Paper Details

ABSTRACT

Background: Baseline positron emission tomography (PET) is routinely used for staging in follicular lymphoma (FL), but whether baseline maximum standardized uptake value (bSUV_max) should guide frontline treatment selection remains unknown. Specifically, it is unclear whether patients (pts) with high bSUV_max, in the absence of histologic transformation (HT), derive greater benefit from anthracycline-based regimens, such as R-CHOP, than bendamustine-rituximab (BR). We previously showed that high bSUV_max was not associated with event-free survival (EFS) or overall survival (OS) after frontline R-CHOP or BR (Mondello P et al, Blood 2024). Here, we investigated whether bSUV_max predicts HT according to frontline therapy and evaluated the prognostic impact of end-of-therapy (EoT) metabolic response and rituximab (R) maintenance.

Patients and Methods: We analyzed 1,572 pts aged < 75 years with newly diagnosed FL grade 1-3A who underwent baseline PET and received frontline R-CHOP (n= 794) or BR (n= 778) between 2010 and 2022 across the FOLL12 and RELEVANCE trials, the MER/LEO cohorts, and a multicenter Australian cohort. EoT response was assessed locally using Lugano PET criteria. Pts achieving complete metabolic response (CMR) or partial metabolic response (PMR) received R maintenance according to protocol (FOLL12/RELEVANCE) or physician discretion (MER/LEO). The Australian cohort was excluded from maintenance analyses because data were unavailable. bSUV_max was analyzed continuously and by tertiles (low, < 9; intermediate, 9-13; high, > 13). HT was evaluated using multivariable Cox proportional hazards and competing-risk models. Landmark analyses assessed the impact of EoT PET response and R maintenance.

Results: Median bSUV_max was similar between the R-CHOP and BR groups (10.8 vs 10.9), but its association with HT differed by frontline therapy. Following R-CHOP, bSUV_max was not associated with HT when analyzed as a continuous variable (HR, 1.02; 95% CI, 0.97-1.09) or by tertiles (Gray’s P=.139). Post-transformation OS was similar across bSUV_max tertiles. However, among pts in the highest SUV_max tertile (>13), HT was associated with inferior subsequent OS compared with indolent relapse (HR, 3.07; 95% CI, 1.09-8-65; P= .025). In contrast, higher bSUV_max was strongly associated with an increased risk of HT after BR. Each unit increase in bSUV_max increased HT risk in both unadjusted (HR, 1.11; 95% CI, 1.06-1.16) and adjusted analyses (HR, 1.10; 95% CI, 1.05-1.15). Pts in the highest SUV_max tertile (>13) had more than a threefold higher HT risk than those in the lowest tertile in both unadjusted (HR, 3.63; 95% CI, 1.66-7.98) and adjusted analyses (HR, 3.34; 95% CI, 1.53-7.31). Within the highest bSUV_max tertile, HT was associated with inferior OS compared with indolent relapse (HR, 2.57; 95% CI, 0.97-7.38; P= .048), whereas post-transformation OS did not differ across bSUV_max tertiles.

CMR at EoT independently predicted superior EFS (HR, 0.41; 95% CI, 0.32-0.53) and OS (HR, 0.27; 95% CI, 0.17-0.42), irrespective of frontline therapy or bSUV_max. CMR was also associated with a lower risk of subsequent HT (HR, 0.37; 95% CI, 0.18-0.74), with the greatest benefit among pts with bSUV_max > 13 (HR, 0.20; 95% CI, 0.07-0.51) and those treated with BR (HR, 0.22; 95% CI, 0.08-0.59), suggesting that deep metabolic remission may attenuate the increased transformation risk in these higher-risk subgroups.

R maintenance improved EFS (HR, 0.66; 95% CI, 0.52-0.84), with the greatest benefit among pts with higher bSUV_max (HR, 0.54; 95% CI, 0.34-0.86). When stratified by frontline treatment, R maintenance remained associated with improved EFS after both R-CHOP (HR, 0.71; 95% CI, 0.53-0.95) and BR (HR, 0.57; 95% CI, 0.37-0.87). This benefit was restricted to pts achieving CMR (R-CHOP: HR, 0.57; 95% CI, 0.41-0.79; BR: HR, 0.46; 95% CI, 0.28-0.75) and was not observed in those with PMR. R maintenance was not associated with improved OS overall or in analyses stratified by frontline regimen, bSUV_max or EoT response.

Conclusion: Higher bSUV_max identifies pts at increased risk of HT after frontline BR but not R-CHOP, supporting a potential role for baseline PET in informing frontline treatment selection. EoT CMR independently predicts favorable outcomes and appears to mitigate the excess HT risk associated with high bSUV_max, particularly after BR. R maintenance prolongs EFS, especially in pts with high bSUV_max and those achieving CMR, but does not improve OS.