A Comprehensive Lymphocyte Analysis of Dasatinib Treated Chronic Myelogenous Leukemia Patients Reveals T-Cell Oligoclonality.

On the forefront of targeted cancer therapy are second generation tyrosine kinase inhibitors (TKIs) which impact the outcome of chronic, accelerated, and blast phase chronic myelogenous leukemia (CML). Among these TKIs dasatinib is particularly effective for the treatment of imatinib-resistant Philadelphia chromosome-positive CML; although this drug has been associated with the generation of pleural effusions, fevers, and colitis in some patients. Recent data links these side effects to oligoclonal expansions of large granular lymphocyte (LGL) immunophenotype. To further characterize these events we conducted a comprehensive immunophenotye, T-cell receptor variable region, KIR, and HLA analysis of seven CML patients receiving dasatinib, two of which developed adverse reactions in association with lymphocytosis. Flow cytometric analysis confirmed these proliferative events and elucidated a previously undescribed CD3-CD8+CD56+ population. In addition, we identified multiple patients with decreased CD4 to CD8 T-cell ratios and a shift in CD4+ and CD8+ lymphocyte populations towards an effector and terminal memory phenotype (CD62L-CD45RA-and CD62L-CD45RA+ respectively). Further analysis of the T-cell receptor beta chain showed that all seven patients had oligoclonal populations of either CD4 or CD8 T-cells significantly greater than that of healthy donors. Most of these findings were independent of the occurrence of adverse reactions. All in all our data implicates dasatinib in generating oligoclonal lymphocyte expansions of various phenotypes in all CML patients. It is still unclear as to the underlying molecular mechanisms inducing these expansions, but further exploration could help to prevent or alleviate these reactions and could conceivably provide new tools for future directed immunotherapy.