Fludarabine, Mitoxantrone and Rituximab in Relapsed or Primary Failing Advanced Follicular Non-Hodgkin's Lymphoma
Condition: Follicular Lymphoma
MeSH terms: Lymphoma; Lymphoma, Follicular; Lymphoma, Non-Hodgkin
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is a multicentric trial evaluating the efficacy of the RFM regimen in patients
      aged 18 to 75 years with relapsed/refractory follicular non-Hodgkin's lymphoma (NHL).
    

Detailed description: 
      Follicular non Hodgkin's lymphoma's (FL), as defined by the Revised European American
      Lymphoma Classification (REAL) Classification, are usually characterized by a slowly
      progressive clinical course, a transient control by standard chemotherapeutic regimen and a
      pattern of repeated relapses until ultimately progressive and fatal disease.

      Standard first line treatment for advanced FL consists of alkylating-based (CVP) or
      anthracycline containing regimen in association to interferon alpha (CHVP+IFN) chemotherapy.
      Others approaches have been developed mostly as secondary therapy including purine analogs
      alone or in combination with alkylators or mitoxantrone, high dose therapy with autologous
      peripheral stem cell transplantation and, more recently, treatment with the unconjugated
      chimeric anti-CD20 antibody (rituximab) to target the CD20 antigen highly expressed on
      follicular lymphoma cells. None of these strategies does appear to give a definitive survival
      advantage. Thus, in patients with FL, the design of novel combination programs is a major
      challenge.

      Combination of fludarabine and mitoxantrone in low grade, predominantly Follicular NHL:
      results of phase II studies in relapsed or refractory patients Fludarabine is expected to
      potentiate other agents through inhibition of DNA polymerase alpha and DNA ligase and its
      consequent interference with the DNA repair process. The addition of mitoxantrone increases
      the cytotoxic effect of fludarabine in vitro. McLaughlin et al developed a combination of
      fludarabine, mitoxantrone and dexamethasone (FND), which was very effective in 51 patients
      with recurrent low-grade lymphoma (including 65% FL), with an overall response rate of 94%
      (47% complete response (CR) rate. The median duration of response in this phase II study was
      21 months for CR patients but only 9 months for partial responders (PR) patients. The median
      survival and failure-free survival times from the time of entry onto the FND study were 34
      and 14 months, respectively. Most major responses were evident after two to four courses of
      chemotherapy. The need for continuation of therapy beyond attainment of remission is
      suggested by early relapses among patients who had early discontinuation of therapy. The
      predominant toxic effects were myelosuppression and infections: neutropenia < 500/µl in 20 %
      of courses, thrombopenia < 50000/µl in 8 % of courses and infections in 12 % of courses.
      Non-hematological toxicity was modest.

      FND appears to be comparable to, and less toxic than the combination of etoposide,
      methylprednisolone, cytarabine, and cisplatin (ESHAP), one of the most effective regimens
      available for patients with relapsed indolent lymphoma. Others studies have confirmed the
      significant efficacy and moderate toxicity profile of this combination as salvage therapy in
      low grade, predominantly follicular lymphoma.

      Moreover, the omission of corticosteroids reduces the risk of opportunistic infections, while
      the activity of the combination against indolent lymphoma is maintained.

      Preliminary data from rituximab studies alone or in combination with chemotherapy in relapsed
      or refractory low grade NHL In vitro, rituximab mediates complement dependent cytotoxicity
      (CDC), antibody dependent cellular cytotoxicity (ADCC) and apoptosis. However, the mechanism
      of in vivo anti-lymphoma effect remains largely unknown. Rituximab received approval for
      recurrent follicular lymphoma based on response rates of about 50% including 6% complete
      responses and duration of responses, which compare favorably to that of all other single
      agents including fludarabine and 2-CdA (15-19). Median time to progression for responders is
      around 13 months. Toxicity of rituximab is low and easily manageable. An 8 doses schedule did
      not show to confer a significant advantage in term of response rate and duration of response
      over the four doses schedule.

      Rituximab has been shown to sensitize drug-resistant lymphoma cell lines to killing by
      cytotoxic drugs including fludarabine.

      Thus, we may hypothesize that the combination of rituximab, fludarabine and mitoxantrone
      might lead to synergistic / additive induction of apoptosis through different pathways in
      lymphoma B-cells which maintain an indolent growth pattern.

      This approach may provide a means to achieve longer progression free survival in relapsed or
      refractory patients with FL.

      We opted for a four induction cycles of rituximab, fludarabine and mitoxantrone since:

        1. Four cycles of a combination of fludarabine and mitoxantrone are generally sufficient to
           assess response,

        2. the 4 doses schedule of rituximab which has been the most studied is efficient 3) The
           omission of dexamethasone does not appear to impair ORR and Duration Response (DR) of a
           combination of fludarabine and novantrone . Recycling will start on day 28.

      Subsequently responding patients according the International criteria Working group will have
      2 more cycle of a combination of fludarabine and mitoxantrone but no rituximab.
    

Intervention name(s): rituximab; fludarabine; mitoxantrone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 375 mg/m² IV, D1 each cycle during 4 cycles; 40 mg/m²/day IV , D1 each cycle during 4 cycles; 10 mg/m² IV, D2-3-4 each cycle during 4 cycles
Intervention MeSH terms: Rituximab; Fludarabine; Mitoxantrone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: relapsed/refractory.; lymphoma, follicular; rituximab; chemotherapy