title: Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia.
abstract: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.
authors.affiliation: Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. waniwani@clin.medic.mie-u.ac.jp
authors.forename: Motoko
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Ritsuro
authors.initials: R
authors.lastname: Suzuki
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Koji
authors.initials: K
authors.lastname: Izutsu
authors.forename: Junji
authors.initials: J
authors.lastname: Suzumiya
authors.forename: Takayuki
authors.initials: T
authors.lastname: Okamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Keisei
authors.initials: K
authors.lastname: Kawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Oshimi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000627:therapeutic use; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000627:therapeutic use; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000517:prevention & control; D054391:Lymphoma, Extranodal NK-T-Cell / Q000188:drug therapy* / Q000517:prevention & control; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D012008:Recurrence
chemical_list: D005047:Etoposide; D003907:Dexamethasone; D001215:Asparaginase; D007069:Ifosfamide; D008727:Methotrexate