Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib

Abstract

Immunomodulation induced by dasatinib is reportedly related to better prognosis in chronic myeloid leukemia (CML). However, the underlying mechanism has not yet been fully elucidated. The immunoprofiles of 63 patients in the chronic phase of CML were evaluated during treatment with a tyrosine kinase inhibitor (imatinib, n = 36; nilotinib, n = 9; dasatinib, n = 18). The numbers of CD56 + CD57 + and CD3 + CD57 + cells increased significantly in the dasatinib group. The numbers of regulatory T-cells were comparable among the three groups. Dasatinib markedly enhanced natural killer (NK)-cell reactivity. Only one patient treated with dasatinib showed a slight cytomegalovirus (CMV) reactivation. In contrast, nilotinib suppressed NK-cell reactivity. Plasma levels of interleukin-8 (IL-8), interferon-γ inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in all three groups, and plasma levels of granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly elevated in the imatinib and dasatinib groups. Our results suggest the presence of a mechanism for dasatinib-associated immunomodulatory effects that is distinct from CMV reactivation and a decreased number of regulatory T-cells.

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

“…In addition, dasatinib reduces the adhesion of neutrophils to blood endothelium, perhaps contributing to the increased accumulation of these cells in blood over the course of the treatment and accounting for the observed increased granulocyte counts (29). The secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) has also been shown to be increased by dasatinib treatment (30). Previously, Fraser and colleagues (31) reported that a higher dose of dasatinib (25 mg/kg/day) reduced the number of extrapulmonary B16.OVA metastases compared with a lower dose (5 mg/kg/day).…”

Monoclonal antibody targeting of IL-3 receptor α with CSL362 effectively depletes CML progenitor and stem cells

“…1 of CML patients, collected at the time of diagnosis, were incubated for 4 hours with NK cells, isolated from the same patients after achieving complete cytogenetic response (see Table 1 Of note, dasatinib, in contrast to nilotinib, inhibited NK cell function in ADCC assays, most likely because of inhibition of Src family kinases as reported previously. 38,39 In vivo dasatinib treatment, in contrast, might cause positive immune-modulatory effects, such as enhanced NK cell activity 40 and clonal expansion of large granular lymphocytes. 41,42 Accordingly, NK cells isolated from 2 dasatinib-treated patients did not show any deficit in conferring CSL362-mediated ADCC.…”

The longitudinal analysis of large granular lymphocytosis in patients with Philadelphia chromosome-positive leukemia treated with dasatinib

“…Local accumulation of Tregs in malignant tissue or a higher proportion of Tregs in peripheral blood has been reported in a variety of tumors from different tissues and organs, and these higher Treg activities have been associated with poor clinical outcomes [24][25][26]. Mustjoki et al [10] revealed that dasatinib-treated patients with LGL lymphocytosis exhibited a lower proportion of Tregs in peripheral blood, and others examined the differences of Treg ratios among TKIs, with conflicting results [18,20]. In our study, there were no differences in the proportion of Treg cells between dasatinib-treated patients and patients treated with other TKIs.…”

“…Second-generation TKIs, especially dasatinib, not only show potent inhibitory effects for the target kinase (ABL), but also possess many off-target effects, which could be responsible for the different properties and adverse event profiles of each TKI [3,4]. Among these, the immunomodulatory effects of dasatinib have been of principal interest and the subject of vigorous investigation as the effects might directly influence the clinical outcome [13,[18][19][20].…”