Dasatinib-induced spleen contraction leads to transient lymphocytosis

Abstract

The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome positive leukemia, including chronic myeloid leukemia (CML). While effective and well tolerated, patients typically exhibit a transient lymphocytosis following dasatinib uptake. The underlying physiological process linking dasatinib to lymphocytosis has remained unknown to date. Here, we used a small rodent model to examine the mechanism of dasatinib-induced lymphocytosis, focusing on lymphocyte trafficking into and out of secondary lymphoid organs (SLO). Our data indicate that lymphocyte homing to lymph nodes (LN) and spleen remained unaffected by dasatinib treatment. In contrast, dasatinib promoted lymphocyte egress from spleen with kinetics consistent with the observed lymphocytosis. Unexpectedly, dasatinib-induced lymphocyte egress occurred independently of canonical sphingosine-1-phosphate-mediated egress signals. Instead, dasatinib treatment led to a decrease in spleen size, concomitant with increased splenic stromal cell contractility as measured by myosin light chain phosphorylation. Accordingly, dasatinib-induced lymphocytosis was partially reversed by pharmacological inhibition of the contraction-promoting factor ROCK. Finally, we uncovered a decrease in spleen size of CML patients who showed lymphocytosis immediately following dasatinib treatment, and this reduction was proportional to the magnitude of lymphocytosis and dasatinib plasma levels. In sum, our work provides evidence that dasatinib-induced lymphocytosis is a consequence of drug-induced contractility of splenic stromal cells.

Transient Stress Lymphocytosis in a Child: A Case Report and Systematic Review of the Literature

“…For completeness, we provide the following summary of the articles that were excluded, as they did not occur in traumatic/emergent settings. TSL was described in splenic contraction secondary to dasatinib [ 14 ], acute illness during chronic lymphocytic leukemia [ 15 ], exposure to catecholamines [ 16 , 17 ] and glucocorticoids [ 18 ], early-phase infection of human immunodeficiency virus [ 19 ], infection with human T-lymphotropic virus type 1 [ 20 ], reactivation of Epstein Barr virus or hepatitis B virus after allogeneic hematopoietic stem cell transplantation [ 21 , 22 ], as an effect of anti-cancer medications such as methotrexate [ 23 ] and tirabrutinib [ 24 ], and in the recovery phase of the recently described multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection [ 25 ]. One case described transient lymphocytosis, but no cause was assigned (idiopathic) [ 26 ].…”