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Targeting BCR-ABL in Chronic Myelogenous Leukemia
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Radiotherapy, busulfan, hydroxyurea, interferon-alfa and steroids, and allogeneic hematopoietic stem cell transplantation were the major modalities for the treatment of CML before 2001. Targeting the BCR-ABL tyrosine kinase activity with small molecule tyrosine kinase inhibitors (TKI) such as imatinib mesylate (STI-571 or Gleevec) represents a major transformation in the treatment of CML. While most patients benefit from imatinib, a substantial number of patients are either initially refractory (primary resistance) or develop resistance during treatment (acquired resistance). In addition to imatinib, several BCR-ABL tyrosine kinase inhibitors targeting imatinib resistance and/or with more potency have been approved for use in the treatment of CML. However, allogeneic hematopoietic stem cell transplantation remains the only known curative therapy for CML [2].
Hyperkeratotic Reactions
Published in Gabriella Fabbrocini, Mario E. Lacouture, Antonella Tosti, Dermatologic Reactions to Cancer Therapies, 2019
Vincent Sibaud, Maria Vastarella
Nilotinib and dasatinib are second-generation Bcr-Abl tyrosine kinase inhibitors that are approved for the treatment of imatinib-resistant (or -intolerant) chronic myeloid leukemia expressing the Bcr-Abl mutation.
Pulmonary reactions to novel chemotherapeutic agents and biomolecules
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Another BCR-ABL tyrosine kinase inhibitor, dasatinib, is two log more potent than imatinib and has activity against imatinib-resistant Philadelphia chromosome-positive ALL or CML.141 Pleural effusions are the most common pulmonary adverse effect of dasatinib therapy. In a series of 138 patients with CML treated with dasatinib, 48 (35 per cent) developed a pleural effusion, of which 78 per cent were exudative.142 Hypertension, a history of cardiac disease, and use of a twice-daily schedule (rather than once daily) were identified on multivariate analysis as risk factors associated with the development of pleural effusions.
Stachydrine is effective and selective against blast phase chronic myeloid leukaemia through inhibition of multiple receptor tyrosine kinases
Published in Pharmaceutical Biology, 2022
Ruixin Gu, Wei Zhang, Dandan Xu
Chronic myeloid leukaemia (CML) is a haematopoietic malignancy caused by the presence of the fusion gene BCR-ABL in stem/progenitor cells (Sawyers 1999). BCR-ABL encodes a constitutively active tyrosine kinase that leads to upregulation of signal transduction pathways involved in cell survival and growth, such as Ras/MEK/MAPK and PI3K/AKT (Ren 2005). The introduction of BCR-ABL tyrosine kinase inhibitors (TKIs, e.g., imatinib, dasatinib and ponatinib) that bind to the ATP-binding site of Abl, has led to a remarkable clinical response to treat CML. However, patients develop resistance to TKIs and progress to blast phase (BP). Mutations in the Abl kinase domain and Bcr-Abl protein overexpression are the main mechanisms that contribute to TKI resistance (Perrotti et al. 2010; Corbin et al. 2011). Therefore, identification of agents that overcome TKI resistance is needed to improve clinical response in blast phase chronic myeloid leukaemia (BP-CML) patients.
Physician risk perceptions and surveillance practices for tyrosine kinase inhibitor long-term effects in pediatric CML
Published in Pediatric Hematology and Oncology, 2022
Stephanie M. Smith, Shiqi Zhang, Vandana Sundaram, Michael Roth, Jeffrey R. Andolina, Lidia Schapira, Kathleen M. Sakamoto, E. Anders Kolb, Nobuko Hijiya, Sonali Chaudhury
Chronic myeloid leukemia (CML) is diagnosed in 1–3 per million children and adolescents and 5–7 per million young adults (ages 20–29 years) annually in the United States.1 While CML accounts for less than 10% of pediatric leukemias,2 the prevalence is increasing due to high survival rates with modern targeted treatment. BCR-ABL tyrosine kinase inhibitors (TKIs), which target the oncogene driving CML, have revolutionized treatment. Most patients are treated with single-agent oral TKIs (e.g., imatinib or dasatinib) and do not require intensive chemotherapy or hematopoietic stem cell transplantation. Although treatment-free remission is attainable for about 50% of adults with CML who have an optimal response to TKI, stopping is not recommended for children and adolescents outside clinical trials.3,4 Thus, children and adolescents with CML are exposed to TKI therapy chronically and require years, even decades, of treatment.
Characterization of anticancer drug resistance by reverse-phase protein array: new targets and strategies
Published in Expert Review of Proteomics, 2022
Ann M. Cathcart, Hannah Smith, Marilyne Labrie, Gordon B. Mills
In the past, precision oncology has been fueled by the prospect that identification of a driver mutation in a patient’s cancer would guide paring that patient with a molecular targeted therapy specially matched to their mutation, and that attacking each tumor’s particular Achilles’ heel would provide a durable response, if not a cure. The early success of imatinib, a BCR-ABL tyrosine kinase inhibitor specifically paired to the constitutive activation of BCR-ABL in chronic myeloid leukemia which saw 98% complete response in its inaugural phase 1 trial [150], spurred hope for this notion of precision oncology. With a handful of additional exceptional examples, imatinib has been an outlier, and most targeted therapies, even when prescribed on the basis of a matched molecular marker, are not cures and indeed durable responses are rare. A meta-analysis of 346 phase 1 oncology trials has found that biomarker-based patient selection is associated with improved response rate (30.6% vs 4.9% of patients not selected on the basis of a biomarker) and improved PFS (5.7 vs 2.95 months); but these humble figures, and in particular the short PFS as a result of emergence of resistance – even with biomarker-based selection – underscore how much is left to be achieved in precision oncology [151].