Chronic myelogenous (or myeloid) leukemia (CML), also known as chronic granulocytic leukemia (CGL), is a cancer of the white blood cells. It 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 mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding.
It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. It is now treated with one of several targeted therapies including imatinib, dasatinib, and nilotinib, which have dramatically improved survival to nearly 90% due to the advent of these targeted therapies.
Signs and symptoms
Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood cell count on a routine laboratory test. In this setting, CML must be distinguished from a leukemoid reaction, which can have a similar appearance on a blood smear. Symptoms of CML may include: enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML)
Diagnosis
CML is often suspected on the basis on the complete blood count, which shows increased granulocytes of all types, typically including mature myeloid cells. Basophils and eosinophils are almost universally increased; this feature may help differentiate CML from a leukemoid reaction. A bone marrow biopsy is often performed as part of the evaluation for CML, and CML is diagnosed by detecting the Philadelphia chromosome. This characteristic chromosomal abnormality can be detected by routine cytogenetics, by fluorescent in situ hybridization, or by PCR for the bcr-abl fusion gene.
Controversy exists over so-called Ph-negative CML, or cases of suspected CML in which the Philadelphia chromosome cannot be detected. Many such patients in fact have complex chromosomal abnormalities which mask the (9;22) translocation, or have evidence of the translocation by FISH or RT-PCR in spite of normal routine karyotyping. The small subset of patients without detectable molecular evidence of bcr-abl fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML.
Treatment
Chronic phase CML is treated with inhibitors of tyrosine kinase, the first of which was imatinib mesylate (marketed as Gleevec or Glivec; previously known as STI-571) approved by the United States FDA in 2001. To overcome imatinib resistance and to increase responsiveness of TK inhibitors, two novel agents were later developed. The first, dasatinib, is a TK inhibitor that blocks several oncogenic proteins and was initially approved by the US FDA in 2007 to treat CML patients who were either resistant to or intolerant of imatinib.
Another TK inhibitor, nilotinib, was also approved by the US FDA for the same indication. Nilotinib and dasatanib were approved for first-line therapy in 2010, so there are now three drugs available for first-line treatment of CML. In the past, antimetabolites (e.g. cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used, but these drugs have been replaced by TK inhibitor drugs. The TK inhibitor drugs specifically target BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation.
The IRIS study is an international study that compared interferon/cytarabine combination with imatinib. Long term follow up demonstrating the superiority of imatinib regimens is clear cut. Bone marrow transplantation was also used as initial treatment for CML before the advent of imatinib, but is now rarely used, primarily for those who fail drug treatment. While transplantation can often be curative, there remains a high rate of transplant-related mortality.
Dasatanib and nilotinib failed to overcome the imatinib resistance caused by the T315I mutation. All current treatments for this mutation are experimental. In October 2010, ponatinib, a small molecule, oral drug developed by Ariad Pharmaceuticals, was entered into evaluation in a pivotal Phase 2 trial. Ponatinib, a pan-BCR-ABL inhibitor, has shown ongoing strong efficacy in its continuing Phase 1 trial in treatment of the T315I mutation CML, as well as all other known mutations.
This drug has also been granted orphan status. Recently Chemgenex released results of their open-label Phase 2/3 study (CGX-635-CML-202) which investigated the use of their non-targeted agent omacetaxine, administered subcutaneously in CML patients who had failed imatinib and who have the highly drug-resistant T315I kinase domain mutation. Stem cell transplantation remains an option for those patients who rarely develop the T315I mutation.
In 2005 encouraging but mixed results of vaccination were reported with the BCR/abl p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.
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