Severe neutropenia after treatment with T-cell engaging bispecific antibodies is associated with higher rates of CRS and disease response

Abstract

Abstract Background T-cell engaging bispecific antibodies (BsAbs) have shown promising activity in patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), including those that have progressed after chimeric antigen receptor (CAR) T-cell therapy. Bispecific antibodies have unique side effect profiles related to robust activation of the immune system. Although the rates of severe cytokine release syndrome (CRS) and neurotoxicity are significantly lower with BsAbs than CAR T, hematological toxicity is increasingly recognized as a common adverse event, with reported rates of grade ≥ 3 neutropenia ranging from 15 to 65% in pivotal trials. We sought to further characterize the incidence of cytopenias in patients receiving BsAbs, evaluate their impact on outcomes and identify predisposing risk factors. Methods We collected baseline, treatment and outcome information from our institutional databases, identifying patients with r/r NHL or MM treated with a BsAb as a single agent between 2020–2024. To test differences between groups, Wilcoxon rank sum test was used on numerical variables, and Fisher's exact test or Pearson's Chi-squared test for categorical variables. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan–Meier methods, with log-rank test used for comparisons between groups. Median follow-up time was estimated using the reverse Kaplan-Meier method. All tests were performed as two-tailed tests, with p < 0.05 considered statistically significant. “Cytopenia” was defined as any grade neutropenia and/or grade ≥3 anemia/thrombocytopenia. Results We identified 199 patients treated with single-agent BsAb, 56 (28%) NHL and 143 (72%) had MM. BsAbs prescribed included teclistamab (n = 80, 40%), talquetamab (n = 38, 19%), epcoritamab (n = 34, 17%), elranatanab (n = 25, 13%), mosunetuzumab (n = 14, 7%), odronextamab (n = 6, 3%) and glofitamab (n = 2, 1%). Median age at initiation of therapy was 68 years (IQR 61 – 76 years), 45% of patients were women, 74% were White, and 22% were Black. Cytopenia was observed in 152 patients (76%). Neutropenia (any grade) occurred in 125 (63%) patients, severe neutropenia (SN; ANC <500 cells/µL) in 51 (26%), grade ≥3 anemia in 84 (34%) and grade ≥3 thrombocytopenia in 66 (34%). The incidence of cytopenia was similar among patients on all BsAbs (p=0.4), ranging from 62% with epcoritamab to 100% with glofitamab. Pre-treatment characteristics associated with development of cytopenia included lower albumin (median 3.7 vs. 3.95 g/dL, p <0.05), higher CRP (median 2.2 vs. 0.4 mg/L, p <0.05), and lower baseline WBC (median 4.4 vs. 6.7x103/µL, p < 0.05), ANC (2.7 vs. 4.5x103/µL, p < 0.05), hemoglobin (9.7 vs. 12.4 g/dL, p < 0.05) and platelets (median 136 vs. 207 x103/µL, p<0.05), when compared to the group with no cytopenias. Previous CAR T cell treatment was not associated with higher incidence of cytopenia (79% vs. 77%, p=0.79), even when CAR T was received in the preceding six months (p = 0.99). Patients experiencing severe neutropenia (SN) had higher rates of CRS (75% vs. 54%, p=0.01), longer time on BsAb therapy (median 5.8 vs. 2.7 months, p=0.01), and higher overall response rate (91% vs. 73%, p=0.01). However, we observed a numeric trend towards higher rates of treatment discontinuation due to BsAb toxicity in patients with SN (25 vs. 14%, p = 0.06). Median follow-up did not differ between patients with SN (13.4 mo, 95% CI 9.9 - 24.8) and no SN (12.6 mo, 95% CI 10.7 - 15.9). The presence of SN was not associated with statistically significant differences in survival outcomes [median PFS: SN 10.4 mo (95% CI 8.1-25.4) vs. no SN 8 mo (95% CI 4.6-12.9); and median OS: SN 24.9 mo (95% CI 14.5-not reached) vs. no SN 14.1 mo (95% CI 11.4-27.4)]. Conclusions In our cohort of patients with r/r NHL and MM treated with a variety of single agent T-cell engaging BsAbs we observed a high incidence of all-grade and severe cytopenias. Higher rates of CRS and disease response in patients experiencing SN suggest the mechanism underlying hematologic toxicity is related to immune activation and possibly anti-tumor immune response. The absence of improved survival outcomes could be due to higher rates of toxicity-related treatment discontinuation. Future studies aimed at prevention and mitigation of BsAb-associated cytopenias while avoiding impacting disease control could improve outcomes of patients treated with this modality.