Evaluation of CAR-Hematotox Scoring As a Predictor of Infection Risk Following Treatment with Odronextamab (a CD20×CD3 Bispecific Antibody) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction

Severe infections and cytokine release syndrome (CRS) are commonly observed following treatment with T-cell-engaging therapies such as CAR-T therapies and CD3-targeting bispecific antibodies (bsAbs). The CAR-HEMATOTOX model includes markers of hematopoietic reserve (absolute neutrophil count [ANC], platelet count, hemoglobin) and inflammation (C-reactive protein [CRP], ferritin), measured at baseline prior to lymphodepletion, and has been shown to help identify patients at heightened risk of severe infections and poor outcomes following CAR-T therapy (Rejeski K et al. J Immunother Cancer 2022). The model was trained and validated using real-world data from patients with large B-cell lymphoma receiving commercial CAR-T therapies (Rejeski K et al. Blood 2021).

Odronextamab, a CD20×CD3 bsAb, has been investigated in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in Phase 1 and 2 studies in patients similar to those receiving third-line or later commercial CAR-T therapy. Here, we evaluate whether CAR-HEMATOTOX scores at baseline can help identify patients with R/R DLBCL at risk of severe infections or CRS when receiving odronextamab.

Methods

This retrospective analysis of the ELM-1 and ELM-2 studies (previously described; Ayyappan S et al. ASH 2023) evaluated infections in 219 patients receiving odronextamab monotherapy for R/R DLBCL. All patients received steroid premedication and infection prophylaxis. Baseline CAR-HEMATOTOX scores were calculated for each patient, with 1 point assigned for ANC ≤1200/µL, hemoglobin ≤9 g/L, platelet count 75-175 × 10⁹/L, CRP ≥3 mg/dL, and ferritin 650-2000 ng/mL, and 2 points assigned for platelet count <75 × 10⁹/L and ferritin >2000 ng/mL. Patients were stratified into 2 groups based on the sum of scores: low risk (HT^low, 0-1) and high risk (HT^high, ≥2). Infection rates were analyzed by risk score for different periods: events occurring during the first 30, 60, and 90 days of treatment, and until end of study. CRS rates were analyzed by risk score for events occurring within the first 30 days.

Results

Of the 219 patients evaluated, complete baseline scores were available for 87% (n=190). A majority of patients were HT^high (51.6%) at baseline. The median age was 65 years (range 24-89), median number of prior lines of therapy was 3 (range 1-9), and 11% of patients had received a prior autologous stem cell transplant. The median values for hematologic baseline measures and the proportion of patients who were HT^high at baseline were similar between the odronextamab group and the original CAR-HEMATOTOX population (51.6% vs 48.9%). The median duration of odronextamab exposure was 13.43 weeks.

In the first 30 days, Grade ≥3 infections were observed more frequently in the HT^high compared with the HT^low group (11.2% vs 5.4%, nominal P-value 0.194). This was consistent at 60 days (17.3% vs 8.7%, nominal P-value 0.089) and 90 days (22.4% vs 16.3%, nominal P-value 0.360), and when excluding COVID-19 infections at 30 days (11.2% vs 4.3%, nominal P-value 0.107), 60 days (17.3% vs 6.5%, nominal P-value 0.026), and 90 days (22.4% vs 14.1%, nominal P-value 0.190).

The rate of Grade ≥2 CRS was more than double in the HT^high group compared with the HT^low group (26.5% vs 12.0%, nominal P-value 0.016).

Conclusions

Simple, accessible tools are needed to help identify patients who may have greater susceptibility to infections and other cytokine-mediated toxicities during odronextamab therapy. This study is the first to evaluate use of CAR-HEMATOTOX scores to identify patients with R/R DLBCL at risk of severe infections and Grade ≥2 CRS events following treatment with odronextamab, a T-cell-engaging bsAb. Preliminary results of this exploratory, post hoc analysis indicate that HT^high may be useful in identifying patients at high risk of developing infections during the first 90 days of treatment with odronextamab and at high risk of CRS events. Additional analyses, including clinical phenotypes of neutrophil recovery, cumulative infection rates, infection types, IgG levels, impact of steroid utilization, infection prophylaxis, re-baselining CAR-HEMATOTOX at 90 days, and association with long-term infection risk, will be presented. Prospective studies to investigate the impact of additional prophylaxis and monitoring measures for patients who are HT^high at baseline are warranted.

Matasar:Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; Merck: Current equity holder in publicly-traded company; Bayer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; GM Biosciences: Consultancy, Research Funding; BMS/Celgene: Honoraria; Kite: Honoraria; Epizyme: Honoraria; IMV Therapeutics: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria. Tucker:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunovant Corps: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:BeiGene: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Samsung Bioepis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IMBDx Inc: Honoraria; Daiichi Sankyo, HK inno.N, F. Hoffmann-La Roche Ltd/Genentech, Yuhan: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Honoraria; Boryung: Consultancy. Luminari:BeiGene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Cheng:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Li:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Shariff:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company.

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed or refractory DLBCL