Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Antibody Therapy, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, Diseases, Indolent lymphoma, Therapy sequence, Immune mechanism, Real-world evidence, Treatment Considerations, Biological therapies, Immunotherapy, Immunology, Lymphoid Malignancies, Biological Processes, Molecular biology, Technology and Procedures, Profiling, Molecular testing
Methods. Pre-treatment tissue biopsies were collected from patients with advanced and high tumor burden FL treated with frontline BR, RCHOP, or R2 and with available follow-up clinical data. Baseline clinical and laboratory characteristics were retrospectively used to calculate FLIPI, FLIPI-,2 and PRIMA-PI scores. Response and survival were assessed according to 2014 Lugano criteria. Bulk RNA sequencing was generated for LME subtyping, cell deconvolution using the Kassandra algorithm (Zaitsev et al., Cancer Cell, 2022), B-cell associated gene signatures (BAGS) analysis, and B-cell receptor (BCR) repertoire analysis. Mann-Whitney test was used for comparing continuous variables between patient groups. The log rank test was used to assess the difference in progression-free survival between patient groups.
Results. The analysis included 35 patients: 12 treated with frontline BR, 12 with frontline RCHOP, and 11 with frontline R2. Twenty-three (66%) had high FLIPI scores, 14 (40%) had high FLIPI-2 scores, and 7 (20%) had high PRIMA-PI scores. Patients with high FLIPI score (3‒5) displayed a significant decrease in BCR diversity as compared to those with low-intermediate FLIPI score (0‒2), shown by smaller Shannon and higher Simpson indexes. In addition, patients with higher FLIPI scores (evaluated as a continuous variable) tended to have higher T-regulatory (T-reg) and T-reg traffic signature scores. No significant associations were observed between LME subtypes, BAGS, cell deconvolution, or BCR repertoire and FLIPI-2 or PRIMA-PI scores.
Median follow-up for the whole cohort was 122 months (95% confidence interval [CI], 107-146 months) and median progression-free survival (PFS) was 143 months (95% CI, 98.6-NA months). No significant difference in median PFS was observed when comparing CIT-treated patients (BR or RCHOP) to R2-treated patients (p=0.27). However, when analyzing PFS within the 4 BAGS subgroups [light-zone like (n=7), dark zone-like (n=10), normal-like (n=13), and plasma cell-like(n=5)], patients with normal-like BAGS experienced a significantly longer median PFS when treated with BR (not reached [NR]) compared to RCHOP (143 months) or R2 (31 months)(p=0.05), and PFS with CIT compared to R2 (NR vs 31 months, p=0.03). In addition, analysis of T-cell signature, including CD3D, CD3G, TRBC1, TRAT1, TRAC, CD3E, CD28, TRBC2, ITK, and TBX21, categorized as high or low based on the cohort median, revealed patients receiving frontline R2 with high T-cell signature scores to experience significantly longer median PFS compared to those with low T-cell signature scores (NR vs 21 months, p=0.04). No association between treatment modality and PFS based on TME subtypes was observed.
Discussion. While FLIPI scores are associated with the molecular features of FL, including BCR diversity and T-reg signatures, clinical prognostic scores have a limited impact in biological signatures. Our findings suggest that longer PFS could be achieved by using CIT to treat patients with normal-like BAGS and R2 to treat those with high T-cell signature scores. Pending validation with large datasets and clinical trials, these findings suggest that pre-treatment molecular immune signatures may facilitate frontline treatment selection in FL.
Disclosures: Chihara: Genentech: Research Funding; Ono pharmaceutical: Research Funding; BeiGene: Honoraria; SymBio pharmaceutical: Honoraria; Genmab: Research Funding; BMS: Research Funding. Nesterenko: BostonGene Corporation: Current Employment, Current holder of stock options in a privately-held company. Meerson: BostonGene: Current Employment. Zornikova: BostonGene: Current Employment. Nomie: BostonGene: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Kotlov: BostonGene, Corp.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene, Corp.. Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; krystle.nomie@bostongene.com: Current Employment. Neelapu: Astellas Pharma: Consultancy; Caribou Biosciences: Consultancy; Athenex: Consultancy; Fosun Kite: Consultancy; Chimagen: Consultancy; Sellas Life Sciences: Consultancy; Sana Biotechnology: Consultancy, Research Funding; Synthekine: Consultancy; Orna Therapeutics: Consultancy; bluebird bio: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Appia Bio: Consultancy; ImmunoACT: Consultancy; Merck: Consultancy; Carsgen: Consultancy; Allogene: Consultancy, Research Funding; Takeda: Consultancy; MorphoSys: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Research Funding; Incyte: Consultancy; Janssen: Consultancy; Anthenex: Consultancy; Adicet Bio: Consultancy, Research Funding; Cargo Therapeutics: Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company. Flowers: Janssen Pharmaceuticals: Research Funding; Pharmacyclics / Janssen: Consultancy; Guardant: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding; Seagen: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; BeiGene: Consultancy; Allogene: Research Funding; Takeda: Research Funding; Ziopharm National Cancer Institute: Research Funding; BostonGene: Research Funding; Iovance: Research Funding; Kite: Research Funding; Burroughs Wellcome Fund: Research Funding; Celgene: Consultancy, Research Funding; Adaptimmune: Research Funding; Bayer: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Nektar: Research Funding; Amgen: Research Funding; EMD Serono: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; Spectrum: Consultancy; Morphosys: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; AstraZeneca: Consultancy; 4D: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; Bio Ascend: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy, Research Funding. Strati: Roche-Genentech: Consultancy; ALX Oncology: Research Funding; Sobi ADC Therapeutics: Consultancy, Other: Travel, accommodations, expenses, Research Funding; TG Therapeutics: Consultancy; Hutchison MediPharma: Consultancy; Ipsen: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; Acerta-Astrazeneca: Consultancy, Research Funding; Abbvie-Genmab: Consultancy.
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