Subject(s)
Cell Transformation, Neoplastic/genetics , Hematopoietic Stem Cells/metabolism , Janus Kinase 2/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Mutation , Polycythemia Vera/complications , Polycythemia Vera/genetics , Aged , Alleles , Amino Acid Substitution , B-Lymphocytes/metabolism , Blood Platelets/metabolism , Cell Lineage , Cell Transformation, Neoplastic/metabolism , Clone Cells , Female , Granulocytes/metabolism , Hematopoietic Stem Cells/pathology , Humans , Janus Kinase 2/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Polycythemia Vera/blood , Polycythemia Vera/metabolism , T-Lymphocytes/metabolism , X Chromosome InactivationABSTRACT
Hematologic toxicity is reported as one of the most important problems connected with imatinib mesylate (IM) treatment in patients with chronic myelogenous leukemia (CML). Withholding the drug or application of growth factors is recommended in this situation. This study introduced a novel approach using intermittent dosage of IM in order to avoid prolonged interruptions in therapy, to allow spontaneous recovery in blood count and, simultaneously, to achieve intermittently therapeutic plasma drug levels. A retrospective analysis of intermittent therapy (iT) in 12 patients with CML is presented. All patients had intermediate-to-high prognostic scores. Two patients had history of autologous stem cell transplantation. Initial standard therapy with IM was indicated for resistance to interferon (eight subjects) and for accelerated phase in four cases (one of them cytogenetic) and lasted for 1 - 6 months. iT with 300 - 600 mg of IM 1 - 5 times a week was started after significant hematologic toxicity occurred. In three patients treated 3 - 5 times a week, hematologic recovery allowed reintroduction of full dose after 3 - 7 (mean 4.6) months. In three patients, one-to-three doses per week were sufficient to maintain the cytogenetic response for a mean of 30.6 months (range 29 - 33). Six patients tolerated more frequent dosage of 4 - 5 times a week for a mean of 17.8 months (range 3 - 28). Five patients improved their cytogenetic response during iT, while hematologic progression occurred in one patient. Development of a cytogenetic abnormality in a Ph-negative clone was observed in one patient. Overall, two complete and five major cytogenetic responses were achieved. The sensitivity of Bcr/Abl kinase to inhibition by IM was proved in seven patients tested by Crkl phosphorylation assay. Measurement of plasma IM concentrations in three subjects showed concentrations fully compatible with the dosage applied suggesting normal intestinal absorption. iT with IM is a feasible and safe strategy for short-time 'bridging' management of patients with significant hematologic toxicity after standard daily dosing. Long-term iT with IM does not seem to compromise the cytogenetic response in patients with sensitivity of Bcr/Abl kinase to IM and should be considered as a plausible treatment option in patients with persistent signs of myelotoxicity.