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.
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) .
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 . 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.
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 . 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 . 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 . Therefore, CP-CML should never be ruled out because of negative results of karyotyping.
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 . 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 . 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 .
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 . Accordingly, interferon-α therapy is no longer part of treatment recommendations for CML patients.
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 . 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 . 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 . It considers the patient's age, platelet counts, blast counts and the presence of splenomegaly.
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 . 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 . 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.
The annual incidence of CP-CML is approximately 0.9 per 100,000 inhabitants, and incidence rates have remained constant for the last decades . 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.
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  .
No specific measures can be recommended to prevent CP-CML.
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 . 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% . 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.
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.