The Predictive Value of Cell-of-Origin Subtype By Hans Algorithm in 718 Patients with Large B Cell Lymphoma Receiving Polatuzumab Vedotin

Background:

Polatuzumab vedotin (Pola) is an antibody drug conjugate targeting CD79b that incorporates the microtubule disrupting monomethyl auristatin E payload. Pola was approved in 2023 for the upfront treatment of diffuse large B cell lymphoma (DLBCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (polaRCHP) based on the POLARIX trial. However, the activity of pola appears to vary based on DLBCL cell of origin (COO) subtype, with greater efficacy in activated B cell (ABC) DLBCL compared to germinal center B cell (GCB) DLBCL (Russler-Germain Blood 2023). When outcomes in POLARIX are stratified by COO, polaRCHP demonstrated progression free survival (PFS) and overall survival (OS) benefits over RCHOP in patients with ABC but not GCB subtype DLBCL (PFS HR 0.34 ABC vs 1.03 GCB, OS HR 0.27 ABC vs 1.64 GCB; Morschhauser ASH 2023 and FDA data). Most prospective studies of pola used gene expression to assess COO, which is not readily clinically available. This study aims to examine if COO subtype by Hans algorithm (based on CD10, BCL6, and MUM1 expression by immunohistochemistry) is predictive of pola responses and outcomes in patients with large B cell lymphoma (LBCL).

Methods:

We conducted a retrospective, multicenter observational study of adults with LBCL who received pola (monotherapy or in combination) from 2015-2024 with Hans algorithm COO data and response assessment available. Patients were stratified by receipt of pola in the frontline vs relapsed/refractory (R/R) setting. The primary endpoint was overall response rate (ORR) to pola-based treatment in GCB vs non-GCB subtypes. Secondary endpoints included complete response rate (CRR), PFS, and OS. For time to event endpoints, patients responding to pola who received CAR T or stem cell transplantation prior to progression were censored at time of cellular therapy. Demographics were summarized by descriptive statistics. Comparative and survival analyses used Chi squared/Fischer exact tests and Kaplan Meier analysis. Data cutoff was July 1, 2024.

Results:

718 patients were included. Median follow-up was 15 months (interquartile range [IQR] 8-32). Median age at LBCL diagnosis was 66 years (IQR 56-74); 62% were men; 69 (10%) had double hit lymphoma (DHL); 129 (18%) had underlying low grade lymphoma. Pola was used in the frontline setting in 293 (41%) patients, of whom 139 (47%) had GCB vs 154 (53%) non-GCB COO. Of the 426 patients receiving pola for R/R LBCL (including one patient receiving pola retreatment), 224 (53%) had GCB vs 202 (47%) non-GCB COO.

Among patients receiving pola-based regimens in the R/R setting (GCB vs non-GCB: pola monotherapy = 7% vs 4%, pola + R = 26% vs 26%, pola + BR = 55% vs 61%, pola + other = 12% vs 9%; p = 0.44), the ORR in GCB vs non-GCB LBCL was 36% vs 61% (p < 0.001), while CRR in GCB vs non-GCB was 17% vs 36% (p < 0.001). COO remained a significant component of logistic multivariate regression models of ORR (p < 0.001) and CRR (p < 0.001) when incorporating IPI at original LBCL diagnosis, histology, DHL status, and refractory status to frontline therapy. Despite this, no significant PFS or OS differences by COO were seen, potentially due to approximately 1/4 patients being censored due to receiving subsequent cellular therapy (e.g. CAR T) prior to progression.

In patients receiving frontline pola-based regimens (of which 275 [94%] included an anthracycline), ORR and CRR were similar in GCB vs non-GCB (ORR 89% vs 88% p > 0.5; CRR 76% vs 77% p > 0.5). While PFS and OS were similar between COO groups in the frontline cohort, follow-up and cohort size were limited.

Conclusion:

Based on this real-world evidence, COO classification by Hans algorithm is a strong predictor of the activity of pola-containing therapy in R/R LBCL, with significantly higher ORR and CRR in patients with non-GCB compared to GCB COO LBCL. This aligns with the cumulative existing evidence. ORR and CRR to pola-containing therapy in the frontline setting did not differ significantly by COO subtype, but longer follow-up of larger cohorts is needed to clarify the predictive role of COO by Hans algorithm in this setting, especially considering the PFS advantage with polaRCHP in POLARIX was not associated with significant differences in ORR or CRR. Overall, clinicians should consider factoring COO subtype into treatment decisions regarding pola-containing regimens, and studies of pola-based therapies should stratify patients and report outcomes by COO subtype.

Major:Roche/Genentech: Consultancy; Incyte: Research Funding. Epperla:Beigene: Speakers Bureau; Genetech: Speakers Bureau; Lilly: Other: Advisory Board; Novartis: Consultancy; Ispen: Other: Advisory Board. Cherng:ADC Therapeutics: Honoraria. Wallace:Integrity CME: Honoraria. Lynch:Merck: Honoraria; SeaGen, Foresight Diagnostics, Abbvie, Janssen: Consultancy; TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt, Merck, Janssen: Research Funding. Mei:Novartis: Consultancy; Synethkine: Consultancy; SeaGen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; BMS: Research Funding; Incyte: Research Funding; Beigene: Research Funding; Genentech: Research Funding. Merryman:Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; DG Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Merck: Research Funding. Fenske:ADC Therapeutics: Consultancy; Lilly: Consultancy; AstraZeneca: Consultancy; Seagen: Consultancy; Kite: Consultancy; Beigene: Consultancy. Alhaj Moustafa:AbbVie: Consultancy. Hilal:BeiGene: Consultancy, Research Funding. Nowakowski:F. Hoffmann-La Roche Limited: Consultancy; Selvita Inc: Consultancy; Zai Laboratory: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; Karyopharm Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Incyte Corporation: Consultancy; Constellation Pharmaceuticals: Consultancy; Blueprint Medicines Corporation: Consultancy; MorphoSys AG: Consultancy, Research Funding; MEI Pharma: Consultancy; Fate Therapeutics: Consultancy; TG Therapeutics Inc: Consultancy; Segen: Consultancy; Curis: Consultancy, Research Funding; Debiopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Ryvu Therapeutics: Consultancy; AbbVie Inc.: Consultancy; Kymera Therapeutics: Consultancy. Wang:Kite: Honoraria; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; InnoCare, AbbVie: Consultancy; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board. Torka:Genmab: Consultancy; Genentech: Consultancy; Lilly Oncology: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy; Seagen: Consultancy. Russler-Germain:Genentech: Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy.