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Page 4 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

POD24 is nowadays a very appealing tool, and it is considered the most important prognostic factor. A
study by Casulo and colleagues, considering patients treated in first line with R-CHOP regimen (rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone), demonstrated that POD24-positive patients
have shorter OS (five-year OS of 34%-50% vs. 93%) and higher risk of histologic transformation compared
to those without early disease recurrence . POD24 is thus able to identify a small subset of FL patients
[28]
(around 20%) at very high risk, who might be candidate for intensive treatment strategies at first relapse [28-32] .

A recent pooled analysis of 13 randomized clinical trials of patients in both pre- and post-rituximab era
identified male gender, poor PS, high FLIPI score, and elevated baseline B2M as predictors of early
progression or death . It is also increasingly evident that the impact of an early relapse or progression is
[32]
greater in patients treated in first line with chemo-immunotherapy than in those treated with rituximab or
observation only [32,33] . Moreover, there is growing evidence about the importance of metabolic response -
evaluated by positron emission tomography (PET) scan - at the end of induction therapy. Particularly, as
demonstrated in a secondary analysis in the PRIMA and GALLIUM studies, 2.5-year PFS is 87% in
complete metabolic responders and 55% in non-complete metabolic responders [34,35] .

Despite being largely used to this day, neither of the existing pre-treatment prognostic indices is able to
reliably identify those highest risk patients who will relapse within two years of frontline chemo-
immunotherapy . Current staging methods, i.e., PET and computed tomography (CT) scans, can provide
[36]
the functional and anatomical data necessary to determine the viable portion of the tumor mass [total
metabolic tumor volume (TMTV)], which has already emerged as an interesting tool in baseline evaluation
[36]
of other types of lymphoma . Meignan and colleagues recently demonstrated its strong independent
predictive value in FL: patients with a high TMTV > 510 cm had significantly inferior five-year PFS and a
3
[36]
median PFS of three years, compared to median PFS of six years in patients with TMTV below that level .
Delfau-Larue and colleagues explored the connection between the metabolic and the circulating tumor
burden in untreated FL through evaluation of TMTV, obtained from PET/CT scans, and either the number
of CTCs or the plasmatic cell-free tumor DNA obtained from peripheral blood. The cutoff for high TMTV
in this study was confirmed at 510 cm , whereas a high load of cfDNA was defined as >2500 Eqg/mL of
3
plasma. The combination of these biomarkers allowed for the identification of a very good prognosis
3
subgroup (TMTV < 510 cm + cfDNA < 2500 Eqg/mL) with 94% four-year PFS, and a poor prognosis
subgroup with four-year PFS of 65% (TMTV > 510 cm + cfDNA > 2500 Eqg/mL) .
3
[22]
The authors suggested that TMTV and cfDNA should not replace the more traditional prognostic tools,
such as FLIPI2 and metabolic response at the end of treatment, but will probably be helpful in refining the
existing scores) [22,36] .

For sure, understanding the clinical and biological features of high-risk FL patients is necessary to improve
their therapeutic sequence and allow the use of novel therapies earlier in their therapeutic path.

FRONTLINE STRATEGIES IN FOLLICULAR LYMPHOMA PATIENTS
Early stage (I/II) FL represents a rare occurrence, consisting in less than 10% of all FL patients. In this
population, first-line treatment is involved field radiotherapy (IF-RT), which can induce long lasting
remissions with prolonged OS . At our Institution, we perform four courses of rituximab (375 mg/m ,
2
[37]
once a week) followed by IF-RT in Stage I/II FL. The aim of rituximab addiction is to eventually treat
undetectable disease and thus prevent relapses in different sites. Moreover, this approach provided good
PFS in a study considering this specific population, without additional toxicity .
[38]