Trial Information

Association of Rituximab to Immunochemotherapy With CVP + Interferon in Newly Diagnosed Follicular Lymphoma Patients With Intermediate-high FLIPI Score. Phase II Study.

This study is a multicentric trial evaluating the efficacy of the CVP+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,
mantained 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.