STI571 (Imatinib Mesylate) Reduces Bone Marrow Cellularity
STI571 (Imatinib Mesylate) Reduces Bone Marrow Cellularity
The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibit features resembling normal hematopoiesis.
Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by a reciprocal chromosomal translocation involving chromosomes 9 and 22, t(9;22). The translocation fuses the bcr and abl genes, resulting in constitutive expression of a chimeric protein, bcr-abl, with enhanced tyrosine kinase activity. The effects of this kinase activation may include prolonged and growth factor-independent proliferation, defective adhesion, and reduced apoptosis of hematopoietic cells. The inhibitory molecule STI571 binds to the adenosine triphosphate binding site of the abl and bcr-abl tyrosine kinases and maintains them in an inactive conformation. STI571 is an effective treatment for patients with CML in the chronic phase; it induces hematologic remission in nearly all patients and cytogenetic responses in many. Although in vitro studies have demonstrated selective killing of CML hematopoietic cells by STI571, presumably resulting from bcr-abl kinase inhibition, its precise mechanism of action in vivo is still unclear. Moreover, its effects on the differentiation and growth of normal and CML hematopoietic cells are unknown. STI571 inhibits at least 2 other related tyrosine kinases, the platelet-derived growth factor receptor and c-kit, both of which are expressed in normal bone marrow.
The bone marrow in CML characteristically shows marked hypercellularity, an elevated myeloid/erythroid ratio, and frequently an increase in megakaryocytes with clustering and hypolobation of nuclei. There often is variable reticulin fibrosis. These features likely are due in part to abnormal differentiation of CML hematopoietic progenitors mediated by bcr-abl kinase activity. The fibrogenic effects of CML may result from contact-mediated effects of bcr-abl hematopoietic cells on bcr-abl- marrow stromal cells as well as production of platelet-derived growth factor by CML cells. To assess the effects of bcr-abl kinase inhibition on bone marrow involved by CML, we examined the morphologic features of sequential samples of bone marrow of patients with CML who were receiving STI571 therapy. We correlated the morphologic changes with the persistence of CML cells as assessed by concomitant karyotyping of these samples.
The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibit features resembling normal hematopoiesis.
Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by a reciprocal chromosomal translocation involving chromosomes 9 and 22, t(9;22). The translocation fuses the bcr and abl genes, resulting in constitutive expression of a chimeric protein, bcr-abl, with enhanced tyrosine kinase activity. The effects of this kinase activation may include prolonged and growth factor-independent proliferation, defective adhesion, and reduced apoptosis of hematopoietic cells. The inhibitory molecule STI571 binds to the adenosine triphosphate binding site of the abl and bcr-abl tyrosine kinases and maintains them in an inactive conformation. STI571 is an effective treatment for patients with CML in the chronic phase; it induces hematologic remission in nearly all patients and cytogenetic responses in many. Although in vitro studies have demonstrated selective killing of CML hematopoietic cells by STI571, presumably resulting from bcr-abl kinase inhibition, its precise mechanism of action in vivo is still unclear. Moreover, its effects on the differentiation and growth of normal and CML hematopoietic cells are unknown. STI571 inhibits at least 2 other related tyrosine kinases, the platelet-derived growth factor receptor and c-kit, both of which are expressed in normal bone marrow.
The bone marrow in CML characteristically shows marked hypercellularity, an elevated myeloid/erythroid ratio, and frequently an increase in megakaryocytes with clustering and hypolobation of nuclei. There often is variable reticulin fibrosis. These features likely are due in part to abnormal differentiation of CML hematopoietic progenitors mediated by bcr-abl kinase activity. The fibrogenic effects of CML may result from contact-mediated effects of bcr-abl hematopoietic cells on bcr-abl- marrow stromal cells as well as production of platelet-derived growth factor by CML cells. To assess the effects of bcr-abl kinase inhibition on bone marrow involved by CML, we examined the morphologic features of sequential samples of bone marrow of patients with CML who were receiving STI571 therapy. We correlated the morphologic changes with the persistence of CML cells as assessed by concomitant karyotyping of these samples.