M., O’Brien, S., et al. (2006). Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106:1306–1315. https://pubmed.ncbi.nlm.nih.gov/16463391/
  3. Konopka, J.B., Witte, O.N. (1985). Detection of c-abl tyrosine kinase activity in vitro permits direct comparison of normal and altered abl gene products. Mol Cell Biol 5:3116–3123. https://pubmed.ncbi.nlm.nih.gov/3879812/
  4. Schiffer, C., Atallah, E. (2021). Overview of the treatment of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved March 27, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-chronic-myeloid-leukemia
  5. Van Etten, R. (2021). Clinical manifestations and diagnosis of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved March 27, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-myeloid-leukemia
  6. Van Etten, R. (2021). Molecular genetics of chronic myeloid leukemia. In Larson, R. (Ed.), UpToDate. Retrieved March 27, 2021, from https://www.uptodate.com/contents/molecular-genetics-of-chronic-myeloid-leukemia
  7. Van Etten, R. (2003). c-Abl regulation: a tail of two lipids. Curr Biol 13:R608–R610. https://pubmed.ncbi.nlm.nih.gov/12906815/
  8. Vardiman, J.W., Harris, N.L., Brunning, R.D. (2002). The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292–2302. https://pubmed.ncbi.nlm.nih.gov/12239137/

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