Rituximab and CVP Plus Interferon for Follicular Non Hodgkins Lymphoma (NHL)
Condition: Non-Hodgkin's Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Study type: Interventional
Phase: Phase 2

Summary: 
      Rituximab plus CVP and Interferon chemoimmunotherapy for newly diagnosed Follicular Lymphoma
      with FLIPI index >2
    

Detailed description: 
      This study is a multicentric trial evaluating the efficacy of the CVP chemotherapy +
      Interferon (IFN) + Rituximab induction regimen in patients aged 18 to 75 years with newly
      diagnosed follicular NHL.

      Follicular non Hodgkin's lymphoma's (FL), as defined by the 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.

      Most standard first line treatment for advanced FL consists of alkylating-based (CVP) or
      anthracycline containing regimens, in association with immunomodulating agents such as
      interferon alpha or the unconjugated chimeric anti-CD20 antibody (rituximab) to target the
      CD20 antigen highly expressed on follicular lymphoma cells. This strategies have
      significantly increased the survival of the patients, but relapses still occur. Thus, the
      treatment of the patients with FL, requires improvements.

      IFN alpha has antiproliferative and immunomodulatory properties. Moreover, it has been
      described a synergistic effect when IFN is given with chemotherapy. This association has
      significantly improved progression free survival (PFS) and overall survival (OS). Our prior
      results with 12 weeks of IFN plus CVP as induction treatment, significantly increased PFS
      when compared with CVP alone (60% median PFS vs. 24%, p: 0.0004).

      We also performed a prospective study to analyze the correlation between the duration of
      remission and MRD in patients who were treated with CVP+IFN . Ninety four percent of patients
      had a molecular marker (60% bcl-2 translocation and 34% IgH rearrangement). Molecular
      response, defined as achieving a negative molecular MRD, was achieved in 76% of patients and
      it was associated with clinical remission. There was also a significant correlation between
      the duration of remission and a sustained indetectable MRD Anti-CD20 monoclonal antibody
      (Rituximab) mediates complement dependent cytotoxicity (CDC), antibody dependent cellular
      cytotoxicity (ADCC) and apoptosis. Rituximab has also shown to sensitize drug-resistant
      lymphoma cell lines to killing by cytotoxic drugs.

      There are some "in vitro" studies that have tested the effect of Rituximab and IFN
      combination. It's been described that when IFN is given with Rituximab, it favours the
      expression of CD20 and therefore increases its cytotoxic effect - . Preliminary phase II
      studies show an increase in response rate with duration of response going up to 12 months.
      Moreover, there are two clinical studies that have tested the efficacy and tolerability of
      Rituximab added to IFN-alpha vi- ix. The Nordic Lymphoma Group showed a significant increase
      in ORR (up to 94%) by adding 5 weeks of IFN to re-treatment with 4 doses of Rituximab in
      patients who had achieved only a minimal or partial remission. Most of these patients,
      maintained their responses for more than 24 months. With a similar trial design, Sacchi et
      al. showed an ORR of 74% (33% of CR) and a median duration of response of 19 months. The
      combination was safe and most grade 3-4 adverse events (15%) were hematologic toxicity
      (leuko-neutropenia and thrombocytopenia).

      Thus, we hypothesize that the combination of rituximab, with our standard induction regimen
      using IFN plus CVP might lead to synergistic / additive induction of apoptosis through
      different pathways in poor prognostic patients with FL, improving our previous results. We
      also hypothesize that this combination will be able to achieve higher molecular remissions,
      determined by real-time PCR of Bcl-2 translocation.
    

Intervention name(s): R+CVP+IFN
Intervention type(s): Biological
Intervention description(s): Immunochemotherapy
Other intervention name(s): Mabthera -Rituximab (375 mg/sm, D1)/cycle; Cyclophosphamide (400 mg/sm, D 1-5)/cycle; Prednisone (100 mg/sm,D 1-5)/cycle; Vincristine (1.4 mg/sm, max 2 mg, D 1)/cycle; Interferon -IFN (3 MU/sm x 3 times/week, x 12 weeks)
Intervention MeSH terms: Interferons; Prednisone; Cyclophosphamide; Vincristine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Intermediate-high FLIPI score; Follicular Lymphoma; Progression free survival