Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome
05 Apr 2001-The New England Journal of Medicine (Massachussetts Medical Society)-Vol. 344, Iss: 14, pp 1038-1042
TL;DR: The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.
Abstract: Background BCR-ABL, a constitutively activated tyrosine kinase, is the product of the Philadelphia (Ph) chromosome. This enzyme is present in virtually all cases of chronic myeloid leukemia (CML) throughout the course of the disease, and in 20 percent of cases of acute lymphoblastic leukemia (ALL). On the basis of the substantial activity of the inhibitor in patients in the chronic phase, we evaluated STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase, in patients who had CML in blast crisis and in patients with Ph-chromosome–positive ALL. Methods In this dose-escalating pilot study, 58 patients were treated with STI571; 38 patients had myeloid blast crisis and 20 had ALL or lymphoid blast crisis. Treatment was given orally at daily doses ranging from 300 to 1000 mg. Results Responses occurred in 21 of 38 patients (55 percent) with a myeloid-blast-crisis phenotype; 4 of these 21 patients had a complete hematologic response. Of 20 patients with lymphoid blast crisis ...
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TL;DR: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Abstract: Background BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic res...
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References
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TL;DR: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Abstract: Background BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. Methods We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic res...
5,037 citations
TL;DR: A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein and it was found that this compound may be useful in the treatment of bcr–abl–positive leukemias.
Abstract: The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
3,616 citations
TL;DR: This work has demonstrated that CML can be curable through immune-mediated elimination of leukemia cells by allogeneic T lymphocytes, and specific inhibition of signal transduction by the tyrosine kinase Bcr-Abl has been found to be active in managing the disease.
Abstract: Over the past twenty years, clinical and laboratory studies have led to important new insights into the biology of chronic myeloid leukemia. Basic science has defined the molecular pathogenesis of chronic myeloid leukemia (CML) as unregulated signal transduction by the Bcr-Abl tyrosine kinase. Clinical studies have demonstrated that CML can be curable through immune-mediated elimination of leukemia cells by allogeneic T lymphocytes. Recently, specific inhibition of signal transduction by the tyrosine kinase Bcr-Abl has been found to be active in managing the disease.
1,603 citations
TL;DR: Although heterogeneous, CML is the best-characterized leukemia at a molecular level, and studies in recent years have helped to define further.
Abstract: Chronic myeloid leukemia (CML) is a clonal myeloproliferative expansion of transformed, primitive hematopoietic progenitor cells. It involves myeloid, monocytic, erythroid, megakaryocytic, B-lymphoid, and occasionally T-lymphoid lineages.1 CML was the first human disease in which a specific abnormality of the karyotype — the Philadelphia (Ph) chromosome — could be linked to pathogenetic events of leukemogenesis.2 It was among the first neoplastic diseases in which therapy with a biologic agent (interferon) was found to suppress the leukemic clone and prolong survival.3 Although heterogeneous, CML is the best-characterized leukemia at a molecular level, and studies in recent years have helped to define further . . .
1,251 citations
Journal Article•
TL;DR: An inhibitor (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phenylaminopyrimidine class is described, which is highly active in vitro and in vivo and may have therapeutic potential for the treatment of diseases that involve abnormal cellular proliferation induced by Abl protein-tiesine kinase deregulation or PDGF receptor activation.
Abstract: Oncogenic activation of Abl proteins due to structural modifications can occur as a result of viral transduction or chromosomal translocation The tyrosine protein kinase activity of oncogenic Abl proteins is known to be essential for their transforming activity Therefore, we have attempted to identify selective inhibitors of the Abl tyrosine protein kinase Herein we describe an inhibitor (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phenylaminopyrimidine class, which is highly active in vitro and in vivo Submicromolar concentrations of the compound inhibited both v-Abl and PDGF receptor autophosphorylation and PDGF-induced c-fos mRNA expression selectively in intact cells In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I, and insulin showed no or weak inhibition by high concentrations of CGP 57148 c-fos mRNA expression induced by EGF, fibroblast growth factor, or phorbol ester was also insensitive to inhibition by CGP 57148 In antiproliferative assays, the compound was more than 30-100-fold more potent in inhibiting growth of v-abl-transformed PB-3c cells and v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/MK cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line Furthermore, anchorage-independent growth of v-abl- and v-sis-transformed BALB/c 3T3 cells was inhibited potently by CGP 57148 When tested in vivo, CGP 57148 showed antitumor activity at tolerated doses against tumorigenic v-abl- and v-sis-transformed BALB/c 3T3 cells In contrast, CGP 57148 had no antitumor activity when tested using src-transformed BALB/c 3T3 cells These findings suggest that CGP 57148 may have therapeutic potential for the treatment of diseases that involve abnormal cellular proliferation induced by Abl protein-tyrosine kinase deregulation or PDGF receptor activation
1,138 citations