title: Phase II study of fludarabine and alpha-interferon in patients with low-grade non-Hodgkin's lymphoma.
abstract: OBJECTIVE
  Low-grade non-Hodgkin's lymphoma (NHL) remains incurable with standard dose chemotherapy. Nucleoside analogs such as fludarabine are effective, but even when used as initial therapy, the median duration of remission ranges from only 16 to 24 months. Interferon (IFN) is also active and has been investigated both by incorporating it into the chemotherapy regimen and/or as maintenance therapy, where it may prolong remission. We designed a phase II trial of alternating fludarabine and IFNalpha2a to determine response rate, time to progression and toxicity of this regimen in patients with advanced stage low-grade NHL or mantle cell lymphoma.
  
  
  METHODS
  Patients had received 0-2 prior regimens that did not include nucleoside analogs or IFN and had adequate organ function. Fludarabine was administered intravenously at 25 mg/m2/day for 5 days once every 6 weeks with IFN in weeks 4 and 5 at 3x10(6) U/m2 subcutaneously three times weekly for 6 doses. Treatment continued in responders for 2 cycles past maximal response (minimum 6 cycles). No maintenance was given.
  
  
  RESULTS
  Between 1994 and 1999, 31 patients were accrued and were evaluable for toxicity, with 29 eligible for evaluation of response. Toxicity was primarily myelosuppression, with grade 3 neutropenia in 12 patients and grade 4 thrombocytopenia in one patient. The overall response rate was 51.7% (15/29), including 6 complete and 9 partial responses. With a median follow-up of 35.6 months, the median overall survival was 60.8 months, and the median time to disease progression (TTP) was 12.6 months. Of the 15 responding patients, treatment-naive patients had a median response duration of 39.6 months with a median TTP of 42.1 months, while the median response duration was 5.2 months with a median TTP of 14.5 months in patients who had received prior treatment (p=0.0065 and 0.0374, respectively).
  
  
  CONCLUSIONS
  This schedule of alternating fludarabine with IFN does not seem to increase response rate appreciably, but there are some prolonged responses, particularly in previously untreated patients. Given the non-overlapping toxicities of IFN with those of chemotherapy and antibody-based therapeutics, there may be a role for combination therapies, especially if the biological basis of response to IFN can be elucidated.
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Morris
authors.forename: Michael M
authors.initials: MM
authors.lastname: Millenson
authors.forename: Kristin
authors.initials: K
authors.lastname: Padavic-Shaller
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Andre
authors.initials: A
authors.lastname: Rogatko
authors.forename: James
authors.initials: J
authors.lastname: Clyde
authors.forename: Robert L
authors.initials: RL
authors.lastname: Boyd
authors.forename: Gwen
authors.initials: G
authors.lastname: Yeslow
authors.forename: Theresa
authors.initials: T
authors.lastname: Halbherr
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D015993:Life Tables; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011994:Recombinant Proteins; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014740:Vidarabine; C024352:fludarabine