- Accounts for 15%–20% of all cases of leukemia in adults
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.
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.
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.
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:
- Bleeding (from thrombocytopenia or platelet dysfunction)
Complete blood count (CBC):Unexplained leukocytosis with left shift (immature myeloid cells including myelocytes, promyelocytes or blasts), basophilia, and splenomegaly are suggestive of CML
- 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.
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
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
- 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
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
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)
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
Allogenic stem cell transplant (allo-SCT):Only curative therapy for CML