ABSTRACT
In the present report, we address the question if the reduction of standard dosage of imatinib mesylate (IM) in imatinib-intolerant chronic myeloid leukemia (CML) patients with undetectable residual disease may impair their outcome. Four patients are described. The median follow up from the beginning of IM therapy was 35 months (33-59). The median duration of real-time quantitative polymerase chain reaction (RQ-PCR) negativity on IM 200 mg daily was 17 months (4-37). We hypothesize that in IM intolerant CML patients with complete molecular remission, the compound dosage might be safely reduced to a lower than standard dose without to lose the response. A tight molecular monitoring of such patients should be required.
Subject(s)
Antineoplastic Agents/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Benzamides , Female , Follow-Up Studies , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Middle Aged , Monitoring, Physiologic , Neoplasm, Residual , Piperazines/adverse effects , Pyrimidines/adverse effects , Remission Induction , Reverse Transcriptase Polymerase Chain ReactionSubject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Graft vs Host Disease/prevention & control , Immunosuppressive Agents/therapeutic use , Lymphoma, B-Cell/drug therapy , Steroids/therapeutic use , Adult , Antibodies, Monoclonal, Murine-Derived , Chronic Disease , Graft vs Host Disease/drug therapy , Humans , Male , RituximabABSTRACT
Chronic myelogenous leukemia is caused by the Bcr-Abl hybrid gene that encodes the p210Bcr-Abl chimeric oncoprotein. Although it reduces the total body burden of leukemia cells, the use of imatinib mesylate as a single agent may be accompanied by the evolution of resistance due mainly to the acquisition of point mutations. Imatinib has been combined with drugs that inhibit both the active and the inactive states of the p210Bcr-Abl kinase. These combinations have reduced but not completely eliminated the rate at which point mutations are acquired in the p210Bcr-Abl kinase. Thus, it is important to identify additional new inhibitors of the p210Bcr-Abl kinase. One possible method to prevent evolution of resistance is to simultaneously use multiple kinase inhibitors each with a different mechanism of action. To identify such a new class of inhibitors that could suppress the growth of chronic myelogenous leukemia cells and prevent the evolution of cells that are resistant to imatinib, we screened two low-complexity libraries of compounds based on planar and linear scaffolds. These libraries were screened using a cell-based assay for molecules that suppress p210Bcr-Abl-dependent cell growth. The application of this method resulted in the isolation of two new classes of drugs, both of which inhibited imatinib-resistant cells in the low micromolar range. Some of these drugs were potent inhibitors not only of Abl tyrosine kinase but also of the Src, Lyn, and Fyn tyrosine kinases.
Subject(s)
Alkynes/pharmacology , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/pharmacology , gamma-Aminobutyric Acid/analogs & derivatives , Alkynes/chemistry , Benzamides , Furans/chemistry , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , Proto-Oncogene Proteins c-fyn/antagonists & inhibitors , Tumor Cells, Cultured/drug effects , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacology , src-Family Kinases/antagonists & inhibitorsABSTRACT
Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily. In this brief review, we discuss the current tools for the effective management of chronic myeloid leukemia with Imatinib, providing the updated results of IRIS and RIGHT clinical trials and then the suggestions how Imatinib-treated patients should be monitored.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Benzamides , Clinical Trials as Topic , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , Leukemia, Myeloid, Chronic-Phase/metabolism , Piperazines/administration & dosage , Piperazines/adverse effects , Practice Guidelines as Topic , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , Pyrimidines/adverse effectsABSTRACT
Contamination of autologous graft by tumor, in addition to incomplete tumor eradication, can partly explain why relapse remains the commonest cause of treatment failure after autologous stem cell transplantation (ASCT) in patients with malignant hematologic disorders. Monitoring of minimal residual disease (MRD) is now recognized as an important diagnostic tool for assessment either of the response to treatments aimed at maximal cytoreduction and the individual risk of relapse. In order to improve cure rates, many strategies to achieve in vivo or in vitro reduction, if not eradication, of residual disease have been proposed. We discuss the significance of MRD and the role of purging in the ASCT setting, focusing on acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma and follicular lymphoma.
