The longitudinal analysis of large granular lymphocytosis in patients with Philadelphia chromosome-positive leukemia treated with dasatinib.
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.
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan. yshimura@koto.kpu-m.ac.jp.
Yuji
http://orcid.org/0000-0001-9309-7902
Y
Shimura
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.|Department of Blood Transfusion and Cell Therapy, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Shigeo
S
Horiike
Division of Hematology, Department of Medicine, Kyoto First Red Cross Hospital, Kyoto, Japan.
Yasuhiko
Y
Tsutsumi
Division of Hematology, Department of Medicine, Kyoto Kuramaguchi Medical Center, Kyoto, Japan.
Mayumi
M
Hatsuse
Division of Hematology, Department of Medicine, Kyoto Kuramaguchi Medical Center, Kyoto, Japan.
Akira
A
Okano
Division of Hematology, Department of Medicine, Kyoto Kuramaguchi Medical Center, Kyoto, Japan.
Shin-Ichi
S
Fuchida
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
Tsutomu
T
Kobayashi
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
Yosuke
Y
Matsumoto
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
Junya
J
Kuroda
Division of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, Japan.
Eri
E
Kawata-Iida
Division of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, Japan.
Hitoji
H
Uchiyama
Division of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, Japan.
Nobuhiko
N
Uoshima
Division of Hematology, Department of Medicine, Kyoto Kuramaguchi Medical Center, Kyoto, Japan.
Chihiro
C
Shimazaki
Division of Hematology, Department of Medicine, Kyoto First Red Cross Hospital, Kyoto, Japan.
Hiroto
H
Kaneko
Division of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, Japan.
Yutaka
Y
Kobayashi
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
Masafumi
M
Taniwaki
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes; D000069439:Dasatinib / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D054066:Leukemia, Large Granular Lymphocytic / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000097:blood / Q000235:genetics
D016692:Receptors, Antigen, T-Cell, gamma-delta; D000069439:Dasatinib
Clonality; Dasatinib; LGL; Regulatory T cell