Outcomes by LymphoMAP archetypes in untreated diffuse large B-cell lymphoma from the POLARIX trial.

Abstract

7017 Background: Single cell multiomics helped identify three tumor microenvironment archetypes: FMAC, high tumor-associated fibroblasts and macrophages; LN, high naive and memory T cells; TEX, high exhausted CD8 + T cells (Li, et al, Cancer Cell 2025) with FMAC associated with inferior outcomes with 1L R-CHOP. The POLARIX study showed sustained and significant 5-year PFS/DFS benefits favoring Pola-R-CHP (Morschhauser et al, JCO 2025) supporting use as a standard of care for pts with untreated intermediate/high-risk LBCL. In this post hoc exploratory analysis, we investigated the clinical outcomes of LymphoMAP subtypes in POLARIX. Methods: LymphoMAP subtypes were determined from global gene expression patterns (GEP) using the LymphoMapR classifier. Cell of origin (COO) status was determined by NanoString. Hazard ratios (HR) were adjusted for IPI score (2 vs 3–5), age (≤ 60 vs > 60 years) and COO. All statistics are descriptive. Results: GEP data were available for 669 pts (Pola-R-CHP, n=331; R-CHOP, n=338; baseline characteristics comparable with ITT); among which 244 (33.5%), 229 (34.2%), 196 (29.3%) were FMAC, LN, and TEX respectively (Table). Balanced baseline clinical characteristics seen across subtypes, except lower proportion of LN with high IPI (3–5) and higher proportion of TEX as ABC-DLBCL (Table). With a median follow-up 61 months, the adjusted HRs for PFS favored Pola-R-CHP compared with R-CHOP in all subtypes and were 0.66 (95% CI: 0.43–1.01) for FMAC, 0.79 (95% CI: 0.51–1.23) for LN, and 0.81 (95% CI: 0.50–1.32) for TEX. The 5-yr PFS estimates (95% CI) were 66.0 (57.1–76.2)%, 64.6 (55.4–75.4)%, 68.8 (59.7–79.4)% for FMAC, LN, and TEX respectively in the Pola-R-CHP arm, and 56.9 (47.6-68.0)%, 61.2 (52.8–70.9)%, 56.6 (45.8–69.9)% for FMAC, LN, and TEX respectively in the R-CHOP arm. A similar trend of OS improvement was observed in the FMAC subtype with 5-yr OS estimates of 82.5 (76.3–89.3)% vs 72.0 (63.8–81.2)% with Pola-R-CHP vs R-CHOP (HR 0.64; 95% CI: 0.37–1.10). Trends of PFS and OS improvements of Pola-R-CHP over R-CHOP were observed in ABC-DLBCL pts across all LymphoMAP subtypes. For GCB-DLBCL pts, no benefit was observed with Pola-R-CHP vs R-CHOP in the TEX subtype. Conclusions: In this exploratory analysis, Pola-R-CHP demonstrated PFS/OS improvement trends over R-CHOP in all three LymphoMAP subtypes, especially for the FMAC subtype. Future prospective validation is required. FMAC (N = 244) LN (N = 229) TEX (N = 196) BEP (N = 669) Pola-R-CHPR-CHOP 134 (55%)110 (45%) 105 (46%)124 (54%) 92 (47%)104 (53%) 331 (50%)338 (50%) Age Median [Min, Max] 65 [22, 80] 66 [19, 80] 64 [22, 80] 65 [19, 80] IPI 3–5 157 (64%) 125 (55%) 133 (68%) 415 (62%) Bulky 109 (45%) 99 (43%) 87 (44%) 295 (44%) Extranodal 174 (71%) 146 (64%) 143 (73%) 463 (69%) COO ABC GCB Unclassified Unknown 68 (28%)138 (57%)20 (8%)18 (7%) 56 (24%)135 (59%)34 (15%)4 (2%) 90 (46%)65 (33%)38 (19%)3 (2%) 214 (32%)338 (50%)92 (14%)25 (4%)