Authors: Eleonora Calabretta | Kun Ping Lu | Xia Zhao | Chip Stewart | Maria C. Palazzo | Jennifer L. Crombie | Motohiro Murakami | Alex F. Herrera | Georg Lenz | Franck Morschhauser | F. Jardin | Matthew Sugidono | Connie Lee Batlevi | Oscar Cazares | W. Harris | Yanwen Jiang | P. Armand | Gaddy Getz | Margaret A. Shipp
Source: Hematological Oncology (article, 2025-06-01)
Field: Chemistry — Spectroscopy

LBA1 | THE BENEFIT OF POLA‐R‐CHP IN DLBclass‐DEFINED MOLECULAR SUBSETS OF NEWLY DIAGNOSED DLBCL IN THE POLARIX TRIAL E. Calabretta, K. Lu, X. Zhao, C. Stewart, G. Getz, and M. Shipp equally contributing author. The POLARIX clinical trial (NCT03274492) was a randomized, double-blind, placebo-controlled, international Phase 3 study that compared the efficacy of pola-R-CHP (polatuzumab [anti-CD79B] vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone) versus R-CHOP (R-CHP and vincristine) in newly diagnosed patients with intermediate- to high-risk (IPI 2–5) DLBCL. The progression-free survival (PFS) benefit for Pola-R-CHP at 2 years (Pola-R-CHP, 76.7% [95% CI: 72.7–80.8] versus R-CHOP, 70.2% [95% CI: 65.8–74.6]) led to its regulatory approval in many countries, and persisted at 5 years (Salles et al., ASH 2024). Given the recognized genetic heterogeneity in DLBCL and the identification of molecular subsets (Clusters 1–5, C1–5) with distinct survival trajectories and candidate therapeutic targets, we examined whether the benefit of Pola-R-CHP in POLARIX varied across these clusters in a retrospective analysis. We performed blended whole exome sequencing with a bait set that captured all DLBclass features including recurrent structural variants in the available diagnostic biopsies from POLARIX trial patients (n = 407 total, R-CHOP n = 198, Pola-R-CHP n = 209; 268× coverage). Thereafter, we used our recently described neural network-based probabilistic classifier, DLBclass, to assign each tumor to a genetic cluster (C1–C5). Treatment arms and baseline clinical characteristics were balanced in this cohort of genetically analyzed patients. All 407 tumors were assigned to a specific DLBclass cluster. In patients with C5 DLBCLs, which are characterized by recurrent MYD88L265P and CD79B gain-of-function mutations and enhanced B-cell receptor signaling, the 5-yr PFS was higher in the Pola-R-CHP arm versus the R-CHOP arm (70.4% [95% CI: 57.6–86.1] versus 42.0% [95% CI: 28.0–63.0]. The hazard ratio (HR) for Pola-R-CHP versus R-CHOP was 0.38 (95% CI: 0.19–0.75, p = 0.005, Figure 1) in patients with C5 DLBCLs, suggesting that the Pola-containing regimen abrogated the predicted poor outcome in this genetic subset. In contrast, the 5-yr PFSs were comparable for patients with C1-C4 DLBCLs in the two treatment arms (Figure 1). These analyses were not adjusted for multiple hypotheses testing. The benefit of Pola-R-CHP in C5 DLBCLs was retained in a multivariate analysis adjusted for IPI score (2 vs. 3–5), age (≤ 60 yrs vs. < 60 yrs), and cell-of-origin (activated B cell, germinal center B cell, unclassified, unknown) (HR 0.42 [95% CI: 0.21–0.82], p = 0.01). These data indicate that newly diagnosed patients with the genetically defined C5 subset of DLBCLs derive the greatest benefit from Pola-R-CHP therapy. More broadly, the study supports the use of DLBclass to design molecularly-driven clinical trials and inform practice. Keywords: aggressive B-cell non-Hodgkin lymphoma; molecular targeted therapies; tumor biology and heterogeneity Potential sources of conflict of interest: C. Stewart Other remuneration: Holds a patent from a discovery or technology relating to health or medicine within the last 2 years (Broad Institute). M. Palazzo Educational grants: Travel reimbursement to conference in the last 2 years (Roche) J. L. Crombie Consultant or advisory role: Consultant for Genentech/Roche, Genmab, Abbvie, Lilly, ADC Therapeutics, Novartis, Regeneron. Educational grants: Travel expenses from Regeneron. Other remuneration: Research funding from Genentech/Roche, Merck. M. A. Murakami Other remuneration: Research funding from imCORE (Genentech/Roche). A. F. Herrera Consultant or advisory role: Consulting for Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, ADC Therapeutics, Takeda, Genmab, Pfizer, Abbvie, Allogene Therapeutics Other remuneration: Research funding from Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca G. Lenz Consultant or advisory role: Consulting for Roche, Novartis, BMS, Abbvie, Sobi, Flindr, AstraZeneca, Gilead, Incyte, Genmab, ADC Therapeutics, PentixaPharm, Hexal-Sandoz, Lilly, MSD, Exscientia, Beigene, Pierre Fabre Honoraria: Honoraria from Roche, Novartis, BMS, Abbvie,Sobi, Flindr, AstraZeneca, Gilead, Incyte, Genmab, ADC Therapeutics, PentixaPharm, Hexal-Sandoz, Lilly, MSD, Exscientia, Beigene, Pierre Fabre Educational grants: Travel expenses from Beigene, Abbvie, Sobi, Roche, Gilead. Other remuneration: Participated in Speaker's Bureau for Sobi, Roche, Abbvie, BMS, Gilead, Incyte, Lilly, Beigene. Research funding from AstraZeneca, Abbvie, Sobi. F. Morschhauser Consultant or advisory role: Consulting for BMS, Abbvie, Roche, Miltenyi, Janssen, Modex therapeutics Honoraria: Honoraria from Takeda, Kite/Gilead, Astra Zeneca Other remuneration: Research funding from Roche, BMS, Kite/Gilead F. Jardin Honoraria: Honoraria from Roche, Gilead, Novartis, BMS, Johnson&Johnson Educational grants: Travel expenses by Abbvie, Roche M. Sugidono Employment or leadership position: Employed by Genentech, Inc. Stock ownership: Stock ownership of Genentech/Roche C. L. Batlevi Employment or leadership position: Employed by Roche/Genentech Consultant or advisory role: Consulting for BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, Abbvie, Genentech, Treeline Bioscience Stock ownership: Stock ownership of Roche Honoraria: Honoraria from Dava Oncology, TouchIME, Medscape Other remuneration: Research funding from Epizyme, Autolus, Roche, Vincerx O. Cazares Employment or leadership position: Employed by Genentech, Inc Stock ownership: Stock ownership Roche/Genentech W. Harris Employment or leadership position: Employed by Genentech, Inc. Stock ownership: Stock ownership of Roche Other remuneration: Holds patent of a discovery or technology relating to health or medicine (Genentech, Inc.) Y. Jiang Employment or leadership position: Employed by Roche/Genentech Stock ownership: Stock ownership of Roche/Genentech Educational grants: Travel grants from Roche/Genentech P. Armand Consultant or advisory role: Consulting for Merck, BMS/Celgene, GenMab, Enterome, Genentech/Roche, ATB Therapeutics, Regeneron Other remuneration: Research funding from Merck, BMS/Celgene, Adaptive, Genentech, IGM, Astra Zeneca, Pfizer, Kite G. Getz Employment or leadership position: Founder of Scorpion Therapeutics and Predicta Biosciences Consultant or advisory role: Consulting for Merck Stock ownership: Stock ownership of Scorpion Therapeutics and Predicta Biosciences Other remuneration: Research funding from IBM, Pharmacyclics/Abbvie, Bayer, Genentech, Calico, Ultima Genomics, Inocras, Google, Kite and Novartis. Inventor on patent applications from a discovery or technology relating to health or medicine (Broad Institute) M. Shipp Consultant or advisory role: Consulting for Bristol-Myers Squibb, AstraZeneca Honoraria: Honoraria from Bristol-Myers Squibb, AstraZeneca Educational grants: Travel expenses from Bristol-Myers Squibb, AstraZeneca Other remuneration: Research funding from Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Genentech. Holds patent from a discovery or technology relating to health or medicine (Broad Institute) Oncology ; Medicine ; Internal medicine Analytical Chemistry and Chromatography