Cherng, Hua‐Jay J.

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.

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival. Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%. Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant. 588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx. With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA. In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse. Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.

7012 Background: DLBCL with expression of MYC and BCL2 (double expressor lymphoma, DEL), has an adverse prognosis. Venetoclax, an inhibitor of BCL2, was previously studied in combination with R-CHOP. A051701 is a phase II/III randomized trial of chemoimmunotherapy +/- venetoclax in DEL and double hit lymphoma cohorts. Here we report initial phase II results from the DEL cohort. Methods: Patients (pts) age ≥ 18 years (y) with untreated DEL were randomized 1:1 to R-CHOP (Arm 1) or R-CHOP-venetoclax (Arm 2). DEL was defined as MYC expression ≥40% and BCL2 expression ≥50%, without double hit cytogenetics. Enrollment was based on local pathology results that were centrally confirmed. Venetoclax 800 mg was given orally days 4-8 of cycle 1 and days 1-5 of subsequent cycles for up to 6 cycles. All cycles were supported by GCSF or peg-GCSF. The primary endpoint was progression-free survival (PFS) with 84% power to detect a HR of 0.518 corresponding to 2y PFS rate of 65% in Arm 1 and 80% in Arm 2 (1-sided α=0.20). Results: 119 DEL pts were enrolled: 60 Arm 1; 59 Arm 2. Analyses were performed for the modified intent-to-treat population, defined as eligible pts with confirmed DEL histology (n=113; 56 Arm 1, 57 Arm 2). Median age was 64 y (range 22-85); baseline demographic factors were well balanced except for advanced stage (more common in Arm 1; (77% vs 60%, p=0.051). Most pts were non-germinal center B cell-like by immunohistochemistry (Arm 1 72%, Arm 2 58%), high-intermediate/high risk IPI (Arm 1 54%, Arm 2 51%) and ECOG performance status 0-1 (Arm 1 95%, Arm 2 86%). BCL2 rearrangements were detected in 25% and 33% of pts on Arm 1 and Arm 2, respectively. Most pts completed therapy per protocol (84% Arm 1, 75% Arm 2). Median follow up is 27 months (m). No difference in PFS was observed with 12-m PFS estimates of 77% in Arm 1, 76% in Arm 2 [HR = 0.98 (95% CI: 0.48 – 2.01), p=0.95]. The end of treatment (EOT) overall and complete response rates among patients with an EOT assessment were 87.5% and 70% in Arm 1, and 90% and 82% in Arm 2. Overall survival (OS) was not statistically significantly different with 12-mo OS estimates of 94% in Arm 1 and 79% in Arm 2 [HR = 1.27 (95% CI: 0.57 – 2.79), p=0.56]. Grade ≥3 adverse events (AEs) occurred more frequently in Arm 2 (42% vs 76%). The most commonly increased grade ≥3 AEs included neutropenia (20% vs 47%), anemia (4% vs 25.5%), thrombocytopenia (5.5% vs 24%), febrile neutropenia (7% vs 16%) and fatigue (0% vs 11%). No grade 5 AEs on treatment were reported on Arm 1, and 3 were reported on Arm 2 (lung infection and sudden death NOS, both possibly related; respiratory failure, unlikely related). Conclusions: Adding venetoclax to R-CHOP in DEL pts did not improve PFS and resulted in increased toxicity. The study did not meet its primary endpoint in phase II, and so did not proceed to phase III. Clinical trial information: NCT03984448 .

Key Points An incidental histologic diagnosis of DLBCL was identified during temporary interruption of ibrutinib treatment in patients with CLL. In contrast to an aggressive clinical course typical of Richter transformation, these patients responded to reinitiation of ibrutinib alone.