Chronic myelogenous leukemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

Chronic myelogenous leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which proliferation of precursor and mature granulocytes (neutrophils, eosinophils, and basophils) occurs. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Chronic myelogenous leukemia is caused by a mutation in BCR-ABL gene. The most potent risk factor in the development of chronic myelogenous leukemia is ionizing radiation.Chronic myelogenous leukemia may be classified into five phases: chronic phase, accelerated phase, blast crisis, relapsed or recurrent CML and refractory disease. Historically, it has been treated with chemotherapy, interferon, bone marrow transplantation, and targeted therapies.

In the 1840s, the first cases of chronic myelogenous leukemia (splenomegaly with high leukocyte count) was reported in France, Germany, and Scotland. In 1960, the association of Philadelphia chromosome with the pathogenesis of  chronic myelogenous leukemia was first discovered. In 1973, (9;22) translocation was first discovered. Definition of the breakpoint cluster region (BCR) on chromosome 22 was first reported in 1984 and the demonstration of the BCR-ABL transcript in CML was first discovered in 1985. CML was previously classified into five subtypes. This has been replaced with a newer model, where it was classified into three phases. In 2022, the World Health Organisation eliminated one of these phases, leaving two remaining categories. From 1980 on wards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. In 1998, the era of tyrosine kinase inhibitors (TKI) began. TKIs have drastically changed the therapeutic landscape of CML, converting it from a fatal leukemia to a chronic, highly manageable disease.

Chronic myelogenous leukemia (CML) may into two phases: CML-chronic phase (CML-CP), CML-blastic phase (CML-BP). A third phase, CML-accelerated phase (CML-AP), is also widely recognised, however removed by the World Health Organisation (WHO) in 2022. Some studies still indicate the importance of this phase due to its distinct prognosis and treatment regiment from CML-CP and CML-BP.

Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-, results in a BCR-ABL fusion gene and production of a BCR-ABL fusion protein. The gene product of the BCR-ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.

Chronic myelogenous leukemia is caused by: First, an abnormal chromosome develops: In people with chronic myelogenous leukemia, the Philadelphia chromosome, named for the city where it was discovered, is present in the blood cells of >95 percent of people. Second, the abnormal chromosome creates a new gene: The Philadelphia chromosome creates a new gene called BCR-ABL. it contains instructions that tell the abnormal blood cell to produce too much of a protein called tyrosine kinase that promotes cancer by allowing certain blood cells to grow out of control. Third, the new gene allows too many diseased blood cells: When the bone marrow functions normally, it produces immature cells in a controlled way. These cells then specialize into the various types of blood cells that circulate in the body. In chronic myelogenous leukemia, this process doesn’t work correctly and the tyrosine kinase caused by the BCR/ABL gene causes too many white blood cells. These diseased white blood cells build up in huge numbers, crowding out healthy blood cells and damaging the bone marrow.

Chronic myelogenous leukemia must be differentiated from:leukemoid reaction, chronic neutrophilic leukemia, and acute myeloid leukemia. Definitive distinction is established by detection of the BCR::ABL1 fusion gene.

The incidence of chronic myeloid leukemia was estimated to be 1–2 cases per 100,000 individuals worldwide. The peak age for the CML is 50 to 55 and some series report a median age of up to 67 years. Incidence in CML increases by age, at least up to 75–80 years and in children, is a very rare disease. Males are more commonly affected with CML than females. The male-to-female ratio varying between 1.2 and 1.7 in different studies. The gender difference in incidence is less prominent in younger people.

The most potent risk factor in the development of chronic myelogenous leukemia is ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.

According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.

If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost. The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. Some complications of chronic myelogenous leukemia include fatigue, excess bleeding, enlarged spleen, and infection. Prognosis is generally poor, and the 5-year survival rate of patients with chronic myelogenous leukemia is approximately 59.9%. Targeted therapy with small molecule tyrosine kinase inhibitors (TKIs) dramatically alter the natural history of the disease, improving 10-year overall survival (OS) from 20 to 80–90%.

Chronic myelogenous leukemia may be classified according to the clinical characteristics and laboratory findings into five phases: Chronic phase, accelerated phase, blast crisis, relapsed or recurrent CML, and refractory disease. The earliest phase is the chronic phase and generally has the best response to treatment. The accelerated phase is a transitional phase and blastic phase is a aggressive phase that becomes life-threatening. Relapsed CML means that the number of blast cells in the blood and bone marrow increase after remission and finally, refractory disease means the leukemia did not respond to treatment.

Up to 50% of patients with CML are asymptomatic and clinical features, when present, are generally nonspecific. Common symptoms of CML include: Fatigue, Weight loss, Fever, malaise, easy satiety, left upper quadrant fullness, and Pain. Less common symptoms of CML include: Bleeding, thrombosis, gouty arthritis, symptoms of hyperviscosity including priapism, retinal hemorrhages, and upper gastrointestinal ulceration and bleeding, Dyspnea, drowsiness, loss of coordination, confusion due to sludging in the pulmonary or cerebral vessels, headaches, Bone pain, arthralgias, and Splenic infarction

Patients with chronic myelogenous leukemia are usually well-appearing. Physical examination of patients with chronic myelogenous leukemia is usually remarkable for following: Skin bruising, fever, splenomegaly, and lymphadenopathy.

Laboratory findings consistent with the diagnosis of chronic myelogenous leukemia in CBC include: thrombocytosis and/or marked leukocytosis (median of 100,000/µL) with a left shift, blasts usually number <2%, absolute basophilia is nearly universal, absolute eosinophilia, monocytosis and normal or elevated platelet count; thrombocytopenia suggests an alternative diagnosis or the presence of advanced stage. Elevated uric acid levels and elevated histamine levels due to basophilia are other laboratory findings.

Chest x-ray may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on chest x-ray suggestive of chronic myelogenous leukemia include enlarged mediastinal lymph nodes, enlarged thymus gland, and pneumonia.

Abdominal and chest CT scan may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on CT scan suggestive of chronic myelogenous leukemia include enlarged lymph nodes.

Brain MRI may be helpful in the detection of brain metastasis in patients with chronic myelogenous leukemia.

Abdominal ultrasound may be helpful in the diagnosis of chronic myelogenous leukemia. Findings on abdominal ultrasound suggestive of chronic myelogenous leukemia include enlarged lymph nodes and splenomegaly.

Other diagnostic studies for chronic myelogenous leukemia include bone marrow aspiration and biopsy, lumbar puncture, and lymph node biopsy. Genomic PCR, Southern blot assay, Reverse transcriptase PCR, Northern blot analysis, Western blot analysis or immunoprecipitation can be helpful in the diagnosis of chronic myelogenous leukemia; the gold standard diagnostic test in chronic myelogenous leukemia is cytogenetic analysis.

Medical therapies for chronic myelogenous leukemia (CML) include chemotherapy, stem cell transplant , and/or biological therapy. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies have been developed (the first of which was imatinib mesylate) which specifically inhibit the activity of the BCR-ABL protein. These tyrosine kinase inhibitors can induce complete remissions in chronic myelogenous leukemia, confirming the central importance of BCR-ABL as the cause of chronic myelogenous leukemia.

Surgery is not the first-line treatment option for patients with chronic myelogenous leukemia. Splenectomy is usually reserved for patients with enlarged spleen and it has no role in curing CML.

There are no primary preventive measures available for chronic myelogenous leukemia.

There are no secondary preventive measures available for chronic myelogenous leukemia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

In the 1840s, the first cases of chronic myelogenous leukemia (splenomegaly with high leukocyte count) was reported in France, Germany, and Scotland. In 1960, the association of Philadelphia chromosome with the pathogenesis of chronic myelogenous leukemia was first discovered. In 1973, (9;22) translocation was first discovered. Definition of the breakpoint cluster region (BCR) on chromosome 22 was first reported in 1984 and the demonstration of the BCR-ABL transcript in CML was first discovered in 1985. CML was previously classified into five subtypes. This has been replaced with a newer model, where it was classified into three phases. In 2022, the World Health Organisation eliminated one of these phases, leaving two remaining categories. From 1980 on wards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. In 1998, the era of tyrosine kinase inhibitors (TKI) began. TKIs have drastically changed the therapeutic landscape of CML, converting it from a fatal leukemia to a chronic, highly manageable disease.

Important dates in chronic myelogenous leukemia:

• The early history of leukemia reaches back 200 years.^[1]
• In 1811, Peter Cullen defined a case of splenitis acutus with un explainable milky blood.
• Alfred Velpeau, mentioned the leukemia associated symptoms, and observed pus in the blood vessels (1825).
• Alfred Donné, demonstrated a maturation arrest of the white blood cells (1844).
• John Bennett named the disease leucocythemia, based on the microscopic collection of purulent leucocytes (1845).

• In 1845, Edinburgh pathologist, John Hughes Bennett, presented a “Case of Hypertrophy of the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal.^[2]
• Few weeks later, Rudolf Virchow, in Berlin published a similar case.
• In 1872, Ernst Neumann stated that leukemia cells originated in the bone marrow.
• The next decades described the pathophysiologic differentiation into myeloid versus lymphoid and acute versus chronic leukemias.

• In 1973, (9;22) translocation was discovery by Philadelphia cytogeneticists Peter Nowel and David Hungerford of an abnormally small G-group chromosome that we know as the Philadelphia chromosome (Ph).^[3]
• In 1986 Janet Rowley established that Ph was the product of a reciprocal translocation between chromosomes 9 and 22 which were termed as BCR and ABL.
• This then lead to discovery of unregulated tyrosine kinase activity is critical to BCR-ABL’s ability to transform cells.

• CML was previously classified into five subtypes: chronic granulocytic leukaemia (CGL), juvenile CML, chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), and atypical CML (aCML).^[4][5]
• CML was then classified into three phases: CML-chronic phase (CML-CP), CML-accelerated phase (CML-AP), and CML-blast phase (CML-BP).^[5]
• In 2022, the World Health Organisation (WHO) classification eliminated CML-AP, leaving only two phases: CML-CP and CML-BP.^[6]
• However, CML-AP is still being discussed as studies indicate it being a distinct entity with a different prognosis and treatment approached compared to CML-CP and CML-BP.^[7][8]

Treatment of chronic myeloid leukemia evolved over an era as described below.^[9]

• In 1865, Heinrich Lissauer, described the use of arsenic in two patients with leukemia.
• In the 1920s, splenic irradiation was performed which resulted in symptomatic relief.
• In 1959, effective control of blood counts became possible with busulfan.
• Ten years later, hydroxyurea was discovered.
• In mid 1970’s, a breakthrough was achieved when the Seattle group described the disappearance of the Ph chromosome in CML patients who underwent allotransplant.
• Interferon-α was discovered to stimulate cytogenetic responses and resultant long-term survival, however, only in a few patients.
• In 1992, Alexander Levitzki, proposed the use of ABL inhibitor.
• At about the same time, scientists at Ciba-Geigy synthesized, a strong inhibitor of ABL that was named GCP57148B and is now known as imatinib.
• For that 20% to 30% who fail imatinib, second-line inhibitors are an effective salvage therapy.
• However, once the disease has progressed beyond the chronic phase, allotransplant is still the recommended.
• Unfortunately, leukemia often persists in the best responders and the therapies directed at the BCR-ABL tyrosine kinase are unable to cure since they can not destroy CML stem cells.

In 2001, the US Food and Drug Administration (FDA) approved the first BCR::ABL1 TKI, imatinib.^[10]

• The FDA has approved 5 additional BCR::ABL1 TKIs since 2001.^[11]
• Due to the BCR::ABL1 TKIs, the 10-year overall survival rate has increased from less than 20% to around 85%. ^[12]
• Although survival benefits are broadly similar among available agents, newer TKIs may enable faster achievement of deep molecular responses.
• Imatinib is the only first-generation TKI.^[13]
• Second-generation TKIs include dasatinib, bosutinib, and nilotinib.^[14]
• Third-generation TKIs include ponatinib and asciminib.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

Chronic myelogenous leukemia (CML) may into two phases: CML-chronic phase (CML-CP), CML-blastic phase (CML-BP). A third phase, CML-accelerated phase (CML-AP), is also widely recognised, however removed by the World Health Organisation (WHO) in 2022. Some studies still indicate the importance of this phase due to its distinct prognosis and treatment regiment from CML-CP and CML-BP.

Chronic myelogenous leukemia is divided into two phases:^[1]

CML-Chronic Phase:^[2]

• Indolent phase.
• Less than 10% blasts in blood and bone marrow.
• Less than 20% basophils.
• Platelet counts of 100 to 1000 x 10⁹/L.
• Absence of extramedullary evidence of leukemia.
• 90% of patients have CML-CP at diagnosis.
• Common findings include: anemia, splenomegaly, fatigue, and malaise.

CML-Blast Phase:^[3]

• Most advanced form of CML.
• 20% or more blasts, according to WHO.
• Common findings include: nose and gum bleeding, bruising, fever, and infections.

CML-Accelerated Phase:

• Removed by WHO in 2022, however still discussed due to its distinct prognosis and treatment from CML-CP and CMP-BP.^[4][5]
• Elevated blasts that do not meet the criteria of 20% or more blasts for CML-BP.^[5]
• Platelet count less than 100 x 10⁹/L.^[5]
• Common findings include: splenomegaly and worsening anemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

Chronic myeloid leukemia (CML), a myeloproliferative disorder, which is characterized by the uncontrolled expansion of immature bone marrow cells of myeloid origin.The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal translation (9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q- ultimately forms a BCR/ABL fusion gene and production of a BCR/ABL fusion protein. The gene product of the BCR/ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.

• The circulating blood cells are produced in bone marrow after a series of events termed as hematopoiesis.^[1]
• The bone marrow has an tremendous regenerative ability; it is estimated that 10 trillion red blood cells and 80 to 90 trillion leukocytes are formed per hour at the basal rate.
• In addition to that, while cell numbers are maintained within narrow limits in normal subjects, they can be promptly increased when required.
• Bone marrow primarily has small percentage of pleuripotent stem cells which give rise to various progenitor cells.
• Hematopoeisis occurs in the vertebrae, pelvic bones, metaphysis of long bones such as femur, humerus in basal state.
• However, during certain stressful conditions that require rapid and massive hematopoiesis such as thalassemia it then returns to its former site, liver, spleen and sometimes lymph nodes.
• These hematopoietic stem cells (HSCs are multipotent and have the ability to differentiate into the cells of all 10 blood lineages:
  • Erythrocytes
  • Platelets
  • Neutrophils
  • Eosinophils
  • Basophils
  • Monocytes
  • T and B lymphocytes
  • Natural killer cells
  • Dendritic cells
• This differentiation is mediated through multiple growth factors and cytokines. ^{[2] [3]}
• The hematopoietic stem cells (HSCs) and progenitor cells are supported by a stromal cell network that provides cell-cell contact support.
• The stromal network provides two major functions:
• An adhesive framework onto which the developing cells are bound, these cells produce:
  • A variety of adhesion molecules.
  • Hematopoietic Growth factors or cytokines that are thought to support the survival, proliferation, and differentiation of HSCs and progenitors. ^[4]
• Primitive mesenchymal stromal cells (MSCs) are thought to have the capacity to differentiate into following:
  • Osteolineage cells
  • Chondrocytes
  • Adipocytes
  • Perivascular cells
• Overall Differentiation of myeloid progenitors is mediated through:^[5]
  • The production of essential hematopoietic growth factors.
  • Several signaling pathways have come up as integral control devices of HSC fate, such as:^[6]
    • Notch
    • Wingless-type (Wnt)
    • Sonic hedgehog (Shh)
    • Smad pathways
• These signaling circuits provide an important structure for our understanding of HSC regulation, alongwith providing information of how the bone marrow micro environment couples and integrates extrinsic with intrinsic factors responsible for HSC differentiation and development of chronic myeloid leukemia.^[7]

• Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the presence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML.^[8]
• In Philadelphia chromosome translocation, parts of two chromosomes (the 9^th and 22^nd by conventional karyotypic numbering) switch places.
• As a result, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 is fused with the ABL (“abelson murine leukemia“) gene on chromosome 9.
• This abnormal “fusion” gene generates a protein of p210 .
• Because ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR/ABL fusion gene product is also a tyrosine kinase.
• The fused BCR/ABL protein interacts with the interleukin 3 beta c receptor subunit.
• The BCR/ABL transcript is continuously active and does not require activation by other cellular messaging proteins that promotes growth and replication through downstream pathways such as:
  • RAS
  • RAF
  • JUN kinase
  • MYC
  • STAT
• In turn BCR/ABL triggers a cascade of proteins which control the cell cycle, speeding up cell division.
• Moreover the BCR/ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic mutations.
• The action of the BCR/ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.^{[9][10][11][12][8][9]}

• Recent studies have demonstarated that BCR/ABL also stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and this in turn increases BCR/ABL self-mutagenesis.
• Tyrosine kinase inhibitor resistance can also be related to higher ROS production.
• Therefore, ROS-induced self-mutagenesis of BCR/ABL is of prime significance for CML progression.
• These can be dependent on DNA repair, which is modulated by BCR/ABL and can be different in CML stem and progenitor cells.^[13]

• Implication of altered bone marrow signalling on stem cell persistence in the bone marrow niche.
• Recent advancements have been trying to establish the relationship between bone marrow pathway and Wnt pathways and their role to alter the Cdx-Hox axi.^[14]

• CML cells present in contact with stroma or fibronectin continue to proliferate, suggesting that failure to adhere through integrin receptors may also underlie the abnormal proliferation of CML progenitors.^[15]
• Although, CML progenitors express the same integrin receptors as normal progenitors, they fail to adhere to stroma and fibronectin.
• This indicates that structural or functional abnormalities of these receptors can be integral part of pathogenesis.

• Chronic myeloid leukemia (CML) in blast crisis is the transition of CML in chronic or accelerated phase to an acute leukemia.
• It is characterized by:
  • ≥ 30% blasts in the bone marrow or peripheral blood.
  • The development of extramedullary disease outside of the spleen.
• In light of recent changes in the World Health Organization, definition of acute leukemia, the percentage of blasts required for CML in blastic phase may someday be reduced to 20%.^[16]
• Consistent with the early stem cell nature of CML, blastic transformation may be:
  • Myeloid
  • Lymphoid
  • Undifferentiated/mixed
• Myeloid blast crisis being about two times more common than lymphoid.

• It is suggested that blast crisis is due to one of following reasons:^[17]
  • BCR/ABL is considered to be responsible for progressive genomic instability or epigenetic changes, which occur at the CML stem cell level and/or in later CML progenitor cells.
  • The degree of genomic instability is directly related to the level of BCR/ABL kinase activity.
  • The third is that CML stem cells are the least vulnerable to ABL-targeted therapy and may serve as reservoirs for CML progression.

• All these events concomitantly result in the acquired loss of hematopoietic cell differentiation, resulting in a highly progressive generation of immature blasts in peripheral blood and in bone marrow.
• Various studies have BCR/ABL is implicated in the generation and maintenance of secondary DNA alterations.

• Following genetic changes have been observed which play crucial role in progression of disease phase.
  • Duplication of the Ph chromosome, trisomy 8, and isochromosome 17.^[18]
  • Alterations in p53 have been found in only a minority of cases.^[19]
  • Loss of p16INK4A/ARF has been reported in up to half of patients with CML in lymphoid blast crisis but is rare in the myeloid form.^[20]
  • Thus, it is hypothesized that clonal evolution plays integral role in blastic progression and is likely facilitated by the dysregulation of normal apoptotic pathways by BCR/ABL.

• Recent studies have implicated activation of the following pathways ^[21]
  • LYN
  • AKT
  • STAT5

• CML-CP is driven by the constitutively active BCR::ABL1 tyrosine kinase, resulting from the t(9;22)(q34;q11) translocation (Philadelphia chromosome).^[22]
• The abnormal BCR::ABL1 protein leads to continuous activation of tyrosine kinase signalling pathways, decreased apoptosis, inadequate cellular differentiation, and accumulation of granulocytic lineage cells. ^[23]
• In CML-CP, myeloproliferation predominates, and many patients are asymptomatic or present with mild symptoms related to anemia or splenomegaly.^[24]

• Accelerated-phase chronic myeloid leukemia (CML-AP) represents disease progression from the indolent chronic phase toward biologic instability and increased leukemic burden. ^[25]
• CML-AP is characterised by rising blast counts, increasing basophilia, worsening cytopenias, and the development of additional cytogenetic abnormalities.^[26]
• CML-AP is associated with decreased responsiveness to tyrosine kinase inhibitor (TKI) therapy and increased progression to blastic-phase CML (CML-BP).^[26]

• CML-BP is characterised by marked expansion of immature blasts in the peripheral blood or bone marrow and clinical deterioration. ^[26]
• Cytogenomic features of CML-CP are associated with disease progression, decreased responsiveness to TKI therapy, and progression to CML-BP. ^[27]

On gross pathology, no distinctive findings are seen in chronic myeloid leukemia.

Blast cells are seen on peripheral blood smear of patients of chronic myeloid leukemia which are present during blast crisis.

• 
  Blast crisis of chronic myelogenous leukemia (CML). Peripheral blood smear revealing the histopathologic features indicative of a blast crisis in the case of chronic myelogenous leukemia.^[28]

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Chronic myelogenous leukemia is caused by an abnormal chromosome develops, the abnormal chromosome creates a new gene which amplifies the production rate of cells derived from hematopoeitic stem cells. First, an abnormal chromosome develops. In people with chronic myelogenous leukemia, the Philadelphia chromosome, named for the city where it was discovered, is present in the blood cells of >95 percent of people. Second, the abnormal chromosome creates a new gene, the Philadelphia chromosome creates a new gene called BCR-ABL. It contains instructions that tell the abnormal blood cell to produce too much of a protein called tyrosine kinase that promotes cancer by allowing certain blood cells to grow out of control.

Chronic myelogenous leukemia is caused by:^[1]

• First, an abnormal chromosome develops.
  • In people with chronic myelogenous leukemia, the Philadelphia chromosome, is present in the blood cells of > 95% of people.^[2]

• Second, the abnormal chromosome creates a new gene.
  • The Philadelphia chromosome creates a new gene called BCR/ABL. It contains instructions that tell the abnormal blood cell to produce too much of a protein called tyrosine kinase that promotes cancer by allowing certain blood cells to grow out of control.^[3]

• Third, the new gene allows too many immature blood cells.
  • In chronic myelogenous leukemia, this process doesn’t work correctly and the tyrosine kinase caused by the BCR/ABL gene causes too many white blood cells. These diseased white blood cells build up in huge numbers, crowding out healthy blood cells and damaging the bone marrow.^[4]

• Fourth, In a very small number of CML patients, the leukemia cells have the BCR/ABL oncogene but not the Philadelphia chromosome.
• In an even smaller number of people who seem to have CML, neither the Philadelphia chromosome nor the BCR-ABL oncogene can be found. They might have other, unknown oncogenes causing their disease.^[5]

• Other causes include, sometimes people inherit DNA mutations from a parent that greatly increase their risk of getting certain types of cancer. But mutations passed on by parents do not cause CML.^[6][7]
• DNA changes related to CML occur during the person’s lifetime, rather than having been inherited before birth.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [1]

Chronic myelogenous leukemia must be differentiated from leukemoid reaction, chronic neutrophilic leukemia, and acute myeloid leukemia. Definitive distinction is established by detection of the BCR::ABL1 fusion gene.

Chronic myelogenous leukemia must be differentiated from:^{[1][2][3][4][5][6][7][8][9][10][11][1]}

• Leukemoid reaction
• Primary myelofibrosis
• Basophils and eosinophils are almost always increased in chronic myelogenous leukemia

• Chronic neutrophilic leukemia
• Acute myeloid leukemia
• Thrombocytosis
• Chronic lymphoid leukemia
• Juvenile myelomonocytic leukemia
• Chronic myelomonocytic leukemia
• Atypical CML
• Chronic eosinophilic leukemia
• Polycythemia vera
• Essential thrombocytosis

• Definitive distinction is established by detection of the BCR::ABL1 fusion gene.
• The following table differentiates chronic myelogenous leukemia from other leukemias that may present with similar clinical features such as fever, fatigue, weight loss, recurrent infections and elevated leukocyte counts. The following are the differentials:

ABBREVIATIONS

N/A: Not available, NL: Normal, FISH: Fluorescence in situ hybridization, PCR: Polymerase chain reaction, LDH: Lactate dehydrogenase, PUD: Peptic ulcer disease, EPO: Erythropoietin, LFTs: Liver function tests, RFTs: Renal function tests, LAP: Leukocyte alkaline phosphatase, LAD: Leukocyte alkaline dehydrgenase, WBCs: White blood cells.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] James Nasr[3]

The incidence of chronic myeloid leukemia (CML) is approximately 1–2 cases per 100,000 individuals worldwide and accounts for 15% of adult leukemias. The peak age for the CML is 50 and the incidence in CML increases by age. Males are more commonly affected with CML than females.

• The incidence of chronic myeloid leukemia (CML) is approximately 1–2 cases per 100,000 individuals worldwide and accounts for 15,000 per 100,000 cases of adult leukemias.^[1]
• In 2024, there were approximately 9300 cases in the US. ^[2]

• The prevalence of chronic myeloid leukemia (CML) is not well known but has been estimated to be 10-12 cases per 100,000 individuals.^[3]
• The prevalence rate has increased due to the dramatic improvement in survival of patients.^[4]
• The number of people with CML in the US has increased from 30000 in 2000 to approximately 70000 in 2021. ^[2]
• Worldwide prevalence is approximately 4 million to 5 million. It is expected to reach 10 million in 2040-2050.^[5]

• The peak age for the CML is 50 and some series report a median age of 60-65 years.
• The incidence in CML increases by age, at least up to 75–80 years and in children it is quiet rare.^[3][6]

• Males are more commonly affected with CML than females.
• The male-to-female ratio varying between 1.2 and 1.7 in different studies.^[1]
• The gender difference in incidence is less prominent in younger people.^[7][8]

• Since 2000, with the introduction of the BCR::ABL1 TKIs, the mortality has decreased from 10-20% to approximately 1-2% per year.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

Common risk factors in the development of chronic myelogenous leukemia include ionizing radiation, formaldehyde, benzene, older age and male gender.

Common risk factors in the development of chronic myelogenous leukemia include: ^[1][2][3]

• Ionizing radiation
• Older age
• Male gender

Less common risk factors in the development of chronic myelogenous leukemia include:^[4][5]

• Radiotherapy
• Chemotherapy
• Benzene
• Formaldehyde
• Obesity
• Smoking
• Pesticides

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According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.

According to the American Cancer Society, screening for chronic myelogenous leukemia is not recommended.^[1]

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If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost. The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. some complications of chronic myelogenous leukemia include fatigue, excess bleeding, enlarged spleen, and infection. Prognosis is generally poor, and the 5-year survival rate of patients with chronic myelogenous leukemia is approximately 59.9%. Targeted therapy with small molecule tyrosine kinase inhibitors (TKIs) dramatically alter the natural history of the disease, improving 10-year overall survival from 20 to 80–90%.

• If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where the disease is relatively asymptomatic and histollogically the differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost completely which concomitantly results in complications and appearance of various symptoms.
• The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. Without treatment, the patient will develop symptoms of anemia, excess bleeding, enlarged spleen, and infection which may eventually lead to death.^{[1][2][3][4][5]}

• Chronic myelogenous leukemia may lead to the following complications:^{[1][6][7][8][9]}
• Fatigue
• Night Sweats
• Bone pain

• Infections
  • Pneumonia
  • Urinary tract infections
  • Gingivitis
  • Anal abscess
  • Herpes labialis
  • Pharyngitis
• Blood related complication:

• Anemia
• Thrombocytopenia
• Leukopenia
• Neutropenia

• Recurrent bleeding due to thrombocytopenia

• Epistaxis
• Bleeding gums
• Menorrhagia
• Metrorrhagia
• Petechiae

• Enlarged spleen
• Weight loss
• Myeloid sarcoma
• Skin changes

• Leukemia cutis

• Leukemic cells enter the skin. The sores or patches can be any size and are usually pink or tan in color.

• Leukocytoclastic vasculitis

• Sores usually appear on the extremities

• Sweet’s syndrome (acute febrile neutrophilic dermatosis)

• Fever
• Painful sores that may appear anywhere on the body

• Prognosis is generally good.
• Between 2004 and 2010, the 5-year relative survival of patients with CML was 59.9%.
• When associated with old age, the 5-year survival rate of patients with chronic myelogenous leukemia was 80.2% and 37.1% for patients <65 and ≥ 65 years of age, respectively.^[4]

• The prognosis and treatment options depend on the following:^[1]
  • The patient’s age

• • Elderly people have a less favorable prognosis

• The phase of CML

• Accelerated or blast phase at the time of diagnosis is a less favorable prognostic factor

• The amount of blasts in the blood or bone marrow

• A high number of blasts in the blood or bone marrow at diagnosis is a less favorable prognostic factor

• The size of the spleen at diagnosis

• Splenomegaly at diagnosis is a less favorable prognostic factor

• Platelet count

• Thrombocytopenia or thrombocytosis at diagnosis is a less favorable prognostic factor

• Eosinophils and basophils

• A higher number of eosinophils and basophils in the blood samples indicates a less favorable prognosis

• The Philadelphia chromosome

• Patients with Philadelphia chromosome (Ph+) at diagnosis have a more favorable prognosis than those who do not have the Philadelphia chromosome (Ph-)

• Anemia

• Presence of anemia at diagnosis is a less favorable prognostic factor

• Bone marrow involvement

• A large number of leukemia cells in the bone marrow at the time of diagnosis is a less favorable prognostic factor

• Performance status

• People with a low performance status at the time of diagnosis have a less favorable prognosis

• Serum lactate dehydrogenase blood level

• High serum lactate dehydrogenase (LDH) in the blood is a less favorable prognostic factor

• Response to treatment

• The treatment is effective if a person has a major cytogenetic response after treatment, which means that less than 30% of a person’s blood cells have the Philadelphia chromosome. A major cytogenetic response occurs in about 50–70% of people considered to have good-risk disease (favorable prognostic factors) and in 20% of people considered to have poor-risk disease (unfavorable prognostic factors).

• The patient’s general health
• Regarding phases, survival is clearly dependent on the phase of disease with an adverse outcome for those who are in an accelerated or blast phase of CML.
• In CML-BP, the survival time is short, only a few patients survive more than 6 months^[10]
• Apart from the phase of disease, a number of individual clinical and pathologic variables have been identified as prognostic factors.^[11]
• Independent prognostic

variables include:

• Splenomegaly
• Basophilia^[12]
• Therefore, a number of attempts have been made to establish scoring systems that predict the risk regarding progression and/or survival in patients with CML.

• These scoring systems include:
  • The “Sokal’s Index”^[13]
  • The “Hasford Score” ^[14]
  • The “Houston Score” ^[15]

• It must be emphasized that stem cell transplant is still the only available curative approach for patients with CML, but is also associated with a considerable risk of therapy-related mortality.
• To estimate the probability of a successful allogeneic stem cell transplant in individual patients with CML, another scoring-system.
• The “Gratwohl Score”.^[16]
• This score includes a number of variables known to be reflective of a higher risk to die from stem cell transplant and related complications.
• Most important ‘risk-indicators’ in this regard appear to be:
  • Age
  • Type
  • Sex of donor
  • Time from disease onset

Rest is described in the following tables:

• An important aspect is that most of the above mentioned scoring systems have been developed and used for CML patients treated with IFNα, i.e. before imatinib has become available.
• Thus, it remains open whether all these risk scores can be translated (one-to-one) and used for patients receiving imatinib in the same way as in the ‘pre imatinib era’.^[17]

• Number of cytogenetic and molecular markers that may reflect a certain prognosis or risk-profile in patients with CML have been developed in the last few years.^[18]

• Among those are:^[19]

• • Novel cytogenetic defects
  • Point mutations or amplifications of BCR/ABL or other genes
  • The quantitative amount of BCR/ABL after STI571 treatment
  • Various hypermethylation patterns
  • Silencing of tumor suppressor genes

• It is also likely that some of the previous markers will be used in the near future using more accurate techiniques. Such as:
  • Quantitative PCR testing using light cycler technique.^[20]

• • COBRAFISH.^[21]
    • A novel FISH technique that may be helpful in the detection of cryptic translocations occurring during disease evolution.
• The counting of basophils may be improved by using specific antibodies or by measurement of cellular histamine levels. ^[22]

• Using such tests, both, the mature basophils as well as the immature basophils (that may escape conventional blood counting especially in patients with CML-AP, can be measured more accurately for prognostic calculations.

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