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.

• Splenomegaly

  Although splenic radiation is rarely used, it may be helpful in refractory cases of CML or in patients with terminal disease and marked splenomegaly. [askhematologist.com]

  Splenomegaly of more than 10 cm, basophilia and leukocytosis were associated with a shorter median survival but was not statistically significant. [ncbi.nlm.nih.gov]

  The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly. [orpha.net]

  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. [symptoma.com]

  He was able to achieve major molecular response with imatinib therapy; however, his splenomegaly persisted and he did not have a hematologic response. [gotoper.com]

• Palpable Spleen

  Physical examination was significant for a palpable spleen (1–2 cm below the left costal margin), which on computed tomographic imaging measured 15 cm in craniocaudal dimension. [archivesofpathology.org]

• Anemia

  It can lead to problems such as infection, anemia, or easy bleeding. What is Ph+ CML? Ph+ CML stands for Philadelphia chromosome–positive chronic myeloid leukemia. You're not born with this disease. [us.tasigna.com]

  Symptoms of anemia. Fever. Night sweats. Easy bleeding. Splenomegaly which may be massive ± spleen pain. Hepatomegaly. [askhematologist.com]

  Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. [ncbi.nlm.nih.gov]

  The most common Grade 3/4 adverse reactions and laboratory abnormalities observed in greater than 10% of patients were thrombocytopenia, anemia, and neutropenia. [press.pfizer.com]

  IMPORTANT SAFETY INFORMATION Myelosuppression Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in [news.bms.com]

• Pain

  The most common — 15% or more — included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity and abdominal pain. [healio.com]

  Safety Profile The most common grade 3 or 4 nonhematologic adverse events by patient group were: hypertension (39%), abdominal pain (10%), and rash (5%) in patients with chronic-phase CML; hypertension (36%), pneumonia (9%), abdominal pain (8%), and rash [ascopost.com]

  One month later, the patient presented with pain and tenderness over thyroid. A provisional diagnosis of acute thyroiditis was made. [ijp-online.com]

  Signs and symptoms of placental abruption include: Vaginal bleeding, although there might not be any Abdominal pain Back pain Uterine tenderness or rigidity Uterine contractions, often coming one right after another Abdominal pain and back pain often [mayoclinic.org]

• Fatigue

  In others, a CBC is performed as a component of a workup for fatigue and other nonspecific symptoms. [symptoma.com]

  The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly. [orpha.net]

  If you have symptoms, they may include: Fatigue Weight loss Night sweats Fever Pain or a feeling of fullness below the ribs on the left side Tests that examine the blood and bone marrow diagnose CML. [icdlist.com]

  The most common side effects include high blood pressure, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. [cancer.net]

  Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. [news.bms.com]

• Fever

  If you have symptoms, they may include: Fatigue Weight loss Night sweats Fever Pain or a feeling of fullness below the ribs on the left side Tests that examine the blood and bone marrow diagnose CML. [icdlist.com]

  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. [symptoma.com]

  Chronic myeloid leukemia symptoms Symptoms of CML include: Easy bleeding Unexplained weight loss Fever Loss of appetite Night sweats Pale skin Chronic myeloid leukemia treatment options Treatment for CML may include radiation therapy, chemotherapy, stem [cancercenter.com]

  Fever. Night sweats. Easy bleeding. Splenomegaly which may be massive ± spleen pain. Hepatomegaly. Investigations: FBC reveals raised white cell count with immature forms in the blood and often increased eosinophils and basophils. [askhematologist.com]

  The boy belonged to low socioeconomic status and he had taken some antipyretics and multivitamins for fever and weakness in outpatient department of a remote village dispensary. [ajmhs.org]

• Weight Loss

  Common features include excessive tiredness (fatigue), fever, and weight loss. Many affected individuals develop an enlarged spleen (splenomegaly), which can cause a feeling of fullness in the abdomen and a loss of appetite. [icdlist.com]

  The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly. [orpha.net]

  Chronic myeloid leukemia symptoms Symptoms of CML include: Easy bleeding Unexplained weight loss Fever Loss of appetite Night sweats Pale skin Chronic myeloid leukemia treatment options Treatment for CML may include radiation therapy, chemotherapy, stem [cancercenter.com]

  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. [symptoma.com]

  When they occur, signs and symptoms may include: Bone pain Easy bleeding Feeling full after eating a small amount of food Feeling run-down or tired Fever Weight loss without trying Loss of appetite Pain or fullness below the ribs on the left side Excessive [mayoclinic.org]

• Cough

  Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as [news.bms.com]

  […] safe and effective way for Ph+ AML patients who were in and unable to receive chemotherapy as first-line therapy because of a poor physical condition. 2 Case presentation A 46-year-old man came to our department in May 2016, complaining of fever and cough [journals.lww.com]

  […] hydroxide, magnesium hydroxide, and simethicone to reduce the amount of acid in the stomach: Take these medicines about 2 hours before or about 2 hours after you take TASIGNA Common Side Effects in Adults and Children Include: • Nausea • Diarrhea • Rash • Cough [gleevec.com]

  She also had a nonproductive cough and postnasal drip. [archivesofpathology.org]

• Postnasal Drip

  She also had a nonproductive cough and postnasal drip. [archivesofpathology.org]

• Abdominal Pain

  Safety Profile The most common grade 3 or 4 nonhematologic adverse events by patient group were: hypertension (39%), abdominal pain (10%), and rash (5%) in patients with chronic-phase CML; hypertension (36%), pneumonia (9%), abdominal pain (8%), and rash [ascopost.com]

  Signs and symptoms of placental abruption include: Vaginal bleeding, although there might not be any Abdominal pain Back pain Uterine tenderness or rigidity Uterine contractions, often coming one right after another Abdominal pain and back pain often [mayoclinic.org]

  The most common — 15% or more — included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity and abdominal pain. [healio.com]

  Adverse Reactions: The most common adverse reactions observed in greater than 20% of patients in the Phase 1/2 safety population (N=546) were diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. [press.pfizer.com]

• Loss of Appetite

  Chronic myeloid leukemia symptoms Symptoms of CML include: Easy bleeding Unexplained weight loss Fever Loss of appetite Night sweats Pale skin Chronic myeloid leukemia treatment options Treatment for CML may include radiation therapy, chemotherapy, stem [cancercenter.com]

  Common features include excessive tiredness (fatigue), fever, and weight loss. Many affected individuals develop an enlarged spleen (splenomegaly), which can cause a feeling of fullness in the abdomen and a loss of appetite. [icdlist.com]

  When they occur, signs and symptoms may include: Bone pain Easy bleeding Feeling full after eating a small amount of food Feeling run-down or tired Fever Weight loss without trying Loss of appetite Pain or fullness below the ribs on the left side Excessive [mayoclinic.org]

  Some common side effects that you may experience include: Fluid retention (holding water) Muscle cramps, pain, or bone pain Abdominal pain Anorexia (loss of appetite) Vomiting Diarrhea Decreased hemoglobin (decrease in blood cells which carry oxygen) [gleevec.com]

  The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss. [en.wikipedia.org]

• Early Satiety

  Additional manifestations include reduced appetite and early satiety, which occur secondary to an enlarged spleen. Petechiae, ecchymoses, and lymphadenopathy are remarkable findings on the physical exam in the later stages. [symptoma.com]

  During this time, the patient also developed constitutional symptoms, such as fatigue and early satiety. Another BM biopsy was performed 6 months from the start of tyrosine kinase inhibitor (TKI) therapy. This was a dry tap, with no aspirate. [gotoper.com]

• Abdominal Fullness

  During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue, left side pain, joint and/or hip pain, or abdominal fullness. [en.wikipedia.org]

• Hepatosplenomegaly

  On physical examination, no hepatosplenomegaly or lymphadenopathy were found. [haematologica.org]

  A 12 -year -male child with generalized lymphadenopathy and hepatosplenomegaly had a crisis phase of presentation instead of the usual chronic phase of onset of disease. Hematological tests and molecular study were performed. [ajmhs.org]

  It constitutes less than 5% of all acute myeloid leukemia cases and usually presents with cytopenias without hepatosplenomegaly. [archivesofpathology.org]

  Splenomegaly was seen in five, hepatomegaly in three other patients, and hepatosplenomegaly in one patient. [ijpmonline.org]

  It can also present with symptoms indicative of hepatosplenomegaly and the resulting upper quadrant pain this causes. The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss. [en.wikipedia.org]

• Night Sweats

  The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly. [orpha.net]

  Chronic myeloid leukemia symptoms Symptoms of CML include: Easy bleeding Unexplained weight loss Fever Loss of appetite Night sweats Pale skin Chronic myeloid leukemia treatment options Treatment for CML may include radiation therapy, chemotherapy, stem [cancercenter.com]

  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. [symptoma.com]

  If you have symptoms, they may include: Fatigue Weight loss Night sweats Fever Pain or a feeling of fullness below the ribs on the left side Tests that examine the blood and bone marrow diagnose CML. [icdlist.com]

  […] during sleep (night sweats) When to see a doctor Make an appointment with your doctor if you have any persistent signs or symptoms that worry you. [mayoclinic.org]

• Petechiae

  Petechiae, ecchymoses, and lymphadenopathy are remarkable findings on the physical exam in the later stages. The disease progresses towards a blast crisis. [symptoma.com]

  It may also present with mild fever and night sweats due to an elevated basal level of metabolism.[4] Some (<10%) are diagnosed during the accelerated stage which most often presents bleeding, petechiae and ecchymosis.[4] In these patients fevers are [en.wikipedia.org]

• Bone Pain

  In blast crisis, 30 percent or more of blood or bone marrow cells are myeloblasts. Signs and symptoms are most severe in this phase, including a massively enlarged spleen, bone pain, and weight loss. [icdlist.com]

  When they occur, signs and symptoms may include: Bone pain Easy bleeding Feeling full after eating a small amount of food Feeling run-down or tired Fever Weight loss without trying Loss of appetite Pain or fullness below the ribs on the left side Excessive [mayoclinic.org]

  The signs and symptoms of Ph+ ALL are the same as standard ALL, which include: enlargement of the liver or spleen, enlarged lymph nodes, paleness, fevers, bruising, weight loss, bone pain, and abnormal blood cell counts. [stbaldricks.org]

  Accelerated phase: Treatment failure with increasing malaise, infections and fevers, bone pain, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing [askhematologist.com]

• Arthralgia

  (facial edema, peripheral edema, arthralgia, GI trouble) * Dasatinib : Pleural effusion 등의 독특한 부작용. Pulmonary HTN 인 경우 약제를 영구중단해야 한다. * Nilotinib : Metabolic event 들을 잘 생기게 한다. [sondoctor.co.kr]

  Grade 3–4 non-hematological AEs occurred in less than 2% of patients and included diarrhea (1.9%), rash (1.9%), headache (1.6%), and arthralgia (1.6%).39 First-line therapy Two separate Phase II studies initially evaluated the efficacy and safety of nilotinib [ncbi.nlm.nih.gov]

• Myalgia

  After a few days of antibiotics, her myalgias and night sweats resolved but the fevers and fatigue continued. [archivesofpathology.org]

  Muscle cramps, musculoskeletal pain, creatine kinase elevations, and myalgia have been reported in up to 50% of patients during imatinib treatment 31, 33, 34 but were infrequent with bosutinib. [bloodjournal.org]

  The most common side effects were myalgia(75%) and peripheral oedema(65%). [iasj.net]

• Sternal Tenderness

  On physical examination, he had huge splenomegaly and hepatomegaly, sternal tenderness and generalized lymphadenopathy. [ajmhs.org]

• Renal Insufficiency

  Age, weight, sex, and ethnicity have not been found to affect the pharmacokinetic properties, efficacy, or toxicity of nilotinib.20 No dose adjustment is necessary for renal insufficiency. [ncbi.nlm.nih.gov]

• Kidney Failure

  TLS can cause you to have kidney failure (with the need for dialysis treatment) and/or an abnormal heartbeat Bleeding Problems: Serious bleeding problems and death have happened during treatment with TASIGNA. [gleevec.com]

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.

• Philadelphia Chromosome Positive

  Europe Approves Expanded Indication for Sprycel The European Commission approved Sprycel (dasatinib) to include the treatment of children and adolescents aged 1 year to 18 years with Philadelphia chromosome-positive CML in chronic phase. [pharmalive.com]

  In a dose-ranging trial no patients had newly diagnosed Philadelphia chromosome-positive CML and 17 were resistant or intolerant to imatinib. [healio.com]

  Ponatinib in refractory Philadelphia chromosome-positive leukemias. N. Engl. J. [futuremedicine.com]

  […] or Confirmed BCR-ABL1 (Abelson-break point cluster) Positive if Philadelphia Chromosome negative Chronic Myeloid Leukemia (from initial diagnosis). [clinicaltrials.gov]

• Thrombocytosis

  Here we report a case of coexistence of BCR-ABL1 fusion gene and CALR mutation, diagnosed due to persistent thrombocytosis while the patient was in treatment-free, complete molecular remission (CMR) from CML. [sci.amegroups.com]

  A Case Report of Chronic Myelogenous Leukemia With JAK2 - and BCR/ABL -Positive Mutation Case Presentation In 1999, a 68-year–old man presented with hematocrit of 50, and associated leukocytosis, erythrocytosis, thrombocytosis and splenomegaly (2-4 cm [gotoper.com]

  […] though all e6a2-expressing cases exhibited an aggressive disease course, a direct comparison between them is not always straightforward since they present distinct clinical, hematological or molecular features, such as accelerated phase disease; marked thrombocytosis [haematologica.org]

  Accelerated phase: Treatment failure with increasing malaise, infections and fevers, bone pain, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing [askhematologist.com]

  Basophils 와 Eosinophils 도 대게 증가되어 있으며, Thrombocytosis 는 흔하지만, anemia 의 경우 환자의 1/3 정도에서만 나타난다. Splenomegaly (Extramedullary hematopoiesis) 가 동반될 수 있다. * 각 그룹마다 Accelerated phase, Blast phase 의 정의가 다르다. [sondoctor.co.kr]

• Hemoglobin Decreased

  Some common side effects that you may experience include: Fluid retention (holding water) Muscle cramps, pain, or bone pain Abdominal pain Anorexia (loss of appetite) Vomiting Diarrhea Decreased hemoglobin (decrease in blood cells which carry oxygen) [gleevec.com]

• Dry Tap Bone Marrow

  Immunophenotypic analysis of cells isolated from bone marrow biopsies in patients with failed bone marrow aspiration (“dry tap”). Am J Clin Pathol. 1990;93(4):545–548. [Google Scholar] 8. [archivesofpathology.org]

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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