Immunoprofile of Patients with Chronic Myeloid Leukemia Treated with Imatinib, Nilotinib or Dasatinib

Autor: Hiroshi Okamura, Masahiro Manabe, Masahiro Yoshida, Mizuki Aimoto, Masayuki Hino, Takako Katayama, Hirohisa Nakamae, Masato Bingo, Mika Nakamae, Mitsutaka Nishimoto, Kiyoyuki Hagihara, Akiko Inaba, Yoshitaka Nakao, Takuro Yoshimura, Takahiko Nakane, Yoshiki Terada, Satoshi Nanno, Yoshiki Hayashi, Hideo Koh
Rok vydání: 2011
Předmět:
Zdroj: Blood. 118:3764-3764
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v118.21.3764.3764
Popis: Abstract 3764 Recent reports showed that dasatinib induces significant immunostimulation with clonal expansion of large granular lymphocytes (LGL) which, in chronic myeloid leukemia (CML), is related to both better prognosis and to autoimmune-like side effects. It is speculated that lower levels of circulating T-regulatory cells play a partial role in LGL proliferation in patients receiving dasatinib. The immunoprofile was studied using flow cytometry to evaluate lymphocyte subsets and NK-cell reactivity in the peripheral blood of 61 patients in the chronic phase of CML during treatment with a tyrosine kinase inhibitor (TKI) (Median age: 58 years; imatinib 36, nilotinib 9, dasatinib 16). Furthermore, we measured plasma levels of 27 types of cytokines or chemokines in 58 patients in the chronic phase of CML so that a comprehensive comparison could be made of the differences in immunoprofile among the patients receiving these three TKIs. There were no significant differences between the three TKI-treated groups in terms of CD4/8 ratios or the number of T-cells (CD3+CD8+ or CD4+) and NK cells (CD3-CD56+). However, the number of NK-LGL (CD56+CD57+) and T-LGL (CD3+CD57+) increased significantly in the group that received dasatinib. Furthermore, dasatinib significantly enhanced NK-cell reactivity as compared to imatinib and nilotinib. In contrast nilotinib significantly suppressed NK-cell reactivity (E/T ratio =10:1: Median (interquartile range), 8.7% (5.0–16.2), 5.2% (4.8–11.4), 20.8% (13.4–33.3), for imatinib, nilotinib and dasatinib, respectively). In addition, the number of regulatory T-cells (CD4+CD25int-hiCD127low) was similar among the three groups (Median (interquartile range), 36/mm3 (27–53), 48/mm3 (34–60), 39/mm3 (26–53), for imatinib, nilotinib and dasatinib, respectively). Furthermore, in the analysis of cytokines and chemokines, plasma levels of IL-8, IP-10, and MCP-1 were significantly elevated while the level of PDGF-bb was significantly decreased in all three groups compared to those of healthy control. Plasma levels of IL-1 beta, IFN-gamma, and FGF-basic were significantly decreased in only the dasatinib group compared to those of control (P=.02, P=.04, P=.03, respectively). In addition, plasma levels of GM-CSF were significantly elevated in the imatinib and dasatinib groups (Median (interquartile range), 6.1 pg/ml (2.7–11.7) and 7.9 pg/ml (4.5–8.2), P=.02, and P=.03, respectively) but not in the nilotinib group (P=.34) when compared to those of control. In the multiple regression analysis that evaluated the relationship between NK-reactivity and cytokines or chemokines in the patients receiving dasatinib, only plasma levels of GM-CSF were significantly associated with NK-reactivity (P=.03). Notably, in our data, dasatinib and nilotinib exerted opposite effects on NK-cell reactivity, expansion of LGL, and showed different cytokine and chemokine profiles. Based on our results, the activation of NK-cell reactivity induced by dasatinib might be caused by a mechanism other than a decrease in the number of regulatory T-cells. Additionally, in an unphysiological immunological status mediated by dasatinib, GM-CSF might make some contribution to NK-cell reactivity. Disclosures: Nakamae: BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Hino:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.
Databáze: OpenAIRE
Externí odkaz: