Faculty Bibliography

IMPORTANCE/UNASSIGNED:T-cell-engaging bispecific antibodies (BsAbs) are increasingly used in B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). As these agents transition into earlier courses of therapy and broader clinical use, understanding their safety profile is critical. While second primary malignant neoplasms (SPMs) represent a key long-term safety signal, small sample sizes, single-arm trials, short follow-up, and heterogeneous reporting have limited reliable estimation of their frequency. OBJECTIVE/UNASSIGNED:To estimate the frequency of reported SPMs after BsAb therapy and evaluate whether study-level characteristics and reporting definitions influence observed estimates. DATA SOURCES/UNASSIGNED:PubMed and Embase were searched from inception through October 1, 2025, following a prespecified protocol registered in PROSPERO. STUDY SELECTION/UNASSIGNED:Clinical trials and real-world studies of BsAbs in adults with NHL or MM reporting SPM outcomes. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Data were extracted following PRISMA guidelines. Pooled SPM frequencies were calculated using random-effects meta-analysis of single proportions. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Reported SPM occurrence during available follow-up was categorized as (1) total SPMs reported, (2) SPMs leading to treatment discontinuation, and (3) SPMs leading to death. RESULTS/UNASSIGNED:Of 494 records, 20 studies (26 cohorts; 2551 patients) met inclusion criteria. Among 8 studies (10 cohorts; 1003 patients) reporting total SPMs, random-effects meta-analysis yielded a pooled estimated proportion of 3.5% (95% CI, 1.8-6.9) at a median (range) follow-up of 17.4 (5.7-25.6) months. Disease-specific estimates were 3.8% (95% CI, 2.3-6.3) for NHL and 3.4% (95% CI, 0-76.7) for MM. A total of 6 studies (8 cohorts; 748 patients) reporting SPMs leading to treatment discontinuation showed a pooled estimate of 2.2% (95% CI, 1.5-3.1). A total of 19 studies (24 cohorts; 2330 patients) reporting SPMs leading to death yielded a pooled estimate of 1.4% (95% CI, 1.1-1.9). In exploratory meta-regression analyses of prespecified study-level covariates (follow-up duration, disease category, prior therapy courses, and age), no variables were associated with total SPM estimates. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this systematic review and meta-analysis, despite relatively short follow-up, SPMs were a measurable and clinically relevant complication of BsAb therapy. Heterogeneous and inconsistent reporting currently complicates their comprehensive assessment, highlighting the need for standardized long-term safety surveillance in clinical trials examining BsAbs.

BACKGROUND:CD19-directed chimeric antigen receptor T-cell (CAR T) therapy has significantly improved outcomes for patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) but is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS), a major cause of morbidity and mortality. Preclinical and early phase clinical studies suggest that interleukin-1 blockade with anakinra may mitigate ICANS without impairing CAR T efficacy. However, real-world data evaluating the efficacy and safety of prophylactic anakinra remain limited. OBJECTIVES/OBJECTIVE:We performed a retrospective analysis comparing CAR T toxicities and clinical outcomes among patients treated with prophylactic anakinra versus controls using inverse probability of treatment weighting (IPTW), hypothesizing that anakinra prophylaxis would be associated with decreased severe ICANS. STUDY DESIGN/METHODS:In 2023, our institution implemented a policy for anakinra prophylaxis for high-risk patients based on promising early phase data. We conducted a single-center retrospective cohort study of 176 adult patients with R/R B-NHL who received CD19 CAR T therapy between 2018 and 2025. The analysis was restricted to patients meeting institutional criteria for anakinra prophylaxis (age ≥65 years or receipt of a CD28 costimulatory domain CAR T product), excluding those with baseline ICE score <8. Patients treated with anakinra in the post-policy era were compared with patients treated prior to the implementation of the policy. Inverse probability of treatment weighting (IPTW) was used to balance baseline clinical and disease-related covariates between groups. RESULTS:After IPTW, patients receiving prophylactic anakinra had a higher incidence of any-grade ICANS compared with those who did not (40.0% vs 23.0%, p = 0.03), while rates of grade ≥3 ICANS were similar between groups (p = 0.62). In multivariate regression, anakinra prophylaxis was associated with increased odds of any-grade ICANS (aOR 3.22; 95% CI 1.39-7.46) but not grade ≥3 ICANS (aOR 1.84; 95% CI 0.61-5.5). Rates of all-grade CRS were comparable (p = 0.74); however, in multivariate regression, anakinra prophylaxis was associated with increased odds of grade ≥3 CRS (aOR 17.83; 95% CI 1.30-245.21), though the estimate was imprecise due to sparse events. Grade ≥3 infections were more common in the anakinra cohort (21.5% vs 7.3%; p = 0.01) by day 30 and by day 90 (27.1% vs 10.4%; p = 0.01). Grade ≥3 infections remained associated with use of anakinra in multivariate regression (day 30: aOR 7.08; 95% CI 1.90-26.30, p = 0.004) (day 90: (aOR 5.59; 95% CI 1.83-17.04; p = 0.003). No differences in response rates, event-free or overall survival were observed between groups. CONCLUSION/CONCLUSIONS:In this single-center historical comparison of high-risk patients receiving CD19 CAR T cells, prophylactic anakinra did not reduce severe ICANS and was associated with increased immune-mediated toxicities and infectious complications. Causal inference is limited by policy-driven treatment assignment, residual temporal confounding, and limited practical overlap. These findings suggest the need for caution in routine use of anakinra prophylaxis outside of clinical trials and underscore the importance of prospective studies to better define optimal toxicity mitigation strategies.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapies have drastically improved outcomes for patients with relapsed or refractory multiple myeloma. While CAR-T associated cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) are well characterized, non-ICANS neurologic toxicities (NINTs) remain poorly defined, with limited data regarding incidence and risk factors. We performed a systematic review and meta-analysis of prospective clinical trials and real-world studies reporting neurologic toxicities following BCMA-directed CAR T therapy, following PRISMA guidelines. Random-effects meta-analysis was used to calculate a pooled point estimate of NINTs. Meta-regression was conducted to evaluate treatment-related predictors of risk. Reported NINTs were categorized by clinical phenotype when sufficient detail was available. Fifty-five cohorts comprising 4,630 treated patients were included. The pooled point estimate for NINTs was 0.81% (95% CI, 0.37-1.77%). Incidence differed significantly by product, with a significantly higher frequency of NINTs following ciltacabtagene autoleucel (cilta-cel) compared with idecabtagene vicleucel (ide-cel) (4.6% vs 0.5%; p=0.001) and experimental BCMA-directed constructs (4.6% vs 0.3%; p=0.02). Additionally, meta-regression identified cilta-cel as independently associated with increased NINTs risk compared with ide-cel. Cranial nerve palsies were the most frequently reported phenotype (32.3% 43 events), followed by movement and neurocognitive treatment-emergent adverse events (12%, 16 events), then peripheral neuropathies (7.5%, 10 events). This meta-analysis establishes that NINTs are a rare but important toxicity following BCMA-directed CAR-T therapy, particularly cilta-cel. Standardized definitions and improved reporting of NINTs are needed to better characterize risk and inform surveillance strategies.

The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post-CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but there are limited real-world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high-grade B cell lymphoma treated with R-GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy (n = 100), those utilizing R-GemOx as a bridge to ASCT or CAR T (n = 83), and those aged 70 and older (n = 71). Overall response rates (ORRs) for all patients treated with R-GemOx were 45% with a complete response (CR) rate of 29%. The median event-free survival (EFS) was 2.3 months, and the median overall survival (OS) was 13.5 months. Patients receiving R-GemOx without intent for ASCT or CAR T had ORR and CR rates of 33% and 18%, respectively, with median EFS and OS of 2.0 and 9.5 months, respectively. Patients receiving R-GemOx as a bridge to ASCT or CAR T had ORR and CR rates of 57% and 36%, respectively, with median EFS and OS of 3.5 and 17.4 months, respectively. Patients receiving R-GemOx aged 70 and older had ORR and CR rates of 53% and 33%, respectively, with median EFS and OS of 2.2 and 13.9 months, respectively. These data provide a benchmark for R-GemOx in the rapidly evolving landscape of R/R DLBCL therapies.

T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.