Research Article: Effect of Imatinib on Bone Marrow Morphology and Angiogenesis in Chronic Myeloid Leukemia

Date Published: January 1, 2019

Publisher: Hindawi

Author(s): Neetu Pandey, Geeta Yadav, Rashmi Kushwaha, Shailendra Prasad Verma, Uma Shankar Singh, Ashutosh Kumar, Prabhaker Mishra.

http://doi.org/10.1155/2019/1835091

Abstract

Chronic myeloid leukemia (CML) is characterized by hyperproliferation of myeloid precursors, increased fibrosis, and neoangiogenesis in the bone marrow. Imatinib inhibits BCR-ABL tyrosine kinase produced due to reciprocal translocation t(9;22) in neoplastic CML cells. It reduces hyperproliferation of myeloid precursors and has been found to affect bone marrow fibrosis and angiogenesis. This study was done to assess the effect of imatinib on bone marrow morphology and angiogenesis in CML.

31 newly diagnosed CML patients were evaluated before and after 3 months of imatinib therapy. A marrow morphological response (MMR) score was used to assess marrow cytological and histological features including grade of fibrosis. Mean microvessel density (MVD) was also assessed. Hematological parameters and BCR-ABL transcript levels were assessed in the peripheral blood.

86.21% of patients showed decrease in marrow cellularity with normalization of M:E ratio. 72.42% of patients had decrease in grade of fibrosis and 17.24% showed no change while 10.34% of patients showed progression of fibrosis grade. Patients with MMR score ≥ 2 (n=4) and those with progression of fibrosis grade (n=3) showed suboptimal molecular response (BCR-ABL transcripts > 10%). Pretherapy mean MVD of patients (14.69 ± 5.28) was higher than that of controls (6.32 ± 1.64). A significant reduction of 66.51% was observed in posttherapy mean MVD (4.98 ± 2.77) of CML patients (p<0.001). Imatinib therapy in CML not only decreases marrow cellularity, but also helps towards normalization of bone marrow microenvironment by reducing fibrosis and angiogenesis.

Partial Text

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive accumulation of apparently normal myeloid cells in the bone marrow and peripheral blood. It is associated with the presence of Philadelphia chromosome, which is the result of a reciprocal translocation between chromosomes 9 and 22 resulting in the formation of BCR-ABL chimeric protein which has uncontrolled tyrosine kinase activity [1]. Besides increase in myeloid cells, the bone marrow microenvironment in CML is also altered. There is an increase in collagen type III (reticulin fibrosis) as well as an increase in angiogenesis [2]. Imatinib mesylate is a selective BCR-ABL protein tyrosine kinase inhibitor which acts by binding to the ATP binding site of BCR-ABL tyrosine kinase, causing its inactivation and thereby effecting apoptosis of leukemic cells which leads to improvement in bone marrow hematological and morphological parameters [3, 4]. Imatinib also inhibits other tyrosine kinases, namely, platelet derived growth factor receptor (PDGFR) and c-KIT [3]. Imatinib also has effects on the bone marrow stroma and microenvironment. A decrease in bone marrow fibrosis has been observed in CML patients on imatinib therapy [2]. Recent studies have emphasized on the antiangiogenic property of imatinib. Angiogenesis plays an important role in progression of solid tumors and angiogenesis induction has been described in several hematological malignancies including leukemias [5]. The present study was done with aim to assess morphological changes and changes in angiogenesis in the bone marrow in patients of CML on imatinib mesylate therapy.

This was a prospective study done over a period of one year between July 2016 and June 2017. The study was approved by the Institutional Ethics Committee. A total of 31 patients of CML were enrolled in this study. Written informed consent was taken from all the patients. Detailed history was obtained from each patient. Detailed clinical examination and blood and bone marrow examination were done in all patients. BCR-ABL status estimation was done by FISH or real-time PCR (RT-PCR). All patients showed presence of BCR-ABL translocation at the time of diagnosis.

Statistical analysis was done using Statistical Package for Social Sciences, version 23 (SPSS-23, IBM, Chicago, USA). Normality of continuous data was assessed. Normally distributed continuous data were presented in Mean ± Standard Deviation (Mean ± SD), while categorical data were presented in frequency and percentage (%). Independent samples t-test was used to compare means between two groups while Fischer’s exact test was used to compare proportions/test associations between two attributes. Paired samples t-test/McNemar’s Chi-Square test was used to test the mean difference/difference in proportions between pre and post observations. p value < 0.05 was considered as statistically significant. In this study, 31 patients of CML (age range 15-65 years, male: female ratio = 1:1.07) were subjected to imatinib therapy. Of these 31 patients, 25 were in the chronic phase of CML, 2 in the accelerated phase, and 4 in the blast phase at the time of diagnosis. All 31 patients were symptomatic at the time of presentation and the most common symptom was easy fatigability (97%). 22 out of 31 patients (70.96%) patients had splenomegaly at the time of presentation with mean spleen size (cm) below costal margin = 6.59 ± 2.61. In 29.03% (n=9) of patients, spleen was not palpable at diagnosis. The mean haemoglobin concentration (gm/dL) was 9.66 ± 2.54 (range = 4.7-16.2, median =10.05). The mean total leucocyte count (lac/mm3) of patients was 1.36 ± 0.81 (range = 0.3 – 3.0, median =1.30). The mean basophil percentage of patients was 3.71 ± 3.79% (range = 0-18%, median = 2.50%). 3-month follow-up of 29 patients was obtained. 2 patients could not be followed up as they died within 3 months of onset of treatment. 51.7% of patients evaluated in this study achieved CHR after 3 months of imatinib therapy. Narang N et al. [10] evaluated sequential hematological parameters at ≤ 1 month, 3 months, 6 months, and 12 months after imatinib therapy and observed that 80% of patients achieved CHR at 3 months. Srinivas BH et al. [10] observed CHR in 15/37 (40.5%) of their patients on first follow-up at 8 months after imatinib therapy. Apart from hyperproliferation of myeloid precursors, the bone marrow microenvironment in CML is also altered. There is significant increase in marrow fibrosis and neovascularization. Imatinib mesylate therapy not only decreases the marrow cellularity, but also helps towards normalization of the bone marrow microenvironment by reducing fibrosis and angiogenesis.   Source: http://doi.org/10.1155/2019/1835091

 

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