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In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multispecific CAR are potential solutions to improving cellular therapy outcomes in BNHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma. [ABSTRACT FROM AUTHOR]

Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma., Competing Interests: NG has received research funding from Genentech, Pharmacyclics, Bristol Myers Squibb, AbbVie, Morphosys, Gilead/Kite Pharma; served as a consultant/advisor for AbbVie, AstraZeneca, Genentech, Beigene, Janssen, Lilly, Gilead/Kite Pharma, ADC Therapeutics, Novartis, Lava Therapeutics, Incyte. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pang and Ghosh.)

In the single-arm, open-label, multicenter, phase II PILOT study, second-line treatment with the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel) in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) for whom hematopoietic stem cell transplantation (HSCT) was not intended resulted in high response rates, durable responses, and a safety profile consistent with previous reports. Here, we analyzed changes in health-related quality of life (HRQOL) in patients who received liso-cel in PILOT. Patients received liso-cel, an autologous, CD19-directed, 4-1BB CAR T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells, for a total target dose of 100×10⁶ CAR+ T cells. HRQOL, a secondary endpoint of PILOT, was assessed as prespecified using three patient-reported outcome instruments (EORTC QLQ-C30; FACT-LymS; EQ-5D-5L). Evaluable datasets for the EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L health utility index, and visual analog scale (EQ-VAS) included 56 (92%), 49 (80%), 55 (90%), and 54 (89%) patients, respectively. Clinically meaningful improvement was achieved across most post-treatment visits for EORTC QLQ-C30 fatigue and FACT-LymS. Overall mean changes from baseline through day 545 showed significant improvements in EORTC QLQ-C30 fatigue, pain, and appetite loss, FACT-LymS, and EQ VAS. In within-patient analyses, clinically meaningful improvements or maintenance in scores were observed in most patients at days 90, 180, 270, and 365. HRQOL was maintained or improved in patients who received liso-cel as second-line therapy in PILOT. These findings support liso-cel as a preferred second-line treatment in patients with R/R LBCL not intended for HSCT (clinicaltrials gov. Identifier: NCT03483103).