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Page 6 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

At present, a phase II study (GALEN) is evaluating the efficacy and safety of lenalidomide plus
obinutuzumab in previously untreated advanced FL patients, with promising preliminary results as the
[51]
combination yields an ORR of 94% and a CR of 80%; three-year PFS is 82% .

Some attempts are also ongoing to explore the possibility of a risk-adapted approach based on metabolic
response or minimal residual disease (MRD) at the end of induction therapy. The Italian FOLL12 study
(NCT02063685), for example, compares a standard rituximab-maintenance arm to a PET- and MRD-based
approach, dividing patients into three groups: MRD-negative, PET-negative patients, who will be observed;
MRD-positive, PET-negative patients, who will receive rituximab maintenance; and MRD-positive, PET-
positive patients who will undergo consolidative radioimmunotherapy (RIT) with Y ibritumumab tiuxetan
90
and rituximab maintenance .
[52]

TREATMENT OF RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA PATIENTS: A PATH
TOWARDS NOVEL AND CHEMO-FREE REGIMENS
When to use high dose salvage chemotherapy and autologous stem cell transplantation
Although the majority of FL patients respond well to rituximab-containing frontline chemo-
immunotherapy, the disease course is inevitably punctuated by subsequent relapses and most patients need
multiple lines of treatment. Moreover, the duration of remission tends to decrease with each successive line
of therapy. As already discussed, one of the main prognostic indicators for relapsed patients is time to
disease progression: about 20% of patients are POD24-positive, and this has been proven to be the strongest
independent risk factor for poor survival thus far [29,32] .

Patients who relapse after the first two years of first-line treatment (POD24-negative patients) do not
necessarily require immediate treatment and clinicians can apply the same criteria used for patients with
newly diagnosed diseases . Those who do not meet the GELF criteria, in other words, patients with low
[53]
[53]
tumor burden and asymptomatic disease, can initially be managed by a watchful waiting approach . In the
case of symptomatic, localized disease, low-dose radiotherapy can be a valid option, whereas cases
presenting with symptomatic, low tumor burden systemic disease can be addressed with single-agent
rituximab . Moreover, clinicians should always be aware of the possibility that FL transforms into an
[53]
aggressive form of lymphoma. It is therefore strongly recommended, whenever possible, to obtain histologic
confirmation of the diagnosis before starting salvage treatment, since aggressive B-cell lymphomas must be
treated accordingly.

As previously said, POD24-positive patients are believed to have a biologically distinct disease, characterized
by clinical and genetic factors that confer resistance to standard chemo-immunotherapy [29,32] . No specific
treatment approach is currently recommended for this population, although some clinical trials are ongoing
to address the role of novel therapies in this setting.

Young patients (under 65 years) with a good PS should be considered for high-dose chemotherapy (HDT)
followed by consolidative autologous stem-cell transplantation (ASCT). This approach can yield prolonged
remissions in a subset of patients, provided they respond to salvage chemotherapy, and its survival benefit
seems to be greater within one year of treatment failure . Casulo and colleagues recently reported a 73%
[54]
five-year OS for patients receiving ASCT in this setting compared to those treated otherwise (five-year
OS: 60%). Similar results were also obtained by a German group (77% vs. 46%) [30,31] . Overall, available data
(largely retrospective in nature) suggest that patients with early treatment failure that achieve a second CR
(or a first CR following a salvage regimen) with HDT benefit from ASCT in terms of both PFS and OS.