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

Abstract

Dasatinib, a 2nd-generation tyrosine kinase inhibitor (TKI), can specifically induce large granular lymphocytes (LGL) in some patients with Philadelphia chromosome (Ph)-positive leukemia. To investigate the properties of the induced LGLs, we performed prospective and longitudinal analyses. From Feb 2011 to Jan 2013, a total of 17 patients with Ph-positive leukemia who were previously untreated or refractory to imatinib were enrolled. T cell receptor (TCR)-γ/δ gene rearrangements and phenotypic profiles of lymphocytes were examined before and during administration of dasatinib. LGL lymphocytosis was observed in half of the dasatinib-treated cases (LGL+ group), showing a relation to increased achievement of complete cytogenetic response within 6 months. The phenotypes of the increased lymphocytes were revealed to be mostly natural killer cells. In the LGL+ group, clonal TCR-γ gene rearrangements were frequently detected at diagnosis (six of nine cases) and persisted during therapy, compared with only two of eight in the LGL- group. The proportion of regulatory T cells to CD4+ T cells at diagnosis was lower in the LGL+ compared with the LGL- group (median 4.2 vs. 6.6 %), and this disparity was sustained throughout the therapeutic period. These results demonstrate that immunological condition at diagnosis may affect LGL lymphocytosis in some dasatinib-treated patients.

• Authors: Yuji Shimura, Shigeo Horiike, Yasuhiko Tsutsumi, Mayumi Hatsuse, Akira Okano, Shin-Ichi Fuchida, Tsutomu Kobayashi, Yosuke Matsumoto, Junya Kuroda, Eri Kawata-Iida, Hitoji Uchiyama, Nobuhiko Uoshima, Chihiro Shimazaki, Hiroto Kaneko, Yutaka Kobayashi, Masafumi Taniwaki
• Journal: International journal of hematology (Int J Hematol) Vol. 102 Issue 4 Pg. 426-33 (Oct 2015) ISSN: 1865-3774 [Electronic] Japan
• PMID: 26267232 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Antigen, T-Cell, gamma-delta
• Dasatinib

Topics

• Adult
• Aged
• CD4-Positive T-Lymphocytes
• Dasatinib (administration & dosage)
• Female
• Follow-Up Studies
• Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
• Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
• Humans
• Killer Cells, Natural (metabolism)
• Leukemia, Large Granular Lymphocytic (blood, drug therapy, genetics)
• Male
• Middle Aged
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy, genetics)
• Receptors, Antigen, T-Cell, gamma-delta (blood, genetics)