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Chronic myeloid leukemia (CML)

Myeloproliferative neoplasm characterized by an increase in myeloid lineage cells at all stages of differentiation.

Chronic Myelogenous Leukemia (CML) is a myeloproliferative disease characterized by proliferation of myeloid cells capable of differentiation. CML is caused by a reciprocal translocation t(9;22), in which a piece of chromosome 9 containing the ABL1 oncogene is translocated to chromosome 22 and fused to the BCR gene. The resulting Philadelphia chromosome harbors the BCR-ABL fusion gene which produces a tyrosine kinase implicated in the pathogenesis of CML. | Jorge Muniz, Medcomic

Myeloproliferative neoplasm characterized by an increase in myeloid lineage cells at all stages of differentiation.

  • Accounts for 15%–20% of all cases of leukemia in adults

History:

The main history of CML begins in 1960 when Peter Nowel and David Hungerford discovered an abnormally small G-group chromosome – now called the Philadelphia (Ph) chromosome. This was the first proof that the disease results in some changes to DNA. In 1973, Janet Rowley recognized that the Ph chromosome was the product of a t(9;22)(q34;q11) reciprocal translocation between chromosomes, and then later in the 1980s, Nora Heisterkamp discovered that this translocation generates the BCR–ABL fusion oncogene.

Classification

nrdp201610-f1
Schematic overview of the main types of leukaemia | Khwaja, A., Bjorkholm, M., Gale, R. E., Levine, R. L., Jordan, C. T., Ehninger, G., … Linch, D. C. (2016). Acute myeloid leukaemia. Nature Reviews Disease Primers, 2, 16010. Retrieved from https://doi.org/10.1038/nrdp.2016.10

Pathophysiology

Generally, CML-CP is a leukemia stem cell (LSC)-derived disease, in which deregulated growth of LSC-derived leukemia progenitor cells (LPCs) leads to the manifestation of disease symptoms.

Philadelphia (Ph) chromosome:

Philadelphia chromosome (derivative 22) derived from the t(9;22)(q34;q11) reciprocal translocation, is the hallmark of the disease, transforming the hematopoietic stem cell (HSC) in to a leukemic stem cell (LSC) that gives rise to the disease. The translocation results in the fusion of the proto-oncogene ABL located on the long arm of chromosome 9, with the BCR gene on chromosome 22

The resulting breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncogene is translated into the BCR-ABL oncoprotein.

The Philadelphia chromosome. ABL, Abelson murine leukemia; BCR, breakpoint cluster region. | Granatowicz, A., Piatek, C. I., Moschiano, E., El-Hemaidi, I., Armitage, J. D., & Akhtari, M. (2015). An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean journal of family medicine, 36(5), 197–202. https://doi.org/10.4082/kjfm.2015.36.5.197

BCR-ABL fusion protein:

The BCR-Abl oncoprotein is a constitutively active tyrosine kinase that provides survival signals to the malignant cells, which drive the disease in terms of cell proliferation and resistance to programmed cell death.

The downstream pathways affected include JAK/STAT, PI3K/AKT, and RAS/MEK; they involve cell growth, cell survival, inhibition of apoptosis, and activation of transcription factors.

Molecular events leading to the expression of CML disease phenotype: Classic CML is characterised by a reciprocal translocation between chromosomes 9 and 22. This results in juxtaposition of 3′ sequences from the Abl-proto-oncogene on chromosome 9, with the 5′ sequences of the truncated Bcr (breakpoint cluster region) on chromosome 22. Fusion mRNA molecules of different lengths, are produced and subsequently transcribed into chimeric protein products, with varying molecular weights, the most common being p210 BCR-ABL | Frazer, R., Irvine, A. E., & McMullin, M. F. (2007). Chronic Myeloid Leukaemia in The 21st Century. The Ulster medical journal, 76(1), 8–17.

Clinical features

Asymptomatic presentation:

40% cases with chronic phase CML are asymptomatic with the diagnosis made solely based on an abnormal blood count

Symptomatic presentation:

CML is a triphasic myeloproliferative disorder that begins from a latent phase called a chronic phase (CP). The natural history of CML is a chronic phase for three to five years followed by rapid progression to the fatal blast phase. In two-thirds of patients, the blast phase is proceeded by an accelerated phase.
  • Anaemia: : Fatigue, weight loss, anorexia,
  • Splenomegaly (50% case): Early satiety, and left upper quadrant pain or fullness
  • Other features:
    • Thrombosis
    • Bleeding (from thrombocytopenia or platelet dysfunction)

Diagnosis

Evaluation of suspected CML. CML, chronic myeloid leukemia; BCR, breakpoint cluster region; ABL, Abelson murine leukemia. | Granatowicz, A., Piatek, C. I., Moschiano, E., El-Hemaidi, I., Armitage, J. D., & Akhtari, M. (2015). An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean journal of family medicine, 36(5), 197–202. https://doi.org/10.4082/kjfm.2015.36.5.197

Complete blood count (CBC):

Unexplained leukocytosis with left shift (immature myeloid cells including myelocytes, promyelocytes or blasts), basophilia, and splenomegaly are suggestive of CML
Clinical course of untreated CML | Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. New Engl J Med. 1999;341(3):164–72 | Goldman JM, Melo JV. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New Engl J Med. 2001;344(14):1084–6.
  • Chronic phase: Blasts < 10%, may last months to years. Most patients present in the chronic phase and are typically asymptomatic.
  • Accelerated phase: Blasts 10-19%, worsening anemia, treatment failure, progressive splenomegaly, and increasing white cell count.
  • Blast phase: Blasts > 20%, accumulation of blasts in extramedullary sites.
Peripheral blood of chronic phase chronic myeloid leukemia showing leukocytosis with circulating immature myeloid cells (Wright-Giemsa stain, ×4). | Granatowicz, A., Piatek, C. I., Moschiano, E., El-Hemaidi, I., Armitage, J. D., & Akhtari, M. (2015). An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean journal of family medicine, 36(5), 197–202. https://doi.org/10.4082/kjfm.2015.36.5.197

Serology markers:

CML-specific surface markers expressed on stem and progenitor cells. CD25, CD26, and CD93 are expressed specifically on the CD34+ CD38− stem cell fraction of CML, while IL1RAP is expressed on both of the CD34+ CD38− stem cell fraction and the CD34+ CD38+ progenitor fraction. The expression of CD25 is reportedly regulated by STAT5 activation | Inoue, A., Kobayashi, C.I., Shinohara, H. et al. Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence. Int J Hematol 108, 365–370 (2018). https://doi.org/10.1007/s12185-018-2519-y

Bone marrow aspirate:

Bone marrow aspiration with cytogenetic analysis (karyotype) is required to appropriately stage as the chronic phase, accelerated phase, or blast phase and to identify chromosomal abnormalities that are not detectable with FISH for BCR-ABL
Bone marrow aspirate of chronic phase chronic myeloid leukemia showing a spectrum of immature myeloid cells including blasts and promyelocytes (Wright-Giemsa stain, ×20). | Granatowicz, A., Piatek, C. I., Moschiano, E., El-Hemaidi, I., Armitage, J. D., & Akhtari, M. (2015). An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean journal of family medicine, 36(5), 197–202. https://doi.org/10.4082/kjfm.2015.36.5.197

Molecular analysis:

Can be performed on peripheral blood
  • Fluorescence in situ hybridization (FISH): For t(9;22)(q34;q11.2)
  • Reverse transcriptase quantitative PCR (RQ-PCR): For BCR-ABL

Differential diagnosis:

  • Chronic myelomonocytic leukemia (CMML): Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) and can be distinguished from CML by the presence of dysplastic features, more prominent cytopenias, more prominent monocytosis and lack of basophilia. CMML will be Ph-negative and may have other cytogenetic abnormalities.
  • Atypical CML: Ph negative MDS/MPN
  • Chronic neutrophilic leukemia (CNL): Version of CML associated with predominant neutrophilia, but cytogenetics showing the Ph-chromosome will easily distinguish them.
  • Essential thrombocythemia (ET): These cases will be distinguished by cytogenetics and molecular studies showing Ph-positivity and BCR-ABL positivity.16

Management

TKI therapy has transformed CML from a fatal disease into a chronic disease for the majority of patients. Prior to 1983, the 8-year survival of CML was less than 15%. The 8-year survival improved from 42% to 65% from 1983 to 2000 with the use of interferon-α-based therapy and allogeneic hematopoietic stem cell transplant (HSCT) therapy. With the introduction of TKI therapy in 2001, the 8-year survival is now 87% and continues to improve with the use of second- and third-generation TKI therapy

CML therapeutic algorithm. | Frazer, R., Irvine, A. E., & McMullin, M. F. (2007). Chronic Myeloid Leukaemia in The 21st Century. The Ulster medical journal, 76(1), 8–17.

Tyrosine kinase inhibitor (TKI) therapy:

TKIs interfere with the interaction between the BCR-ABL oncoprotein and adenosine triphosphate, thereby blocking proliferation of the malignant clone.
  • First-line treatment of chronic phase CML: Imatinib
  • Second-generation TKIs (if refractory/intolerant to first-line TKI therapy): Dasatinib, nilotinib, and bosutinib
  • Ponatinib (third-generation TKI): Only TKI effective in threonine-to-isoleucine mutation at position 315 (T315I)
Tyrosine kinase inhibitors available for treatment of chronic phase chronic myeloid leukemia | ALT, alanine aminotransferase. | Granatowicz, A., Piatek, C. I., Moschiano, E., El-Hemaidi, I., Armitage, J. D., & Akhtari, M. (2015). An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean journal of family medicine, 36(5), 197–202. https://doi.org/10.4082/kjfm.2015.36.5.197

Treatment response:

Molecular techniques are used in the diagnosis and monitoring response to therapy. Response to treatment may be defined as occurring at haematologic, cytogenetic, or molecular levels
Defining response to treatment and minimal residual disease, for patients diagnosed with chronic phase CML, treated with imatinib. | Frazer, R., Irvine, A. E., & McMullin, M. F. (2007). Chronic Myeloid Leukaemia in The 21st Century. The Ulster medical journal, 76(1), 8–17.

Allogenic stem cell transplant (allo-SCT):

Only curative therapy for CML

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