Abstract
Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET).
Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age < 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes.
Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p<0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p<0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease > 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS >1 7% vs 13%, p<0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died.
Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets.
Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.
Arcaini:Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Link:Genentech: Research Funding. Feldman:Seattle Genetics: Research Funding; Zeno Pharmaceuticals: Patents & Royalties. Chihara:Genmab: Research Funding; BMS: Research Funding; Ono pharmaceutical: Research Funding; MorPhosys: Research Funding; SymBio pharmaceutical: Honoraria; BeiGene: Honoraria. Casulo:Verastem: Research Funding; Genmab: Research Funding; Gilead Sciences, Secura Bio: Research Funding; AbbVie: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Romancik:Kite: Consultancy; ADC Therapeutics: Consultancy; Astra Zeneca: Consultancy. Cheah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria; Dizal: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding. Habermann:Lilly: Other: Data Monitoring Committee. Martin:AbbVie, AstraZeneca, Beigene, Daiichi Sankyo, Genentech, Janssen, Merck, Pepromene: Consultancy. Kahl:Novartis: Consultancy; BeiGene: Consultancy, Research Funding; Lilly: Consultancy; Bristol Myers Squibb: Consultancy; ADCT: Consultancy; Roche: Consultancy, Research Funding; Kite: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Merck: Consultancy. Nowakowski:TG Therapeutics Inc: Consultancy; Incyte Corporation: Consultancy; ADC Therapeutics: Consultancy; Constellation Pharmaceuticals: Consultancy; Selvita Inc: Consultancy; Debiopharm: Consultancy; Curis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Zai Laboratory: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kymera Therapeutics: Consultancy; Genentech: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; AbbVie Inc.: Consultancy; Celgene Corporation: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy; MorphoSys AG: Consultancy, Research Funding; Segen: Consultancy; Fate Therapeutics: Consultancy; MEI Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy; Ryvu Therapeutics: Consultancy; F. Hoffmann-La Roche Limited: Consultancy. Nastoupil:Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. Talaulikar:Janssen: Research Funding; Roche: Research Funding; Antengene: Honoraria; Beigene: Speakers Bureau; Immutep: Current equity holder in publicly-traded company. Trotman:BeiGene: Research Funding; Roche: Research Funding; Cellectar: Research Funding; Bristol Myers Squibb: Research Funding. Cerhan:BMS: Research Funding; Genentech: Research Funding; Protagonist Therapeutics: Other: SMC; GenMab: Research Funding. Flowers:Cellectis: Research Funding; BostonGene: Research Funding; TG Therapeutics: Research Funding; Ziopharm National Cancer Institute: Research Funding; Xencor: Research Funding; Karyopharm: Consultancy; Kite: Research Funding; Iovance: Research Funding; Janssen