الفهرس 
Review of Literature
Chronic Myeloid LeukemiaOnly 14 pages are availabe for public view
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Abstract
Chronic myeloid leukemia is a MPN that originates in an abnormal pluripotent stem cell (Vardiman et al. 2008).
At diagnosis, all cases of CML have the characteristic t(9;22) translocation that results in the Ph chromosome. This translocation fuses sequences of BCR gene on chromosome 22 with regions of ABL1 gene from chromosome 9 resulting in the formation of BCR/ABL chimeric protein with enhanced tyrosine kinase activity. This enhanced tyrosine kinase activity is associated with expansion of pluripotent stem cells, defective adhesion and decreased apoptosis of the hematopoietic cells (Hasserjian et al. 2002).
A significant advance in the treatment of CML was achieved with the introduction of imatinibmesylate, a signal transduction inhibitor that specifically targets a set of protein tyrosine kinases (ABL, Arg, KIT, and PDGFR) and their oncogenic forms, most notably BCR/ABL(Peggs and Mackinnon 2003).
It binds to the ATP binding site of the tyrosine kinases and maintains them in an inactive form. Imatinib is the gold standard for first line pharmacotherapy of CML, in any phase (Guilhot 2004).
The drug also acts by blocking the bind site of PDGF, present in fibroblasts. These cells are involved in the release of various elements that compose the extracellular matrix of bone marrow, such as reticulin(Kantarjian et al. 2005).
Bone marrow fibrosis is another typical feature of CML. It affects only a minority of patients at diagnosis, but a significant proportion of patients develop fibrosis during the course of disease, especially when therapy has lost its efficacy.In patients not responding to therapy, the cumulative proportion of cases with BM fibrosis amounts to more than 90%.Therefore, CML is the second MPN besides PMF characterized by a high risk of bone marrow fibrosis (Buesche et al. 2007).
Marked BM fibrosis at the time of diagnosis and worsening BM fibrosis while the patient is receiving therapy are markers of CML disease progression and poor prognosis. Fibrosis is believed to be a secondary event resulting from the abnormal interactions between the malignant CML clone and the BM fibroblasts (Bueso-Ramos et al. 2004).
Imatinib has an independent anti-fibrotic effect on BM of CML patients.This significant resolution of marrow fibrosis with imatinib therapy may further improve prognosis in CML through mechanisms either independent of or related to suppression of BCR/ABL(Kantarjian et al. 2005).
Other studies showed that imatinib does not absolutely guarantee against evolution of MF(Buesche et al. 2007). Expansion of JAK-2 mutated clone (V617F) as a possible mechanism of emerging MF during imatinib therapy has been reported (Hussein K et al. 2007). A loss of the inhibitory effect on PDGF receptor protein kinase activity might explain the emergence of foci with fiber increase during a cytogenetic and molecular response (Buesche et al. 2007).
This retrospective study was doneon 46 patients with CML from 2010 to 2012 treated with imatinibmesylate. Assessment of reticulin fibrosis in CML patients treated with imatinibmesylatewas done using reticulum staining kit.
Bone marrow fibrosis at presentation was assessed using reticulin stain on paraffin-embedded BM blocks of those patients. Thirty-two patients (69.6%) had MF at presentation. Fourteen patients (30.4%) had MF 0, 24 patients (52.2%) had MF 1 and 8 patients (17.4%) had MF 2.
Bone marrow fibrosis was reassessed in all of the 46 patients after one year of treatment with imatinibmesylate. Thirty-six patients had BM fibrosis after one year of treatment.
Of the 32 patients who had BM fibrosis at presentation, 8patients (25%) showed regression of BM fibrosis, 23 patients (75%) showed progression of BM fibrosis after one year of treatment. Thirty-three patients (71.7%) of the 46 patients in our study showed progression of MF after one year of treatment with imatinibmesylate.
Conclusion:
In conclusion, our findings indicate that imatinibmesylatemay be associated with progression of BM fibrosis in CML patients.
Our findings also indicate that CML is associated with BM fibrosis at presentation and this is a poor prognostic factor in CML patients.