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Chronic Phase of Chronic Myeloid Leukemia

Leukemia Myeloid Chronic Phase

Chronic myelogenous leukemia is a myeloproliferative disease that may eventually lead to bone marrow failure and death. Staging of this neoplastic disorder considers three phases, namely the chronic phase of chronic myelogenous leukemia, the accelerated phase and the blast phase.


Presentation

CP-CML patients are generally asymptomatic and diagnosis of the disease is based on the incidental detection of hematological alterations: While leukocytosis >50*10^9/l is characteristic of CML even in early phases of the disease, the left shift is mild to moderate in CP-CML. Only occasionally, blasts are observed in peripheral blood. The majority of white blood cells is still functional and an enhanced susceptibility to infection cannot yet be observed.

If patients experience symptoms related to CP-CML, they may claim fatigue, malaise and weakness, early satiety and a feeling of fullness, possibly abdominal pain and weight loss. Those complaints are generally associated with anemia and splenomegaly. Rarely, the aforementioned hematological disturbances manifest in dyspnea, transient ischemic attacks, or cerebrovascular accidents (related to leukostasis), gastrointestinal bleedings (related to basophilia and enhanced histamine release), spontaneous bleedings or thrombosis (due to thrombocytopenia or thrombocytosis, respectively) [10].

Additional symptoms may manifest upon disease progression to AP-CML and BP-CML, a development that affects up to 2.8% of CP-CML patients per year [8]. In few cases, CML may directly progress from CP-CML to BP-CML. Fever, susceptibility to infection, lymphadenopathy, bone pain, infiltration of extramedullary tissues, prominent splenomegaly, splenic infarction, thrombosis, retinal hemorrhages, arthralgia and renal failure indicate transformation.

Easy Bruising
  • Initially asymptomatic, CML progression is insidious, with a nonspecific “benign” stage (malaise, anorexia, weight loss) eventually giving way to accelerated or blast phases with more ominous signs, such as splenomegaly, pallor, easy bruising and bleeding[merckmanuals.com]
  • bruising or bleeding because the bone marrow doesn't make enough (cells that help blood clotting) bone and joint pain because the bone marrow is full of abnormal cells belly pain and swelling caused by abnormal blood cells building up in organs like[kidshealth.org]
  • Accelerated or blast phase CML symptoms Abnormal bleeding or easy bruising as a result of decreased production of platelets in the bone marrow. Anemia as a result of decreased production of platelets in the bone marrow.[danafarberbostonchildrens.org]
  • Easy bruising. Fever. Gout due to rapid cell turnover.[patient.info]
Splenomegaly
  • Those complaints are generally associated with anemia and splenomegaly.[symptoma.com]
  • A 55-year-old man presented with splenomegaly (10 cm below left costal margin) and leucocytosis (145 10(9)/L). Differential showed neutrophilia with increased basophils (2%), eosinophils (1.5%), and left shift including myeloblasts (3%).[ncbi.nlm.nih.gov]
  • […] use Leukemia, Myeloid, Chronic-Phase/drug therapy Leukemia, Myeloid, Chronic-Phase/genetics* Leukemia, Myeloid, Chronic-Phase/mortality Leukemia, Myeloid, Chronic-Phase/pathology* Male Middle Aged Prognosis Protein Kinase Inhibitors/therapeutic use Splenomegaly[ncbi.nlm.nih.gov]
  • The chronic phase is characterized by nonspecific symptoms ( fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years.[amboss.com]
  • Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases). With disease progression, splenomegaly may increase, and pallor and bleeding occur.[merckmanuals.com]
Fatigue
  • In the accelerated phase, the number of CML cells is growing faster and causing symptoms such as fatigue, fever, weight loss and an enlarged spleen. If untreated, accelerated phase CML will eventually transform to blast phase CML.[lls.org]
  • People in this phase may notice symptoms like fatigue, caused by a lower number of red blood cells, and stomach pain due to an enlarged spleen.[healthline.com]
  • If patients experience symptoms related to CP-CML, they may claim fatigue, malaise and weakness, early satiety and a feeling of fullness, possibly abdominal pain and weight loss.[symptoma.com]
  • Despite her excellent response to therapy, she continues to complain of fatigue, intermittent nausea, and weight gain. She is asking to discontinue imatinib mesylate and is not interested in second-line therapy.[ncbi.nlm.nih.gov]
  • Signs and Symptoms Diagnosis Treatment Most patients with CML initially visit their doctor because of: Fatigue Low-grade fevers or sweats Fullness in the abdomen caused by an enlarged spleen Chronic myelogenous leukemia is generally suspected when tests[ucsfhealth.org]
Weight Loss
  • These patients often have fever, poor appetite, and weight loss. In this phase, the CML acts a lot like an acute leukemia.[cancer.org]
  • Patients in blast phase often have a fever, an enlarged spleen, weight loss, and generally feel unwell. Resistant CML. Resistant CML is CML that has come back after treatment or does not respond to treatment.[cancer.net]
  • Symptoms are more severe, and can include: rash bruising and bleeding easily bone and joint pain stomach pain more pronounced fatigue difficulty breathing increased risk of infection night sweats weight loss During the blastic phase, CML is difficult[healthline.com]
  • If patients experience symptoms related to CP-CML, they may claim fatigue, malaise and weakness, early satiety and a feeling of fullness, possibly abdominal pain and weight loss.[symptoma.com]
Fever
  • In the accelerated phase, the number of CML cells is growing faster and causing symptoms such as fatigue, fever, weight loss and an enlarged spleen. If untreated, accelerated phase CML will eventually transform to blast phase CML.[lls.org]
  • These patients often have fever, poor appetite, and weight loss. In this phase, the CML acts a lot like an acute leukemia.[cancer.org]
  • Patients in blast phase often have a fever, an enlarged spleen, weight loss, and generally feel unwell. Resistant CML. Resistant CML is CML that has come back after treatment or does not respond to treatment.[cancer.net]
  • The chronic phase is characterized by nonspecific symptoms ( fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years.[amboss.com]
  • Fever, susceptibility to infection, lymphadenopathy, bone pain, infiltration of extramedullary tissues, prominent splenomegaly, splenic infarction, thrombosis, retinal hemorrhages, arthralgia and renal failure indicate transformation.[symptoma.com]
Anemia
  • Those complaints are generally associated with anemia and splenomegaly.[symptoma.com]
  • People with accelerated phase CML may have More than 20 percent basophils (type of white blood cell) in the bloodstream High white blood cell counts Very high or very low platelet counts Increasing spleen size Anemia Additional chromosome abnormalities[lls.org]
  • The influences of moderate anemia with hemoglobin (Hb) RESULTS: Moderate anemia was identified in 44 (28.6%) patients.[ncbi.nlm.nih.gov]
  • The accelerated phase is characterized by complications secondary to the suppression of the other cell lines ( thrombocytopenia, anemia, recurrent infections).[amboss.com]
  • Anemia Anemia (low red blood cell count) at diagnosis is a less favourable prognostic factor. Leukemia cells in the bone marrow The prognosis is less favourable if there is a large number of leukemia cells in the bone marrow.[cancer.ca]
Pallor
  • Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases). With disease progression, splenomegaly may increase, and pallor and bleeding occur.[merckmanuals.com]
Abdominal Fullness
  • Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, night sweats, a sense of abdominal fullness particularly in left upper quadrant, gouty arthritis, symptoms of leukostasis[merckmanuals.com]
  • Splenomegaly, which tends to be present in the blast phase, causes abdominal fullness or discomfort, feeling full early when eating (the spleen is pressing on the stomach), and weight loss.[oncolink.org]
  • Abdominal fullness or abdominal distension. Left upper quadrant pain due to splenic infarction. Signs Splenomegaly - the most common physical finding, which may extend towards the right iliac fossa. Hepatomegaly.[patient.info]
  • 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]
Early Satiety
  • If patients experience symptoms related to CP-CML, they may claim fatigue, malaise and weakness, early satiety and a feeling of fullness, possibly abdominal pain and weight loss.[symptoma.com]
  • Symptoms that may develop as CML progresses include anemia (abnormally low RBCs), which contributes to feelings of fatigue and weakness; fullness or bloating in the left upper abdominal area, or feeling full after eating a small amount of food (early[mpninfo.org]
Abdominal Distension
  • Abdominal fullness or abdominal distension. Left upper quadrant pain due to splenic infarction. Signs Splenomegaly - the most common physical finding, which may extend towards the right iliac fossa. Hepatomegaly.[patient.info]
Left Upper Quadrant Pain
  • Left upper quadrant pain due to splenic infarction. Signs Splenomegaly - the most common physical finding, which may extend towards the right iliac fossa. Hepatomegaly. Enlarged lymph nodes are also a possibility.[patient.info]
Hepatosplenomegaly
  • 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]
  • A computed tomography scan demonstrated hepatosplenomegaly. She was later seen by a hematologist who, after examining a bone marrow aspirate and biopsy, made a diagnosis of CML. Marrow cytogenetics are not available from that time.[hematologyandoncology.net]
Hepatomegaly
  • Hepatomegaly. Enlarged lymph nodes are also a possibility. Anaemia can produce a hyperdynamic circulation. Easy bruising. Fever. Gout due to rapid cell turnover.[patient.info]
Bone Pain
  • pain Enlarged spleen Poor appetite and weight loss Bleeding Infections.[lls.org]
  • Fever, susceptibility to infection, lymphadenopathy, bone pain, infiltration of extramedullary tissues, prominent splenomegaly, splenic infarction, thrombosis, retinal hemorrhages, arthralgia and renal failure indicate transformation.[symptoma.com]
  • When this happens, the blood counts worsen and patients can experience high fever, bone pain and painful enlargement of the spleen. The blast phase of CML is a form of acute leukemia that is very difficult to treat.[ucsfhealth.org]
  • Signs and symptoms are most severe in this phase, including a massively enlarged spleen, bone pain, and weight loss. Serious infections and uncontrolled bleeding can be life-threatening. [ Read More ][icdlist.com]
  • However, once symptoms do occur they may include: Fatigue Frequent Infections Loss of Appetite Paleness Enlarged Spleen Weight Loss Fever Pain or Fullness Below Left Ribs Stomach or Bone Pain Easy Bleeding Night Sweats Stroke or Excess Blood Clotting[knowcancer.com]
Sternal Tenderness
  • […] weeks to months) *Attributable to splenic enlargement *Splenic infarcts Histamine perivascular infiltrate of neutrophils in the dermis fever and painful maculonodular violaceous lesions trunk, arms, legs, and face *Massive - and in almost all patients Sternal[slideshare.net]
Night Sweats
  • Symptoms are more severe, and can include: rash bruising and bleeding easily bone and joint pain stomach pain more pronounced fatigue difficulty breathing increased risk of infection night sweats weight loss During the blastic phase, CML is difficult[healthline.com]
  • The chronic phase is characterized by nonspecific symptoms ( fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years.[amboss.com]
  • Clinical Findings · Most pts are asymptomatic at diagnosis, leukocytosis is found incidentally · Can develop fatigue, night sweats, weight loss and splenomegaly on exam · The peripheral smear typically demonstrates a leukocytosis with a median white count[errolozdalga.com]
  • sweats. 2 Complications As CML progresses, headaches; bone and joint pain; severe abdominal pain; fever; worsening anemia, splenomegaly, and night sweats; bleeding complications; and infections may occur. 2 Diagnosis Both physical examination and a series[mpninfo.org]
  • Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly.[icd10data.com]
Petechiae
  • Other possible symptoms of a blast crisis include: Bruising Excessive sweating (night sweats) Fatigue Fever Pressure under the lower left ribs from a swollen spleen Rash -- small pinpoint red marks on the skin ( petechiae ) Weakness A physical examination[medlineplus.gov]
  • It may also present with mild fever and night sweats due to an elevated basal level of metabolism. [4] Some ( petechiae and ecchymosis. [4] In these patients fevers are most commonly the result of opportunistic infections. [4] Some patients are initially[en.wikipedia.org]
Urticaria
  • […] early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, night sweats, a sense of abdominal fullness particularly in left upper quadrant, gouty arthritis, symptoms of leukostasis such as tinnitus, stupor, and urticaria[merckmanuals.com]

Workup

If hematological findings imply CML, complete blood counts with differential should be evaluated. Analyses of peripheral blood smears and bone marrow specimens allow for an estimation of their content of blasts and basophils. However, definitive diagnosis of CP-CML requires the identification of Ph by means of routine cytogenetics, fluorescence in situ hybridization (FISH) or molecular biological techniques. In this context, results obtained with blood and bone marrow specimens show high concordance [10]. Reverse transcriptase polymerase chain reaction (RT-PCR) is more sensitive than cytogenetic analysis and FISH. In fact, with regards to a patient's response to therapy, cytogenetic remission is generally considered a favorable prognostic factor, whereas the reduction of BCR-ABL-to-ABL ratios below 10^-5 indicates molecular remission and imminent cure [11]. Accordingly, diagnosis may be based on the findings of qualitative RT-PCR, but quantitative RT-PCR should be employed for monitoring.

In minor shares of patients, nuclei show additional chromosomal aberrations, such as trisomy 8, or uncommon translocations and variants of Ph. In order to detect the latter, multiplex PCR and FISH with alternative probes have been applied successfully [4]. Therefore, CP-CML should never be ruled out because of negative results of karyotyping.

Thrombocytosis
  • KEYWORDS: Acute compartment syndrome; Bleeding complications; Chronic myeloid leukemia; Thrombocytosis[ncbi.nlm.nih.gov]
  • An adolescent with chronic myeloid leukemia initially presented with extreme thrombocytosis, increased megakaryopoiesis with dysmorphic features, and focal myelofibrosis in bone marrow examinations and then developed isolated myelosarcoma 1 year after[ncbi.nlm.nih.gov]
  • […] phase is characterized by leukocytosis and hypercellular marrow Peripheral blood leukocytosis Granulocytes at all stages of maturation Two peaks: segmented neutrophils and myelocytes Basophilia Eosinophilia (frequent) Special forms may have prominent thrombocytosis[surgpathcriteria.stanford.edu]
  • […] manifest in dyspnea, transient ischemic attacks, or cerebrovascular accidents (related to leukostasis), gastrointestinal bleedings (related to basophilia and enhanced histamine release), spontaneous bleedings or thrombosis (due to thrombocytopenia or thrombocytosis[symptoma.com]
  • Peripheral blood blasts fewer than 10% in the blood and bone marrow Accelerated phase Blasts 10-19% of white blood cells in peripheral and/or nucleated bone marrow cells ; persistent thrombocytopenia ( 100 10 9 /L) unrelated to therapy or persistent thrombocytosis[emedicine.medscape.com]
Philadelphia Chromosome Positive
  • Bosutinib was superior to imatinib as first-line therapy for patients with Philadelphia chromosome-positive (Ph ) chronic myeloid leukemia in chronic phase (CML-CP), according to preliminary findings from the BFORE (Bosutinib Trial in First Line Chronic[oncologynurseadvisor.com]
  • Gleevec (imatinib) Tasigna (nilotinib) Sprycel (dasatinib) Iclusig (ponatinib) Bosulif (bosutinib) Recent studies have demonstrated that Tasigna is superior to Gleevec for the treatment of patients with Philadelphia chromosome-positive chronic myeloid[news.cancerconnect.com]
  • Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children’s Oncology Group phase 1 study. Blood. 2004;104:2655–60. CrossRef PubMed Google Scholar 8.[link.springer.com]
  • Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP.[ncbi.nlm.nih.gov]
  • About Iclusig Iclusig is a kinase inhibitor with a target of BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia.[raredr.com]
Hypercellular Bone Marrow
  • bone marrow biopsy with numerous megakaryocytes Increased reticulin fibers (reticulin stain) Marked hypercellularity Myeloblastic transformation - bone marrow biopsy: Increase in stromal and vascular structures Marked increase in fibroblasts Numerous[pathologyoutlines.com]

Treatment

First-line treatment comprises the administration of tyrosine kinase inhibitors such as imatinib, dasatinib or nilotinib; their target is the BCR-ABL tyrosine kinase that shows constitutive activity. Patients generally receive imatinib at a dose of 400 mg per day. Those who prove intolerant to imatinib may alternatively be administered dasatinib or nilotinib. In case they don't respond satisfactorily to either compound, doses may be increased [12]. Determined mutations of BCR-ABL, mainly the replacement of threonine with isoleucine at position 315 (T315I), renders transformed cells insensitive to the aforementioned conventional tyrosine kinase inhibitors. In this context, third-generation tyrosine kinase inhibitor ponatinib has recently been approved for patients with refractory CP-CML including those individuals carrying the T315I mutation.

Pharmacological inhibition of BCR-ABL aims at inducing hematologic, cytogenetic and molecular remission [11]. In this line, cytogenetic remission refers to the absence of Ph as evaluated by karyotyping or FISH, and patients who achieve this condition within six months of therapy are likely to test negative for BCR-ABL mRNA in follow-ups. On the other hand, relapses are possible and patients who accomplished cytogenetic remission may prove positive for Ph later on.

CP-CML patients that fail to respond to tyrosine kinase inhibitor treatment should be considered for hematopoietic stem cell transplantation (HSCT). Of note, allogeneic HSCT preceded by the administration of tyrosine kinase inhibitors is also recommended for patients who developed AP-CML or BP-CML [12].

Besides causative treatment, supportive care should be provided in any phase of CML. Transfusion of blood products is indicated to compensate for anemia and thrombocytopenia.

Of note, administration of interferon-α plus cytarabine had been the treatment of choice before tyrosine kinase inhibitors became available. In a clinical trial comprising more than 1,000 CML patients, the latter have been shown to be significantly more effective than the former: After one year of therapy, 74% of patients who received imatinib reached cytogenetic remission vs. 9% of the interferon-α plus cytarabine group [13]. Accordingly, interferon-α therapy is no longer part of treatment recommendations for CML patients.

Prognosis

The majority of CML patients is diagnosed while suffering from CP-CML, the least advanced stage of the disease. Tyrosine kinase inhibition is highly effective in these patients and according to a recent study, 69% and 87% of patients treated with imatinib achieved complete cytogenetic remission within one and five years, respectively [8]. Furthermore, treatment time until cytogenetic remission did negatively correlate with the likelihood of progression to AP-CML and BP-CML. Overall survival after five years was 89%, and similar values have been reported elsewhere [1]. The respective treatment may be associated with minor side effects such as fatigue, headaches, edema, arthralgia, myalgia and muscle cramps, gastrointestinal complaints, and, less frequently, with adverse events like severe neutropenia, anemia and thrombocytopenia.

A scoring system has been developed to identify low-, intermediate- and high-risk patients. The interested reader is referred to the original publication, which includes both the equation for the Sokal score and its derivation [9]. It considers the patient's age, platelet counts, blast counts and the presence of splenomegaly.

Etiology

Precursor cells isolated from CP-CML patients show homogeneous chromosomal aberrations commonly referred to as Philadelphia chromosome (Ph). Ph is detected in more than 90% of cases and results from a reciprocal translocation of sequence segments between chromosomes 9 and 22. This process is associated with the assembly of the BCR-ABL gene on chromosome 22: BCR is physiologically located on chromosome 22 and encodes for a protein that displays serine/threonine kinase activity but whose precise function is still unknown; ABL is a protooncogene encoding for a tyrosine kinase. The gene product of BCR-ABL is a deregulated, constitutively active tyrosine kinase that may be encountered in the cytoplasm of cells and has been shown to form complexes with cytoskeletal proteins; it is sufficient to induce malignant transformation [3]. No pathogenetic role has been ascribed to the reciprocal ABL-BCR gene forming on chromosome 9.

The triggers of Ph-negative CML are less well understood. In a recent study on the genotype of three patients diagnosed with this form of the disease, uncommon rearrangements of BCR and ABL have been encountered [4]. Based on the results of conventional cytogenetics, the respective karyotypes had been erroneously classified as Ph-negative. Treatment of Ph-negative CP-CML does not differ from therapy of Ph-positive forms of the disease, and patients have a similar prognosis. These observations are in agreement with the hypothesis that BCR-ABL is involved in the pathogenesis of Ph-negative CML, too.

In contrast, the genetic basis of BP-CML varies largely, and this is due to the fact that degenerated cells acquire additional mutations during AP-CML. Their heterogeneity explains hematological and clinical differences among BP-CML patients, and it also renders the malignancy resistant to treatment with tyrosine kinase inhibitors.

Epidemiology

The annual incidence of CP-CML is approximately 0.9 per 100,000 inhabitants, and incidence rates have remained constant for the last decades [5]. Due to improved therapy and reduced mortality, CP-CML prevalence has been increasing within that same period of time. In 1985, CML prevalence was 3.9 per 100,000 people, by 2012, this value had augmented to 11.9 per 100,000 persons. This same trend has been observed in other countries, although absolute figures may vary slightly.

Neither racial nor gender predilection has been reported. The median age at diagnosis is 60 years.

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, the hallmark of CP-CML is a chromosomal aberration resulting in formation of the oncogene BCR-ABL. Expression of this gene yields the BCR-ABL protein with a constitutive tyrosine kinase activity, and this enzyme promotes cell growth and proliferation. Several signaling cascades are modulated accordingly: Increased proliferation results from disturbance of the Ras/Raf/MEK/ERK pathway, interaction with members of the JAK/STAT and PI3K/AKT pathway alter transcriptional activity and resistance to apoptosis [6] [7].

Prevention

No specific measures can be recommended to prevent CP-CML.

Summary

Chronic myelogenous leukemia (CML) is a myeloproliferative disease also referred to as chronic myeloid leukemia. This condition is caused by the malignant transformation of hematopoietic stem cells and uncontrolled proliferation of the respective clones. Initially, an enhanced proliferation of mature granulocytes can be observed. Hematopoietic differentiation is only mildly disturbed, and this condition is associated with a slight increase in immature cells. This stage of the disease is designated chronic phase of chronic myelogenous leukemia (CP-CML) and people diagnosed with CP-CML have a favorable prognosis: To date, eight-year-survival rates are >85% and due to the continuous improvement of treatment, even resistant cases are likely to resolve favorably [1]. The patient's prognosis worsens considerably if CML advances to the accelerated phase or blast phase (AP-CML and BP-CML, respectively). During AP-CML, degenerated cells acquire further genetic anomalies and while patients still present with leukocytosis, the left shift becomes more pronounced. This development culminates in the terminal phase of the disease, in BP-CML, which clinically mimics acute leukemia. Myeloid or lymphoid precursor cells, megakaryocytes or undifferentiated immature cells are increasingly replacing mature ones and in peripheral blood or bone marrow, blast counts exceed 20 or 30% [2]. Furthermore, blasts are likely to infiltrate extramedullary tissues in BP-CML. As of 2012, median survival after diagnosis of BP-CML was seven to eleven months.

Patient Information

Chronic myelogenous leukemia (CML), sometimes also referred to as chronic myeloid leukemia, is a type of blood cancer. It is triggered by a gene defect acquired by hematopoietic stem cells: These cells start to proliferate in an uncontrolled manner in the bone marrow, spread to circulation, and may eventually infiltrate extramedullary tissues. It may take several years until this terminal stage of the disease is reached, and previous stages have to be passed until this point. The initial stage is termed chronic phase of chronic myelogenous leukemia (CP-CML), advanced stages are the accelerated phase and blast phase (AP-CML and BP-CML, respectively).

The aforementioned gene defect, the trigger of CP-CML, consists in an exchange of DNA sequence segments between chromosomes 9 and 22. The result of this reciprocal translocation is an altered activity of the enzyme tyrosine kinase. Under physiological conditions, this enzyme is regulated by external factors, but in CP-CML patients, it escapes from regulatory mechanisms and becomes constitutively active. The name of this enzyme is BCR-ABL and this single mutation is sufficient to induce CML.

Unless degenerated cells acquire further mutations - which may lead to AP-CML and BP-CML - the consequences of BCR-ABL are mild to moderate. Patients are usually asymptomatic, and the disease is most commonly diagnosed incidentally, e.g., when blood samples are analyzed in routine screens. Nevertheless, treatment is crucial. Most CP-CML patients respond well to therapy, in contrast to those individuals suffering from advanced CML. To date, it is not possible to predict transformation into AP-CML and BP-CML. Thus, the earlier an appropriate therapy is initiated, the better the outcome.

First-line treatment consists in the administration of tyrosine kinase inhibitors such as imatinib, dasatinib or nilotinib. This medication may cure the disease. Minor shares of patients have refractory CP-CML and prove to be insensitive to tyrosine kinase inhibitors. These patients may require hematopoietic stem cell transplantation. In sum, eight-year-survival rates are currently >85%. However, the outcome worsens considerably if the patient develops AP-CML or BP-CML.

References

Article

  1. Fava C, Rege-Cambrin G, Saglio G. Chronic myeloid leukemia: state of the art in 2012. Curr Oncol Rep. 2012; 14(5):379-386.
  2. Hehlmann R. How I treat CML blast crisis. Blood. 2012; 120(4):737-747.
  3. Salesse S, Verfaillie CM. BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002; 21(56):8547-8559.
  4. Bennour A, Bellaaj H, Ben Youssef Y, et al. Molecular cytogenetic characterization of Philadelphia-negative rearrangements in chronic myeloid leukemia patients. J Cancer Res Clin Oncol. 2011; 137(9):1329-1336.
  5. Gunnarsson N, Sandin F, Hoglund M, et al. Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence. Eur J Haematol. 2016.
  6. Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res. 2012; 18(4):930-937.
  7. Danisz K, Blasiak J. Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors. Acta Biochim Pol. 2013; 60(4):503-514.
  8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355(23):2408-2417.
  9. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984; 63(4):789-799.
  10. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring. Am J Hematol. 2016; 91(2):252-265.
  11. Colombat M, Fort MP, Chollet C, et al. Molecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatment. Haematologica. 2006; 91(2):162-168.
  12. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27(35):6041-6051.
  13. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348(11):994-1004.

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Last updated: 2018-06-21 17:07