Optimization and validation of the international metabolic prognostic index for CD19 CAR-T in large B-cell lymphoma.

While CD19-directed CAR T-cell therapy represents a transformative immunotherapy for relapsed/refractory large B-cell lymphoma (r/r LBCL), more than 50% of patients ultimately progress or relapse. Recently, the International Metabolic Prognostic Index (IMPI) - incorporating age, stage, and metabolic tumor volume (MTV) - was shown to improve prognostication for LBCL frontline treatment. Here, we examine its utility to predict toxicity and survival in CAR-T recipients.

New Comorbidity Index Associated with Survival After Chimeric Antigen Receptor T Cell Therapy for Large B-Cell Lymphoma.

The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T cell (CAR-T) therapy is not well-established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017-2020 were selected from the CIBMTR registry.

Comparison of axicabtagene ciloleucel and tisagenlecleucel patient CAR-T cell products by single-cell RNA sequencing.

Background: Autologous CD19 chimeric antigen receptor (CAR) T-cell therapy leads to durable responses and improved survival in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). Among approved CAR T-cell products, axicabtagene ciloleucel (axi-cel; CD19/CD28) has greater real-world efficacy and cytokine-associated toxicity than tisagenlecleucel (tisa-cel; CD19/4-1BB), for reasons that are poorly understood.

Methods: Here we report single-cell RNA sequencing (scRNA-seq) of 57 pre-infusion CAR T-cell products from axi-cel (n=39) and tisa-cel (n=18) patients treated as standard-of-care for R/R LBCL, and their biological associations with clinical outcomes.

Noncanonical and mortality-defining toxicities of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy is associated with a unique spectrum of toxicities that drive morbidity, mortality and patient quality of life. Previous efforts yielded consensus grading systems for the prototypical immunotoxicities-namely, cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These grading systems set the stage for severity-based and standardized treatment protocols that have contributed to a reduction in the acute toxicity burden of CAR T cell therapy and have enabled outpatient administration.

Mutagenic Impact and Evolutionary Influence of Chemoradiotherapy in Hematologic Malignancies.

Unlabelled: Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of insertion-deletions (indels; ID), and their repair by nonhomologous end joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored.

Intravenous Immunoglobulin (IVIG) for Patients with Severe Neurotoxicity Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy.

Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in about 30% of all patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel). There are currently limited treatment strategies other than the standard corticosteroids, and it is essential to find additional therapies to manage severe ICANS. We conducted a retrospective study of neurologic outcomes among patients who received axi-cel for LBCL from May 2015 to February 2019.

Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies.

Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.

Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma.

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity.

Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B-cell Lymphoma.

Purpose: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship among CAR T-cell therapy, sarcopenia, and metabolism is poorly understood.

Bridging radiotherapy before chimeric antigen receptor T cells for B-cell lymphomas: an ILROG multicenter study.

Despite the increasing utilization of bridging radiotherapy (Br-RT), its impact on chimeric antigen receptor T-cell therapy (CAR-T) efficacy and toxicity remains poorly characterized. We retrospectively reviewed patients with relapsed/refractory B-cell lymphomas (BCLs) who received Br-RT followed by CAR-T from 2018 to 2020 across 10 institutions. Br-RT toxicities were graded per Common Terminology Criteria for Adverse Events version 5.

Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel.

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities.

RHOA Loss of Function Impairs the IFNγ Response and Promotes CD19 Antigen Escape to Drive CAR-T Resistance in Diffuse Large B-cell Lymphoma.

CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for aggressive B-cell lymphomas, but less than half of patients achieve durable responses. We previously showed through whole-genome sequencing of tumors from CAR-T-treated patients that deletions of (3p21.31) are enriched in cases progressing after treatment.

Chimeric antigen receptor T cell therapy in octogenarians with B cell lymphoma: a real-world US multicenter collaborative study.

Older patients with lymphoma are typically underrepresented in clinical trials with chimeric antigen receptor T cell (CAR T) therapy. In this multicenter, observational study we aimed to assess the safety and efficacy of standard CD19 CAR T in patients 80 years of age or older. At total of 88 patients, median age 82 (range, 80-89) years, were included.

Outcomes among adult recipients of CAR T-cell therapy for Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that is associated with poor outcomes in patients with relapsed/refractory disease. This multicenter, retrospective study evaluated real-world CD19 chimeric antigen receptor (CAR) T-cell therapy outcomes in patients with relapsed/refractory BL using data abstracted from the medical records. In total, 31 patients received CAR T cells after a median of 3 previous therapies (range, 1-6).

Real-World Patient-Reported and Neurocognitive Outcomes in the Year After Axicabtagene Ciloleucel.

Axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T-cell therapy, has significantly improved clinical outcomes in adult patients with relapsed/refractory large B-cell lymphoma. However, few studies have examined patient-reported outcomes (PROs) or neurocognitive performance in patients treated with axi-cel. Moreover, no longitudinal PRO study has reported on patients treated with axi-cel as standard of care in the United States, to our knowledge.

Mutagenic impact and evolutionary influence of radiotherapy in hematologic malignancies.

Ionizing radiotherapy (RT) is a widely used palliative and curative treatment strategy for malignancies. In solid tumors, RT-induced double strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in resistant cells. However, the extent of RT-induced DNA damage in hematologic malignancies and its impact on their evolution and interplay with commonly used chemotherapies has not yet been explored.

Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.

Antibiotic (ABX)-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n = 58).

Outcomes of Haploidentical Stem Cell Transplant Recipients With HHV-6B Reactivation.

Background: Human herpesvirus 6B (HHV-6B) frequently reactivates following allogeneic stem cell transplant (alloHCT). Consensus guidelines note that haploidentical alloHCT may represent a high-risk population for which there is little evidence; this warrants further investigation.

Methods: In this single-center retrospective study, we evaluated 188 consecutive adult patients receiving haploidentical alloHCT between 11/2014 and 11/2020 and compared outcomes between patients with HHV-6B reactivation receiving targeted antiviral therapy and those who were clinically observed.

Five-Year Follow-Up of Standard-of-Care Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

Purpose: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy.

Methods: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.

Autologous Hematopoietic Cell Transplantation Consolidation for First Response is Associated With Longer Survival Among Patients With Nodal Peripheral T Cell Lymphoma.

Nodal peripheral T cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-HCT) as a consolidation strategy following initial chemotherapy response remains uncertain. This study aims to evaluate the impact of upfront auto-HCT consolidation on overall survival (OS) and event-free survival (EFS) among patients with nodal PTCL who achieved a complete or partial response to initial chemotherapy.

Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management.

Genetically engineered chimeric antigen receptor (CAR) T cells have become an effective treatment option for several advanced B-cell malignancies. Haematological side-effects, classified in 2023 as immune effector cell-associated haematotoxicity (ICAHT), are very common and can predispose for clinically relevant infections. As haematopoietic reconstitution after CAR T-cell therapy differs from chemotherapy-associated myelosuppression, a novel classification system for early and late ICAHT has been introduced.