Assessment of the prognostic value of FDG PET-derived markers and responses in POLARIX Free

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and accurate outcome prediction is essential for optimizing treatment. Baseline total metabolic tumor volume (TMTV; Vercellino et al. Blood 2020), and interim and end-of-treatment (EOT) FDG-PET responses are established prognostic indicators in frontline DLBCL treatment (Kostakoglu et al. Blood Adv 2021; Jemaa et al. J Clin Oncol 2024). However, their relevance in regimens other than rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) remains unclear (Kostakoglu et al. Haematologica 2022). Polatuzumab vedotin (Pola) with R-CHP is a new standard-of-care therapy based on the POLARIX study (NCT03274492; Phase III Pola-R-CHP vs R-CHOP). This analysis evaluates the prognostic value of quantitative PET parameters, including baseline TMTV, total lesion glycolysis (TLG), and interim (iPET) and EOT PET responses in patients with previously untreated DLBCL in the POLARIX study.

Methods: Available baseline FDG-PET/CT scans were centrally reviewed for TMTV by an Independent Review Committee, using a standardized uptake value (SUV) threshold of 1.5 times the liver reference plus 2 standard deviations, with a minimum lesion volume of 1mL. After 4 cycles, iPET (iPET4) positivity was defined as a reduction in maximum SUV (SUV_max) of <70%. At EOT, metabolic response was assessed according to the 2014 Lugano criteria. Prognosis of FDG-PET-derived metrics, and treatment effects stratified by FDG-PET-derived metrics and other predictive covariates, were analyzed using the Kaplan–Meier method and Cox proportional hazards model in the POLARIX population with 5-years' follow-up.

Results: In the POLARIX global population,835 patients had evaluable baseline FDG-PET/CT scans, 661 had evaluable iPET4, and 760 had evaluable EOT FDG-PET/CT scans. Median TMTV was 411mL (range: 0–10,881). In the R-CHOP arm, high (>411mL) baseline TMTV (HR: 2.05 [95% CI: 1.49–2.83]) and high TLG (HR: 1.55 [95% CI: 1.13–2.12]) were strong predictors of progression-free survival (PFS). Notably, high TMTV and TLG were similarly predictive in the Pola-R-CHP arm, HR: 1.85 (95% CI: 1.30–2.63) and HR: 1.60 (95% CI: 1.13–2.27), respectively. There was no significant evidence of association between Pola-R-CHP benefit and TMTV or TLG (treatment interaction: TMTV p=0.67; TLG p=0.92), or association between baseline TMTV and cell-of-origin (COO [by Nanostring]; activated B-cell [ABC] interaction: TMTV p=0.38; TLG p=0.99). In the ABC COO population with high TMTV, 5-year PFS and OS rates were significantly higher (PFS HR: 0.27 [95% CI: 0.14–0.50]; OS HR: 0.28 [95% CI: 0.13–0.63]) with Pola-R-CHP (PFS: 74% [95% CI: 63–87]; OS: 84% [95% CI: 75–95]) compared with R-CHOP (PFS: 28% [95% CI: 17–45]; OS: 54% [95% CI: 42–69]). In 661 evaluable patients from POLARIX, 583 (88%) had negative iPET4 (Pola-R-CHP: 312/340 [92%]; R-CHOP: 271/321 [84%]); of 760 patients with evaluable EOT scans, 627 (83%) achieved complete metabolic response (CMR) at EOT (Pola-R-CHP: 327/387 [84%]; R-CHOP: 300/373 [80%]). In the Pola-R-CHP arm, negative iPET4 and CMR at EOT differentiated patients at high risk of relapse (5-year PFS rates from iPET4 positive vs negative: 69% [95% CI: 63–75] vs 46% [95% CI: 29–71], respectively; HR:0.38 [95% CI: 0.22–0.68]) and high risk of death (5-year OS rates from EOT CMR vs non-CMR: 91% [95% CI: 88–95] vs 58% [95% CI: 47–73], respectively; HR:0.17 [95% CI: 0.10–0.29]). Similar results were also observed in the R-CHOP arm (iPET4 PFS HR: 0.42 [95% CI: 0.27–0.65]; CMR at EOT OS HR: 0.41 [95% CI: 0.25–0.67]). No significant evidence of association between EOT or iPET4 responses and COO was found (ABC interaction: EOT response p=0.76; iPET4 p=0.75). Among patients with CMR at EOT, significant OS and PFS benefits were observed with Pola-R-CHP relative to R-CHOP (OS HR: 0.55 [95% CI: 0.35–0.88]; PFS HR:0.66 [95% CI: 0.48–0.91]).Conclusions: In the POLARIX study, baseline TMTV was a strong prognostic factor of patient outcomes and consistent across treatment arms, suggesting its relevance regardless of DLBCL biological subtype or therapy received. FDG-PET responses at both interim and EOT assessments were also prognostic. These findings confirm that well-established PET prognostic factors remain relevant in patients treated with Pola-R-CHP. In addition, Pola-R-CHP led to more sustained responses and longer survival among patients with EOT CMR compared with R-CHOP.