title: Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study.
abstract: Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.
authors.affiliation: Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Iriyama
authors.affiliation: Department of Hematology, Yokohama City University Medical Center, Kanagawa, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Fujisawa
authors.affiliation: Department of Hematology, National Hospital Organization, Mito Medical Center, Ibaraki, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Yoshida
authors.affiliation: Division of Hematology and Oncology, Japanese Red Cross Society, Narita Red Cross Hospital, Narita, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wakita
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Hematology and Clinical Oncology, Kagawa Prefectural Central Hospital, Kagawa, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takezako
authors.affiliation: Department of Hematology, Ohme Municipal General Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Koiti
authors.initials: K
authors.lastname: Inokuchi
authors.affiliation: Department of Hematology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.affiliation: Department of Hematology, Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Taguchi
authors.affiliation: Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yano
authors.affiliation: Division of Hematology and Oncology, Gunma Prefectural Cancer Center, Gunma, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: Department of Hematology, Tokyo Metropolitan Tama Synthesis Medical Center, Tokyo, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Kouzai
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Tokai Central Hospital, Gifu, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sakamaki
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008218:Lymphocytosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012372:ROC Curve; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib