Assessment of fibrosis and vascularization of bone marrow stroma of chronic myeloid Leukemia patients treated with imatinib mesylate and their relationship with the cytogenetic response

Abstract

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of the Philadelphia chromosome (translocation between chromosomes 9 and 22), resulting in the formation of the hybrid BCR-ABL protein. Currently, the treatment of CML patients is performed with imatinib mesylate (IM), which promotes the elimination of leukemic cells by inhibiting the kinase activity of BCR-ABL. This study evaluated the effectiveness of IM by monitoring 22 CML patients in a chronic phase treated at the CEPON/SC with IM for a minimum follow-up period of two years. Cytogenetic Response (CR) and bone marrow biopsies (BMB) were evaluated before and after IM treatment. BMB were evaluated by detection of reticulin degree and vascularization. The results were correlated to the CR. Mean time to achieve CR was 9 months and was attained by 77.27% of the patients. The results from the initial BMB analysis showed that 59.09% presented reticulin of between 2+ and 4+ whereas after treatment, only 27.17% presented this degree. With regard to vascularization of the initial sample, 90.91% were graded between II and IV, whereas after treatment, 40.91% had this degree. The results suggest a positive correlation of degree of reticulin and vascularization with CR.Uniterms: Chronic myeloid leukemia/treatment. Imatinib mesylate/effectiveness/leukemia treatment. Bone marrow/biopsies. Fibrosis. Vascularization.A Leucemia Mielóide Crônica (LMC) é uma doença mieloproliferativa caracterizada pela presença do cromossomo Filadélfia (translocação entre os cromossomos 9 e 22), que resulta na formação da proteína híbrida BCR-ABL. Atualmente o tratamento de pacientes com LMC é realizado com mesilato de imatinibe (MI), o qual promove a eliminação das células leucêmicas pela inibição da atividade quinase de BCR-ABL. O presente estudo avaliou a eficácia do MI por meio do acompanhamento de pacientes portadores de LMC em fase crônica, atendidos no CEPON/SC tratados com MI pelo tempo mínimo de dois anos. Foram avaliadas a Resposta Citogenética (RC) e as biópsias de medula óssea (BMO) antes e após o tratamento com MI. As BMO foram avaliadas quanto ao grau de reticulina e vascularização. Os resultados correlacionaram-se com a RC cujo tempo médio para obtenção da RC foi de 9 meses, sendo atingida por 77.27% dos pacientes. Na primeira BMO, 59.09% dos pacientes apresentaram grau de reticulina entre 2+ e 4+ e após o tratamento, apenas 27.17% apresentaram esta graduação. Quanto à vascularização da primeira amostra, 90.91% foram graduadas entre II e IV e após o tratamento, 40.91% apresentaram esta graduação. Os resultados sugerem uma correlação diretamente proporcional entre os graus de reticulina e vascularização com a RC.

In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow

“…In previous studies, our group demonstrated that IM acts to decrease the production of reticular fibers produced by stromal cells, suggesting a main activity in fibroblasts. Furthermore, we observed a correlation between fibrosis and vascularization of BM and cytogenetic response in patients with CML 37 .…”

Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital

“…There is a change in the distribution of elements in the extracellular matrix of the bone marrow and it has been suggested that the leukemia cells are protected or "hidden" by these elements. Some studies have shown that IM acts on bone marrow stroma ( 19 , 20 ) . The drug acts by blocking binding to the adenosine triphosphate (ATP), the binding site of the tyrosine kinase domain in the breakpoint cluster region/Abelson (BCR/ABL) protein and has also an independent anti-fibrotic effect in patients with CML.…”

“…The drug acts by blocking binding to the adenosine triphosphate (ATP), the binding site of the tyrosine kinase domain in the breakpoint cluster region/Abelson (BCR/ABL) protein and has also an independent anti-fibrotic effect in patients with CML. However, an increase of fibrosis could prevent the drug to act by not allowing apoptosis of Ph + cells ( 20 ) . A recent study demonstrated a significant correlation between cytogenetic response and the degree of reticulin thickening.…”

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

“…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 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.…”