title: Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study.
abstract: Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD), which are unaffected by MDR1-encoded P-glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2-yr period. The median age was 63 yr. Eleven patients had T/NK-cell malignancies, six had B-cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged >/=60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment-related death because of systemic mucormycosis was observed in one patient. Major treatment-related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose-limiting toxicity. The most common grade 3 non-hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK-cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK-cell malignancies should be further evaluated.
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsukune
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Isobe
authors.forename: Hajime
authors.initials: H
authors.lastname: Yasuda
authors.forename: Seiichi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yuna
authors.initials: Y
authors.lastname: Katsuoka
authors.forename: Masaru
authors.initials: M
authors.lastname: Hosone
authors.forename: Kazuo
authors.initials: K
authors.lastname: Oshimi
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001215:Asparaginase / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009091:Mucormycosis / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D010865:Pilot Projects
chemical_list: D001215:Asparaginase; D007069:Ifosfamide; D008727:Methotrexate