title: Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up--a report from the Eastern Cooperative Oncology Group.
abstract: OBJECTIVE
  To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma.
  
  
  METHODS
  Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1, 000 mg/m(2). Fludarabine 20 mg/m(2) was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required.
  
  
  RESULTS
  Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m(2)), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively.
  
  
  CONCLUSIONS
  The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1, 000 mg/m(2) day 1 and fludarabine 20 mg/m(2) days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.
authors.affiliation: New York University, New York, NY, USA. howard.hochster@med.nyu.edu
authors.forename: H S
authors.initials: HS
authors.lastname: Hochster
authors.forename: M M
authors.initials: MM
authors.lastname: Oken
authors.forename: J N
authors.initials: JN
authors.lastname: Winter
authors.forename: L I
authors.initials: LI
authors.lastname: Gordon
authors.forename: B G
authors.initials: BG
authors.lastname: Raphael
authors.forename: J M
authors.initials: JM
authors.lastname: Bennett
authors.forename: P A
authors.initials: PA
authors.lastname: Cassileth
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine