A 3-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma.

Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (Double Expressor Lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (Double/Triple-Hit Lymphomas, DH/TH). TP53 mutations are detected in 20-25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or High-Grade Lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven pts (55%) had high-intermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progressionfree survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, p=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, p=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (p=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; p= 0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like proinflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3 high patients displayed longer survival compared with NR1H3 low cases and a highresolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.

688 Introduction. The prognosis of young DLBCL patients at high risk treated with standard R-CHOP is still rather poor. The role of intensified HDC+ASCT in first line treatment is still a matter of debate in the Rituximab era. The FIL planned a prospective randomized phase III trial with a 2×2 factorial design aimed at investigating the possible benefit of intensification with R-HDC+ASCT after R-dose-dense chemotherapy delivered at two different level of dose (R-CHOP14/R-MegaCHOP14). Patients and methods. The primary end-point was to increase 2-year Progression Free Survival (PFS) from 50% of the standard dose-dense arm (R-dose-dense chemotherapy) to 65% in the experimental arm (R-dose-dense chemotherapy followed by R-HDC +ASCT). Secondary end-point was the comparison between two different schemes of dose dense chemotherapy, R-CHOP14 and R-MegaCHOP14. Inclusion criteria were: age 18–65; untreated DLBCL; age-adjusted IPI (aa-IPI) score 2 or 3. Patients were stratified according to aa-IPI and randomized at diagnosis to receive: R-CHOP14 × 8 cycles; R-MegaCHOP14 (1200 mg/sqm Cyclophosphamide, 70 mg/sqm Doxorubicin, standard dose Vincristine and Prednisone) × 6; R-CHOP14 × 4 + R-HDC (Rituximab + High Dose Cytarabine + Mitoxantrone + Dexamethasone) followed by BEAM and ASCT; R-MegaCHOP14 × 4 + R-HDC + BEAM and ASCT. G-CSF support was mandatory. Central nervous system prophylaxis was done according to the Italian Society of Hematology guidelines. Results. From June 2005 to September 2010, 412 patients were enrolled. Histology was centrally reviewed in 90% of cases. Thirteen patients were excluded because of different histological subtypes in 10 and active hepatitis HCV and HBV in 3. 399 patients were eligible and randomized: 199 to R-HDC+ASCT and 200 to R-dose-dense chemotherapy without ASCT; according to the type of chemotherapy 203 were randomized to RCHOP14 and 196 to R-MegaCHOP14. All patients were evaluable for analysis. Clinical characteristics were: median age 49 (range 18;65); stage II/III/IV 6/29/65%; LDH higher than normal value 89%; ECOG PS >1 43%; aa-IPI score 2/3 74/26%; all characteristics were well balanced between patients treated with or without ASCT. In the R-HDC+ASCT group, 151 patients (76%) completed the treatment and 177 (88%) in the R-dose-dense chemotherapy arms. Complete Remission (CR) was seen in 296 (74%) patients; CR was 76% in R-HDC+ASCT vs. 72% in the R-dose-dense chemotherapy arms. Overall 26 patients (7%) had a partial remission and 64 (16%) did not respond. Treatment-related deaths occurred in 13 (3%) patients: 8 (4%) in the R-HDC+ASCT arms vs. 5 (2.5%) in R-dose-dense arms. Grade III/IV extrahematological toxicities were reported in 85 patients (43%) in the R-HDC+ASCT vs. 38 (19%) in R-dose-dense arms. With a median follow-up of 36 months, 3-year PFS and 3-year Overall Survival (OS) rates for the whole series were: 64% (95% CI:59–69) and 79% (95% CI:74–83) respectively. Patients randomized to R-HDC+ASCT had a 3-year PFS of 70% (95% CI:63–76) compared to 59% of those treated with R-dose-dense only (95% CI:51–66); p = .010 (Figure 1) with a HR of 0.64 (95% CI: 0.46–0.91, p = .012). No difference in 3-year PFS was observed between R-CHOP14 and R-MegaCHOP14. According to aa-IPI, 3-year PFS in R-HDC+ASCT vs R-dose-dense arms were: aa-IPI score 2 74% (95%CI:65–80) vs. 63% (95%CI:54–71) p = .047; aa-IPI score 3 59% (95% CI:45–71) vs. 46% (95% CI:32–59), p= .121. At the time of this analysis, 3-year OS is 81% (95% CI:74–86) in R-HDC+ASCT vs. 78% (95% CI:70–83) in R-dose-dense chemotherapy patients, p= .556. In a Cox-model including the four arms and assuming R-CHOP14 as reference, the risk of relapse was significantly reduced in both ASCT arms with a major effect in the R-CHOP14+R-HDC+ASCT arm (HR=0.58, 95% CI=0.36–0.93, p= .025) and a slight minor HR reduction in the R-MegaCHOP14+R-HDC+ASCT arm (HR=0.68, 95% CI=0.42–1.09 p= .109). Moreover PFS in both arms (ASCT vs no ASCT) was further compared within pre-planned subgroups analysis according to the type of dose-dense chemotherapy, age, gender, aa-IPI and bone marrow involvement: the benefit of R-HDC+ASCT in PFS was maintained across all subgroups with no statistically significant interaction. Conclusions. R-dose-dense chemotherapy followed by R-HDC and BEAM with ASCT significantly reduced the risk of progression compared to standard dose-dense chemotherapy (R-CHOP14 or R-MegaCHOP14) in young patients with high-risk DLBCL. Disclosures: Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees. Zaja:Roche: Membership on an entity's Board of Directors or advisory committees.

Introduction Brexucabtagene autoleucel (brexu-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy approved for relapsed or refractory (R/R) mantle cell lymphoma (MCL). The pivotal phase 2 trial ZUMA-2 enrolled 74 patients and infused 68, with an overall response rate (ORR) of 85% (complete response rate, 59%) among all patients who underwent apheresis (intention-to-treat, ITT). Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 15% and 31% of patients, respectively. However, very little is known regarding its safety and efficacy in the real-world setting. In our study, we report clinical outcomes of patients with R/R MCL treated with commercial brexu-cel. Methods Data were collected retrospectively from all consecutive patients with R/R MCL who underwent apheresis for brexu-cel at 7 European sites, in 3 different countries, from start of the Compassionate Use Program in Europe (February 2020) until June 2021. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for brexu-cel (ITT). Results During the study period 28 patients with R/R MCL underwent apheresis for brexu-cel. At data cutoff, 19 (68%) patients had received a CAR T-cell infusion whereas 9 (32%) had not due to progressive disease (n=4), pending manufacturing process (n=4) or achieving a complete response with bridging (n=1). Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 67 years (range 51-78) and 89% were male. Most of the patients had a high-risk simplified Mantle Cell Lymphoma International Prognostic Index score (63%), an advanced stage (84%) and 32% had received a prior autologous stem cell transplant. Median follow-up after CAR T-cell infusion was 5 months (range 1-10). Fifteen patients (79%) received bridging therapy after apheresis, including ibrutinib in 8/15 (53%) patients, immunochemotherapy in 7/15 (47%) and radiotherapy in 6/15 (40%). Half the patients (53%) had progressive disease as best response to bridging; 4 (27%) patients had stable disease, 2 (13%) partial response and 1 (7%) achieved a complete response. Median time from apheresis to brexu-cel delivery was 30 days (range 22-48) and median time from apheresis to infusion was 42 days (range 28-77). Among the infused patients, 17 (89%) and 12 (63%) developed any grade of CRS and neurotoxicity, respectively. Grade >2 CRS and neurotoxicity events occurred in 1 (5%) and 5 (26%) patients, respectively. Tocilizumab was administered to 16 (84%) patients and steroids to 12 (63%) patients. Two (11%) patients required admission to the Intensive Care Unit for grade 4 neurotoxicity and septic shock, respectively. At data cutoff, all infused patients were alive except for 1 patient who died due to progressive disease. Other adverse events are summarized in table 2. Best response achieved among the infused patients included complete remission in 13 (68%) patients and partial remission in 4 (21%) patients, with an ORR of 89%. Stable disease and progressive disease were the best response in 1 (5%) patient each. Median progression-free survival (PFS) and overall survival (OS) for infused patients were not reached with the current follow-up (Figure 1); estimated 6-month OS was 91% (95%CI 50.8-98.6) and 6-month PFS was 83% (95%CI 55.4-94.2). Three (16%) patients progressed at days 14, 33 and 90 post-infusion. In the univariate analysis, the percentage of patients with complete response was consistent across key subgroups with high-risk features (including blastoid morphology and TP53 mutation). Response rate and survival analysis by ITT will be presented at the meeting when all products still undergoing manufacturing are complete. Conclusion This multicenter, international study confirms that treatment with brexu-cel in patients with R/R MCL in the real-world setting has very promising efficacy, including in high-risk patients. The early safety profile was manageable and similar to the pivotal trial. Longer follow-up is needed to better assess long-term efficacy and ITT analysis. Figure 1 Figure 1. Disclosures Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Chiappella: Takeda: Other: advisory board; Clinigen: Other: lecture fee, advisory board; Novartis: Other: lecture fee; Gilead Sciences: Other: lecture fee, advisory board; Janssen: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Servier: Other: lecture fee; Celgene Bristol Myers Squibb: Other: lecture fee, advisory board; Astrazeneca: Other: lecture fee; Incyte: Other: lecture fee. Corral: Gileqd: Honoraria; Gilead: Consultancy; Novartis: Consultancy. Bastos-Oreiro: BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Kite: Speakers Bureau. Schmidt: Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Consultancy, Other: Travel, Accommodations, Expenses; Bayer Healthcare: Research Funding; Janssen: Other: Travel, Accommodations, Expenses. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Kwon: Gilead: Honoraria. Martín García-Sancho: Janssen: Honoraria, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Zinzani: Beigene: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Incyte: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Subklewe: Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Speakers Bureau; Klinikum der Universität München: Current Employment; Gilead: Consultancy, Research Funding, Speakers Bureau; Miltenyi: Research Funding; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Barba: Novartis: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria.