The clinical course of CML is characterized by three stages, which are the chronic, accelerated, and blast phases [10] [11]. CML has an insidious chronic onset that takes months to years. It is often asymptomatic as it is typically diagnosed incidentally with neutrophilic leukocytosis or splenomegaly on routine testing or physical exam while in the chronic phase of the disease. When symptoms do present usually months after the onset, patients report nonspecific features such as fatigue and left upper quadrant fullness [12].

In the accelerated period, the symptoms become rapidly worse. Weight loss, fever, night sweats, and reduced exercise tolerance are common complaints. Additional manifestations include reduced appetite and early satiety, which occur secondary to an enlarged spleen [12]. Petechiae, ecchymoses, and lymphadenopathy are remarkable findings on the physical exam in the later stages.

The disease progresses towards a blast crisis. This latter is complicated with ominous signs such as infections, bleeding, and pain in the abdomen and bones [12]. The blast stage is aggressive and may lead to death within six months to a year.

Staging

According to the WHO, the following are the criteria defining each phase [13]:

In the chronic phase, the blast cells are below 10% of the white blood cells in the blood and/or bone marrow.

The accelerated phase features 1) blasts accounting for 10% to 19% of white blood cells in the peripheral blood and/or bone marrow, 2) a platelet count that is severely reduced or elevated regardless of treatment, and 3) progressively increasing leukocytosis and spleen size refractory to treatment, and 4) new mutations.

The blast phase is characterized by least 20% blasts in the peripheral blood or bone marrow along with extramedullary blasts.

CML is often diagnosed incidentally while the patient is undergoing routine testing. In others, a CBC is performed as a component of a workup for fatigue and other nonspecific symptoms. In either scenario, the CBC with differential will reveal an elevated white blood count [14], which will warrant further investigation that includes a thorough personal and family history, a complete physical exam, and key studies. Analysis of a peripheral smear and a bone marrow biopsy/aspiration will diagnose Ph+ CML and provide information about the phase [15].

Diagnostic methods

A histologic analysis of a peripheral smear will display immature granulocytes as well as eosinophilia and basophilia.

As the confirmatory diagnostic tool, cytogenic analysis detects the Philadelphia chromosome and other chromosomal abnormalities [15]. This defect is present in all phases of CML.

Fluorescence in situ hybridization (FISH) is a technique that identifies the Philadelphia chromosome on peripheral smears by using double DNA probes for the BCR and ABL genes. FISH is more sensitive than cytogenic testing but does not display other abnormalities [15] [16].

Another diagnostic modality involves molecular testing through real-time polymerase chain reactions (RT-PCR). Qualitative RT-PCR determines the presence of the BCR-ABL mRNA while the quantitative form measures the levels of the BCR-ABL mRNA. The latter test can be used at the time of diagnosis and through the course of therapy [15]. Moreover, it demonstrates the greatest sensitivity in the quantifying residual disease [16].

Since there is variability between different laboratories with regards to quantitative RT-PCR, standard procedures are used to improve the reproducibility of the test [17].

Other

Remarkable laboratory findings include a significantly increased vitamin B-12–binding protein (TC-I) and hyperuricemia, The former is indicative of leukocytosis and the latter is suggestive of bone marrow cell turnover.

The therapeutic goals for CML are multifold. The treatment aims to achieve hematologic, cytogenic, and molecular remission. The disease is easiest to control when in the chronic phase as the advanced forms are aggressive, unstable, and fatal.

Tyrosine kinase inhibitors (TKIs)

This category represents the standard treatment as it targets the BCR-ABL tyrosine kinase. The first generation agent, imatinib (Gleevec), was approved by the US Food and Drug Administration (FDA) in 2001 and is very effective. Newer drugs dasatinib and nilotinib were approved as first-line therapies in 2010 although both were approved prior as second-line treatments. Furthermore, bosutinib and ponatinib were established as second-line drugs in 2012.

As the mainstay therapy, TKIs deliver a durable response, prolong overall survival as well as progression-free survival. However, resistance to imatinib and other TKIs have emerged secondary to mutations in the BCR-ABL gene [18]. Additionally, there are side effects that arise from these medications.

Other

Older regimens such as the chemotherapy agents busulfan and hydroxyurea are associated with severe adverse effects. Also, they have not been linked to cytogenetic remission as they lack a solid impact on the evolution of the disease [19].

Interferon has been noted to promote cytogenetic responses in a subset of patients [20] and can be used as an adjunct to TKIs.

In the 1980s, allogeneic stem cell transplant (allo-SCT) [21] was the preferred treatment. However, it is limited by risks of morbidity and mortality, age restrictions, and donor availability.

It is estimated that there will be 1070 deaths in 2016, of which 570 are males and 500 are females [5].

Previously, the median survival of individuals with CML was 3 to 5 years post diagnosis. However, there has been an improvement as the median survival has been extended to 5 years or beyond. Moreover, there is a drastic increase in the 5-year survival rate over the past two decades that doubled from 31% to 63% [9]. The drug therapy imatinib has played a role in prolonging survival.

The clinical course varies widely as some patients may have an aggressive and rapidly fatal disease while others will have a long life. As with other diseases, the clinical heterogeneity of this disease likely reflects additional genetic effects that supplement the underlying translocation and induce the blast phase.

CML is attributed to the reciprocal translocation segments on chromosomes 9 and 22. Specifically, the Abelson gene located on chromosome 9 is transferred to the breakpoint cluster region (BCR) on chromosome 22. The result is the BCR-ABL fusion oncogene [4], which codes for a tyrosine kinase that is constantly activated. Consequently, this leads to uncontrolled proliferation of early myeloid cells.

The risk factors are advanced age, male gender, and radiation exposure [5].

The incidence of CML is 1.8 per population of 100,000 [6]. An increase in incidence is expected to occur as the population continues to age.

With regards to the patient demographics, the median age of onset is 64 years [6], and there is a predilection for males [6].

The American Cancer Society predicts that there will be 8220 new cases in 2016, in which males account for 4610 and females for 3610. Furthermore, it estimates that there will be 1070 deaths [5].

The underlying chromosomal abnormality of Ph+ CML occurs as a consequence of a translocation between the long arms of chromosomes 9 and 22. The Philadelphia chromosome is present in 95% of CML cases. This new hybrid gene, BCR-ABL, encodes a constitutively active tyrosine kinase that plays a role in the increase of cell proliferation, reduction of apoptosis, alteration of cell adhesion, and degradation of key proteins. Furthermore, the genomic instability is implicated in the progression of CML [7].

The Philadelphia chromosome triggers the abnormal pluripotent progenitor cell to produce an excessive quantity of granulocytes as well as red blood cells, monocytes, megakaryocytes, B-lymphoid and T lymphoid cells [2]. Normally, the proliferative process of blood cells undergoes regulatory mechanisms [8] whereas Ph+ cells lack normal signaling including that of pro-apoptosis [3].

There is no prevention for CML.

Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) is a myeloproliferative disorder resulting from a malignancy of a pluripotent stem cell [1], which leads to the expansion of hematopoietic progenitor cells [2]. The molecular pathogenesis of CML is explained by a chromosomal abnormality in which portions of chromosomes 9 and 22 undergo a balanced and reciprocal translocation resulting in the BCR-ABL fusion oncogene. The latter, also known as the Philadelphia chromosome, codes for the BCR-ABL tyrosine kinase which is continuously activated and hence responsible for the proliferation and differentiation of immature myeloid progenitor cells [3].

There are three stages of CML, which are the chronic, accelerated, and blast phases. The World Health Organization (WHO) has defined the criteria for each in accordance with the percentage of blast cells and other important values. Furthermore, the clinical presentation and disease duration of the phases vary from each other. The chronic phase is insidious and features no symptoms or vague ones such as fatigue. Patients diagnosed during the chronic period are incidentally found to have CML during routine testing. The accelerated phase and blast crisis present with fever, splenomegaly, ecchymoses, bleeding, and bone pain.

The assessment is comprised of the patient's clinical manifestations, history, physical exam, and investigative studies. The latter includes complete blood count (CBC) with differential, peripheral smear, and bone marrow analysis. There are diagnostic techniques used to demonstrate the presence of the Philadelphia chromosome. Early recognition and treatment, particularity if in the chronic phase, allow for easier control of the disease.

The standard therapeutic approach is to target the underlying chromosomal defect. Hence, the main class of drugs, tyrosine kinase inhibitors (TKIs) are profoundly effective in producing cytogenic and clinical remission. TKIs have been crucial in prolonging survival. There are other regimens as well but these are inferior to TKIs.

What is Chronic Myelogenous Leukemia?

Philadelphia chromosome-positive chronic Myelogenous Leukemia (CML) is a form of leukemia. In other words, it is cancer of the blood.

What causes CML?

This type of leukemia occurs when chromosomes 9 and 22 exchange genetic material with each other. The new chromosome 22 is now called the Philadelphia chromosome. In fact, the Philadelphia chromosome contains the BCR-ABL gene, which produces a protein known as tyrosine kinase. This tyrosine kinase is always switched on and its role is to allow the bone marrow to synthesize an excessive amount of white blood cells. Therefore, there is no more control on the production of the blood cells.

This disease is not inherited and therefore is not passed on from parent to child. The risk factors are advanced age, being a male, and exposure to radiation.

What are the signs and symptoms?

The 3 phases are chronic, accelerated, and blast phases. The chronic phase takes months to years and is slow and gradual. The accelerated and blast stages are very aggressive and fatal.

• Fatigue
• Weight loss
• Fever
• Night sweats
• Reduced exercise tolerance
• Enlarged spleen
• Enlarged lymph nodes
• Feeling full early
• Decreased appetite
• Bruising easily
• Bleeding easily
• Pain in the bones and joints
• Pain in the abdomen

How is CML diagnosed?

Most people diagnosed with this disease are diagnosed in the early stages during routine blood work. At this time, they either have no symptoms or vague ones such as fatigue. All patients with testing that suggests this diagnosis as well as patients with actual symptoms should be evaluated carefully by their physician. The medical team will obtain a thorough history of the patient, perform a physical exam, and order testing such as:

• Complete blood count with differential
• Peripheral blood smear
• Bone marrow analysis

The above studies will provide key information such as the percentage of immature types of blood cells. Also, analysis of blood and bone marrow samples are used in diagnostic techniques such as cytogenic testing, FISH, and PCR for the detection of the Philadelphia chromosome.

How is it treated?

The main treatment for Philadelphia chromosome-positive CML is by targeting the abnormality, which is the tyrosine kinase protein. Therefore, there is a family of drugs called the tyrosine kinase inhibitors. The first-line medication is known as imatinib or Gleevec. There are other similar ones as well. These medications have made a difference in prolonging the survival rates in the patients with this type of leukemia.

Chemotherapy, stem cell transplants, and interferons have been used in the past but have undesirable side effects.

What is the prognosis?

Generally, the earlier the diagnosis and treatment, the better outcomes for the patients. The 5-year survival rate has improved significantly with the use of the Gleevec and other similar medications.

However, it has been observed that some patients will do better overall than others. Scientists are investigating the reasons for why this is the case.

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