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1714 Inflammation-Based Scores Predict Survival after CD3xCD20 Bispecific T Cell Engagers in R/R LBCL

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Diseases, Aggressive lymphoma, Lymphoid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Giulia Magno1*, Kai Rejeski, MD2,3, Giulia Rappa2,4*, Sissi Kupf2*, Sophia Stock, MD2,5,6*, Alessandra M. E. Holzem, MD2*, Julia Katharina Scholz, MD7*, Rebecca Wurm-Kuczera, MD8*, Shimrit Harlev9*, Nadine Kutsch, MD10*, Giuliano Filippini Velazquez, MD11*, Stephanie Mayer12*, Maria Landwehr, MD13*, Jamila Mammadova, MD14*, Sandeep S. Raj, MD3, Roni Shouval, MD, PhD3, Fabian Mueller, MD7, Björn Chapuy8, Ofrat Beyar-Katz, MD, PhD9*, Udo Holtick10*, Christoph Schmidt, MD, PhD11*, Hendrik Poeck12*, Gloria Iacoboni, MD13*, Pere Barba, MD13, Ning Dong, MD MS15, Veit L. Buecklein, MD2,4,5* and Marion Subklewe, MD2,4,5

1Department of Medicine III, LMU University Hospital, LMU Munich, Bolzano, Germany
2Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
3Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
4Laboratory for Translational Cancer Immunology, LMU Gene Center, LMU Munich, Munich, Germany
5German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
6Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany
7Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
8Department of Hematology, Oncology and Cancer Immunology, Charité - University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
9Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
10Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; German CLL Study Group, University of Cologne, Cologne, Germany
11Department of Hematology, University Hospital Augsburg, Augsburg, Germany
12Department of Internal Medicine III (Haematology/Oncology), University Hospital Regensburg, Regensburg, Germany
13Department of Hematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
14Vanderbilt University Medical Center, Nashville, TN
15Moffitt Cancer Center, Tampa, FL

Management of relapsed/refractory Large B Cell Lymphoma (r/r LCBL) after CD19 Chimeric Antigen Receptor (CAR) T cells represents a major clinical challenge. Glofitamab and Epcoritamab, two CD3xCD20 bispecific T cell-recruiting antibodies, have recently been approved for third-line treatment. However, real-world experience with these bispecifics is limited, and predictive biomarkers for efficacy are lacking. Given that both bispecifics and CAR-T cells mediate their antineoplastic activity by redirecting the patient’s T cells, we hypothesized that biomarkers associated with outcomes from CD19 CAR-T therapy would similarly predict outcomes post-CD20-directed bispecifics. To test this, we applied two established models from CAR-T cell therapy—CAR-HEMATOTOX (Rejeski et al, Blood 2021) and InflaMix (Raj et al, ASH Annual Meeting 2023) to our cohort of 63 patients treated with bispecifics.

In this international, multicenter observational study, we analyzed outcomes of r/r LBCL patients treated with Glofitamab (n=55) or Epcoritamab (n=8) monotherapy. Baseline features were assessed on the first day of the first treatment cycle. Parameters were derived from standard laboratory analysis. For a subset of patients, cytokines were measured using the Legendplex flow-cytometry based multiplex immunoassay. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Univariate and multivariate analyses of PFS were conducted using the Cox proportional hazards model.

The CAR-HEMATOTOX model integrates five variables (ANC, hemoglobin, platelet count, C-reactive protein, and ferritin) determined at the time of lymphodepletion. The InflaMix model, based on up to 14 laboratory values assessed prior to CAR-T cell infusion, stratifies patients into inflammatory and non-inflammatory clusters. Both models discriminate between cohorts with significantly different clinical outcome.

Median age was 67 years (range 35-86). Patients had received a median of 3 prior therapy lines (range 1-8), 46 patients (73%) underwent prior CAR-T cell therapy and 21 patients (33%) were refractory to their latest line of therapy. The objective response rate was 54%, with 16 complete remissions (25%) and 18 partial remissions (29%). With a median follow up of 4.1 months, median PFS was 3.5 months and median OS was 13.5 months. Cytokine release syndrome (CRS) occurred in 38.6% of patients (22/57), high grade CRS (grade ≥3) was reported in 3 cases. ICANS was noted in 5.3% of patients (3/57), with one patient experiencing high grade ICANS.

In a univariate Cox regression analysis, the examined clinical factors (including sex, age, ECOG performance status, histology, Ann Arbor stage, presence of extranodal disease, number of prior lines of therapy and prior CAR-T exposure) were not significantly associated with PFS. Among the analyzed laboratory values, however, higher LDH (p<0.001), CRP (p=0.002), and ferritin levels (p=0.006) as well as low hemoglobin (p=0.021) were significantly associated with inferior PFS, highlighting inflammation as a key factor associated with response.

Based on data availability, CAR-HEMATOTOX and InflaMix were applied to 45 and 55 patients, respectively. Patients presenting with a CAR-HEMATOTOX score ≥2 (24/45) showed inferior PFS (1.9 months vs not reached, p=0.005) and OS (3.9 vs 13.7 months, p=0.027). When applying InflaMix, 38.2% of the patients were assigned to the inflammatory cluster, showing a significantly shorter median PFS (1.7 vs 6.9 months, p<0.001) and OS (2.7 months vs not reached, p<0.001). In a multivariable Cox regression analysis accounting for LDH, age, prior CAR-T exposure and bispecific product, higher LDH and assignment to the inflammatory cluster by InflaMix remained independent risk factors for inferior PFS. Notably, InflaMix had the most significant effect on PFS (p=0.005).

In summary, our multi-center international real-world data analysis demonstrates that the CAR-HEMATOTOX and the InflaMix models effectively identify LBCL patients with high risk of treatment failure, highlighting the importance of immune dysregulation in failure to bispecifics. Further validation of both models is ongoing. These scores may guide patient stratification into bispecifics monotherapy, combinatorial approaches and inclusion in clinical trials to further advance treatment approaches in LBCL.

Disclosures: Rejeski: Kite/Gilead: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Pierre-Fabre: Other: Travel Support. Scholz: Beigene, Abbvie, Janssen, Novartis: Other: travel support . Kutsch: BMS: Honoraria; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Abbvie: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Lilly: Honoraria, Other: Travel grants; BeiGene: Other: Travel grants. Mueller: Kite/Gilead; Astrazeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Miltenyi, BMS, Janssen, Novartis: Consultancy, Honoraria, Speakers Bureau; Sobi, Abbvie, Beigene: Honoraria, Speakers Bureau; ArgoBio, CRISPRTherapeutics: Consultancy. Chapuy: Sobi, Roche: Other: travel support ; AbbVie, Ars tempi, Astra Zeneca, BMS, Incyte, Janssen, Gilead, KML, Roche, Sobi, Ono: Honoraria; AbbVie, Bristol Myers Squibb, Incyte, Janssen, Roche, and Sobi: Consultancy. Holtick: Roche: Honoraria. Iacoboni: AbbVie: Honoraria, Other: Travel Support; AstraZeneca: Honoraria, Other: Travel support; BMS: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Autolus: Consultancy; Miltenyi: Consultancy, Honoraria; Novartis: Honoraria; Autolus, Bristol-Myers Squibb, Kite/Gilead, Miltenyi, Novartis: Consultancy; AbbVie, AstraZeneca, Autolus, Bristol-Myers Squibb, Kite/Gilead, Miltenyi, Novartis, Lilly and Sandoz: Honoraria; AbbVie, AstraZeneca, Kite/Gilead, Miltenyi: Other: Travel support. Barba: Autolus: Consultancy; Kite-Gielead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Dong: Robert A. Winn Diversity in Clinical Trials Career Development Award, funded by Gilead Sciences: Research Funding; EUSA Pharma, a Recordati Group company.: Research Funding. Buecklein: Otsuka: Consultancy; Pfizer: Consultancy, Honoraria; Pierre Fabre: Consultancy; Amgen: Consultancy, Honoraria; BMS: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Novartis: Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Subklewe: Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Roche, Seagen, Takeda: Research Funding; AbbVie, Amgen, Autolus, AvenCell, BMS, CanCell Therapeutics, Genmab US, Gilead, Ichnos Sciences, Incyte Biosciences, Interius BioTherapeutics, Janssen, Miltenyi Biomedicine, Molecular Partners, Nektar Therapeutics, Novartis, Orbital Therapeutics, Pfizer,: Honoraria; AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche, Springer Healthcare: Speakers Bureau.

*signifies non-member of ASH