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Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05 Page 5 of 19

Most FL patients have advanced-stage disease, but these patients do not all require therapy immediately
after diagnosis. Today, the most used criteria to decide when therapy is needed are the GELF criteria
(Groupe d'Etude des Lymphomes Folliculaires), based on a large study resulting in no significant OS
[39]
difference with the “wait and see” strategy vs. treatment upfront . For some researchers, the “watch and
wait” attitude is questionable in the rituximab era , but, as no conclusive evidence is available, we prefer to
[40]
reserve therapy for when it is really needed.

When it is time to start first-line treatment, the road traveled generally consists of chemo-immunotherapy,
which is almost worldwide the standard of care. The alkylating agent bendamustine, in combination with
rituximab (BR), remains the first choice, considering its superiority in terms of PFS and complete response
(CR) rates over R-CHOP/R-CVP (rituximab, cyclophosphamide, and prednisone) [41-43] . In those patients
who obtained at least a partial response after a frontline rituximab containing regimen, 24 months of
rituximab maintenance prolongs the time to disease progression, although no improvement in OS has been
demonstrated .
[44]

In the phase III GALLIUM study, obinutuzumab, a Type II anti-CD20 monoclonal antibody, whose Fc
region is defucosylated in order to have greater affinity for receptors FcRIIIa on effector cells and increased
antibody-dependent cell-mediated cytotoxicity (ADCC), was combined with chemotherapy . The
[45]
association was compared to rituximab-based chemo-immunotherapy. A longer PFS was seen with
obinutuzumab than with rituximab (estimated three-year PFS: 80% vs. 73.3%), although no statistical
[45]
differences were observed in terms of CR and OS rates . The obinutuzumab plus chemotherapy
combination resulted in a higher rate of adverse events (AEs) in comparison to the rituximab arm. In
particular, the obinutuzumab - CHOP association was characterized by Grade > 3 cytopenia, while the
association with bendamustine led to a higher rate of Grade > 3 infections and deaths . For this reason, we
[45]
prefer not to associate obinutuzumab with bendamustine, and we believe that this combination must be
used with caution. In frontline setting, we reserve obinutuzumab treatment for those patients in whom we
can choose CHOP as the chemotherapy backbone, such as young, fit patients with intermediate- to high-
risk disease, as per FLIPI score.

In the last decades, following the development of novel immunotherapies and targeted agents, a
chemotherapy-free approach has been explored, initially for relapsed/refractory patients but also in the
frontline setting.

Other attempts to spare chemotherapy to FL patients at diagnosis have included using frontline
epratuzumab combined with rituximab. Epratuzumab is a humanized monoclonal IgG1 antibody targeting
the B cell = specific transmembrane phosphoglycoprotein CD22. The drug showed significant activity both
as a single agent and in combination with rituximab in heavily pre-treated FL patients [46-48] . A phase II study
by Grant and colleagues published in 2013 demonstrated the efficacy of its association with rituximab even
in the frontline setting (CALGB 50701), with 88% overall response rate (ORR) and 42.4% complete response
rate (CRR). After a three-year follow-up, PFS was 60% .
[49]

Although the RELEVANCE study failed to reach its first endpoint, demonstrating a comparable clinical
efficacy of rituximab-lenalidomide compared to standard R-chemotherapy, it showed the safety and efficacy
of immunomodulating agents also in the first-line setting, paving the way to chemo-free regimens in FL
patients at frontline .
[50]