Combined use of minimal residual disease monitoring and fdg‐pet for outcome prediction in follicular lymphoma: results from the fondazione italiana linfomi (fil) foll12 trial

Introduction: In follicular lymphoma (FL), FDG-PET is routinely employed to evaluate response at the end of induction (EoI), while minimal residual disease (MRD) analysis is highly reliable in predicting relapse over the entire disease history. Nonetheless, scant data are available describing the integration of these powerful prognostic tools for response evaluation in FL. This issue was investigated in the phase III FIL “FOLL12” trial [Luminari, JCO 2022]. Methods: Only patients with an available molecular marker for MRD and centrally reviewed EoI PET were included. MRD was systematically assessed by RQ-PCR with BCL2::IGH consensus primers in peripheral blood (PB) and bone marrow (BM), as previously reported with inferior follow-up [Ladetto ASH 2021]. PET scans were classified according to Deauville score (DS) criteria: DS1–3 was negative and DS4–5 positive. Results: Overall, 394 patients out of 780 were included (51%), as expected based on the MRD marker availability. These patients had a slightly better outcome than excluded cases (CR rate 82% vs. 73%, p = 0.003, 5y PFS 66% vs. 61%, p = 0.046). At EoI, both BM MRD and PET positivity were independent predictors of poor PFS in multivariate analysis (HR 1.66, CI: 1.01–2.71 and HR 2.03, CI: 1.30–3.18). The 68 discordant cases (i.e., MRD+/PET− or MRD−/PET+) showed an intermediate outcome (PFS HR 1.93, CI: 1.28–2.92) between the 314 double negative (reference) and the 10 double positive ones (HR 6.22, CI: 2.99–12.9), Figure 1A. Moreover, both EoI PET+ and the persistence/reappearance of MRD positivity in BM during the 18 months of rituximab maintenance/observation were independently associated to a higher risk of POD24 (HR 5.61, CI: 2.59–12.1, and HR 2.37, CI: 1.15–4.84, respectively). On the other hand, MRD kinetic analysis by non-invasive PB sampling during the rituximab maintenance/observation period substantially updated the risk status over PET results. Indeed, the marginal PFS HR for an MRD+ after an EoI PET negative result increased from 1.36 (CI: 0.47–3.96) at 6 months, to 2.09 (CI: 1.01–4.18) at 12 months, up to 3.60 (CI: 2.30–5.64) at 24 months (Figure 1B, blue curve). This means that patients scoring PET- at EoI but showing a persistent or reappearing MRD+ signal during the following 24 months had a dismal PFS, superimposable to that of PET+ patients (Figure 1C). Accordingly, in landmark multivariate analysis PB MRD+ either at 12 or 24 months predicted adverse PFS (HR 3.79, CI: 1.60–8.96 and HR 5.21, CI: 1.88–14.4, respectively), independently from EoI PET result. Keywords: indolent non-Hodgkin lymphoma, minimal residual disease, PET-CT Conflicts of interests pertinent to the abstract S. Ferrero Consultant or advisory role: Janssen, EUSA Pharma, Abbvie, Incyte, Clinigen, Sandoz, Italfarmaco Honoraria: Janssen, EUSA Pharma, Servier, Gentili Research funding: Morphosys, Janssen, Gilead, Beigene Educational grants: Takeda, Janssen, EUSA Pharma