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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 7 of 19

Older patients and people with comorbidities that contraindicate ASCT should, whenever possible, be
enrolled in clinical trials. Alternatively, a different, non-cross-resistant chemotherapy schedule can be
employed, such as bendamustine in those previously treated with an anthracycline-containing regimen.
Single-agent bendamustine can achieve ORR of approximately 75%-80% in this setting, but with
disappointing median PFS of 7-9 months . The bendamustine-rituximab association, on the other hand,
[55]
showed a similar ORR of approximately 74% in the phase II study by Rueda and colleagues, with a 48% CRR
and five-year PFS of 40% . Some patients, however, present with disease progression within six months of
[56]
completing a rituximab-containing frontline treatment (rituximab-refractory patients). Obinutuzumab has
shown activity in relapsed FL patients, both as a single agent and in association with chemotherapy [57-59] . The
Gadolin study, in particular, demonstrated the superiority of the obinutuzumab-bendamustine regimen
compared to bendamustine alone in rituximab-refractory FL patients, with ORR of 69% and median PFS
not reached after a median follow-up time of 21.9 months (vs. 14.9 months in the bendamustine arm) .
[59]
[60]
The updated analysis published in 2018 also demonstrated a significant OS benefit . These results led to
the approval of the obinutuzumab-bendamustine regimen for the treatment of this subgroup of patients.
The association can therefore be considered a suitable second-line option for ASCT-ineligible patients with
FL who received CHOP-like chemotherapy and rituximab as a frontline therapy.

In recent years, the introduction of multiple novel agents has transformed our approach to relapsed-
refractory FL, progressively confining chemotherapy to the earliest phases of the disease course. The
treatment of multiple-relapsed FL is now largely chemo-free and based on several effective biological agents.

Chemo-free strategies for relapsed/refractory follicular lymphoma patients
Despite the prolonged PFS and OS achieved with chemo-immunotherapy, it has by now been established
that hardly any patient with FL can be cured through this approach. New therapeutic strategies are therefore
being pursued, which should not only be able to increase the patients’ life expectancy but also minimize
toxicity, ensuring them a good quality of life. The long-term side effects of frontline chemotherapy are also a
concern, which is why many efforts are being made to find adequate alternatives; the most significant
advances, however, can be seen in the setting of relapsed and refractory patients, where many novel targeted
and immunomodulatory agents are being tested.

Monoclonal antibodies
The radical change that rituximab brought to the management of NHL led to the development of various
other monoclonal antibodies (mAb) targeting different antigens. We discussed the anti-CD22 epratuzumab
previously [46-49] . Galiximab is a chimeric anti-CD80 mAb whose linking to the costimulatory molecule CD80
on the surface of B lymphocytes inhibits cell proliferation, upregulates proapoptotic molecules, and induces
ADCC. The drug showed a favorable safety profile in pre-treated FL patients, with modest single-agent
activity (ORR 11%) but good efficacy when associated with rituximab (ORR of 63% with a median PFS of
[61]
[62]
11.7 months) . Seen these promising results, the combination of rituximab plus galiximab was also
explored in the frontline setting (CALGB 50402), obtaining a 72% ORR and 41% CRR in 61 previously
untreated FL patients. Notably, the trial showed that FLIPI score correlated with response and PFS: low-risk
patients had a 92% ORR, 75% CRR, and three-year PFS of 75% .
[63]

Interestingly, a retrospective pooled analysis of patients enrolled in three phase II trials evaluating the
aforementioned frontline chemo-free regimens (CALGB 50402, CALGB 50701, and CALGB 50803)
confirmed the adverse prognostic role of POD24 even in this setting, stressing the need for early
[64]
identification of higher risk patients .