title: Fludarabine and bendamustine in refractory and relapsed indolent lymphoma--a multicenter phase I/II Trial of the east german society of hematology and oncology (OSHO).
abstract: The therapy of patients with relapsed or refractory indolent lymphoma relies on the development of new drug combinations. The drugs bendamustine and fludarabine have cytotoxic activity as monotherapy in indolent lymphoma and show synergism in vitro. In this study, we combined both drugs in a multicenter clinical phase I/II trial to evaluate their toxicity and efficacy. Bendamustine was given at 30 or 40 mg/m2/d (dose levels 1 and 2), fludarabine at 30 mg/m2/d, each drug on days 1 to 3. Six cycles were to be given every 4 weeks. A total of 29 patients with relapsed or refractory indolent lymphoma were included in the study. During phase I, 9 patients were treated at dose level 1 and 7 patients at dose level 2. Thirteen patients were added to the study during phase II. Fourteen patients had follicular lymphoma, 11 patients mantle cell lymphoma, 2 patients lymphoplasmocytic and 2 patients nodal marginal zone lymphoma. Median age was 62 years (range 39-74). All patients were in stages III or IV of their disease and had received prior chemotherapy with or without additional radio- or immunotherapy. The dose limiting toxicity was hematotoxicity in all cases and occurred in 3 of 7 evaluable patients at dose level I and in 3 of 7 patients at dose level 2. One patient at dose level 2 died of sepsis in neutropenia with persistent thrombocytopenia. The study was continued at dose level 1 (phase II). Analysis of 19 evaluable patients treated at dose level 1 reveiled hematotoxicity CTC grade III in 47% and grade IV in 26%. Neutropenic fever occurred in 4 patients (21%). On an intent-to-treat basis, 45% or 32% of all patients at dose level 1 reached CR or PR, respectively. Nine of 9 patients with mantle cell lymphoma responded to therapy. The overall response rate was 77%. Eight of 15 responders relapsed after a median follow-up time of 14 months (range 2-43). The major complication of fludarabine in combination with bendamustine is hematotoxicity. Dose level 1 with 30 mg/m2/d of both drugs on days 1 to 3 was defined as the recommended dose. Despite unfavorable prognostic features (histologic subtype, stage of disease, pretreatment) response rates were good with this regimen.
authors.affiliation: Hematology/Oncology Departments, University Magdeburg, Germany. Michael.Koenigsmann@medizin.uni-magdebrug.de
authors.forename: Michael
authors.initials: M
authors.lastname: Koenigsmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Knauf
authors.forename: Michael
authors.initials: M
authors.lastname: Herold
authors.forename: Rita
authors.initials: R
authors.lastname: Pasold
authors.forename: Gerd
authors.initials: G
authors.lastname: Müller
authors.forename: Henning
authors.initials: H
authors.lastname: Eschenburg
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahl
authors.forename: Volker
authors.initials: V
authors.lastname: Lakner
authors.forename: Michael
authors.initials: M
authors.lastname: Assmann
authors.forename: Kathleen
authors.initials: K
authors.lastname: Jentsch-Ullrich
authors.forename: Martin
authors.initials: M
authors.lastname: Mohren
authors.forename: Rainer
authors.initials: R
authors.lastname: Bartsch
authors.forename: Astrid
authors.initials: A
authors.lastname: Franke
mesh_terms: D000328:Adult; D000368:Aged; D000069461:Bendamustine Hydrochloride; D005260:Female; D005858:Germany; D006405:Hematology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008495:Medical Oncology; D008875:Middle Aged; D009367:Neoplasm Staging; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D012955:Societies, Medical; D013997:Time Factors; D014740:Vidarabine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*
chemical_list: D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine