Chronic myelogenous leukemia Totally Explained

Everything about Chronic Myelogenous Leukemia totally explained

| ICD9 = | ICDO = | Image = bcrablmet.jpg|thumb| Caption = The Philadelphia chromosome as seen by metaphase FISH.| OMIM = | OMIM_mult = | MedlinePlus = 000570 | eMedicineSubj = med | eMedicineTopic = 371 | DiseasesDB = 2659 | MeshID = D015464 | }} Chronic myelogenous leukemia (CML) 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. Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies introduced at the beginning of the 21st century have radically changed the management of CML.

Epidemiology

CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. CML represents about 15–20% of all cases of adult leukemia in Western populations. The only well-described risk factor for CML is exposure to ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.

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: malaise, low-grade fever, gout, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML). Splenomegaly may also be seen.

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, but bone marrow morphology alone is insufficient to diagnose CML. 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.

Pathophysiology

CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania: Peter Nowell of the University of Pennsylvania and David Hungerford of the Fox Chase Cancer Center.
In this translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase.
The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl transcript is continuously active and doesn't require activation by other cellular messaging proteins. In turn, bcr-abl activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover, the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the bcr-abl protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the bcr-abl protein and its action as a tyrosine kinase, targeted therapies have been developed (the first of which was imatinib mesylate) which specifically inhibit the activity of the bcr-abl protein. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML. by Sokal et al, and the World Health Organization.

>20% myeloblasts or lymphoblasts in the blood or bone marrow

Large clusters of blasts in the bone marrow on biopsy

Development of a chloroma (solid focus of leukemia outside the bone marrow)

Treatment

Chronic phase

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). In the past, antimetabolites (for example cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used, but these drugs have been replaced by imatinib. Imatinib was approved by the United States FDA in 2001 and specifically targets BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. It is better tolerated and more effective than previous therapies. Bone marrow transplantation was also used as initial treatment for CML in younger patients before the advent of imatinib, and while it can often be curative, there's a high rate of transplant-related mortality.. Another drug in development for the T315I mutation is Omacetaxine (formerly known as Ceflatonin). Clinical data from the first 21 patients enrolled in a Phase 2/3 trial were presented at the American Society of Hematology (ASH) Annual Meeting . Another agent, nilotinib, is a selective kinase inhibitor, but is currently undergoing clinical development and testing. Nilotinib is designed to bind more tightly than imatinib to the Bcr-Abl abnormal fusion protein responsible for chronic myeloid leukemia. Stem cell transplantation is a secondary option for treatment of CML.
In 2005 favourable results of vaccination were reported with the BCR/abl p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.

Blast crisis

Blast crisis carries all the symptoms and characteristics of either acute myelogenous leukemia or acute lymphoblastic leukemia, and has a very high mortality rate. This stage can most effectively be treated by a bone marrow transplant after high-dose chemotherapy. In young patients in the accelerated phase, a transplant may also be an option. However the likelihood of relapse after a bone marrow transplant is higher in patients in blast crisis or in the accelerated phase as compared to patients in the chronic phase. However, this study pre-dates the advent of treatments using targeted therapy. A follow-up on patients using imatinib published in the New England Journal of Medicine shows an overall survival rate of 89% after five years.

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