Diminished durability of <scp>chimeric antigen receptor</scp> T‐cell efficacy with severe or prolonged <scp>postinfusion</scp> cytopenias

Tabbara, Nadeem; Sharp, Jack; Gaut, Daria; Pham, Thanh Thuy Dan; Tang, Kevin; Oliai, Caspian; Sim, Myung Shin; Schiller, Gary J.; Young, Patricia A.; Sasine, Joshua P.

doi:10.1002/ajh.26551

Cited by 3 publications

(2 citation statements)

References 11 publications

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“…The impact of prolonged cytopenia is great because of infection risk ( 33 , 34 ), transfusion support ( 33 ), healthcare resources for laboratory monitoring through hospitalization ( 18 ), and therapeutic limitations to treat disease relapse, especially in the clinical trial setting ( 35 ). Also, some studies tried to correlate late cytopenia with outcomes such as response, progression-free survival (PFS), and overall survival (OS), but this is not well-established ( 36 , 37 ).…”

Section: Resultsmentioning

confidence: 99%

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma

Cordeiro,

Durisek,

Batista

et al. 2024

Front. Oncol.

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BackgroundThe short-term complications from chimeric antigen receptor T-cell therapy (CART) are well characterized, but the long-term complications still need to be further investigated. Therefore, herein, we will review the currently available literature published on the late adverse events following CART.MethodsWe reviewed published data available from pivotal trials and real-world experiences with anti-CD19 CART (CART19) for adults with lymphoma. We defined late events as occurring or persisting beyond 1 month after CART infusion. We focused our literature review on the following late-event outcomes post-CART19: cytopenia, immune reconstitution, infections, and subsequent malignancies.ResultsGrade 3–4 cytopenia beyond 30 days occurs in 30%–40% of patients and beyond 90 days in 3%–22% of patients and is usually managed with growth-factor and transfusion support, along with neutropenic prophylaxis. B-cell aplasia and hypogammaglobulinemia are expected on-target off-tumor effects of CART19, 44%–53% of patients have IgG < 400 mg/dL, and approximately 27%–38% of patients receive intravenous immunoglobulin (IVIG) replacement. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they are more prevalent and severe when patients receive subsequent therapies post-CART19 for their underlying disease. Late neurotoxicity and neurocognitive impairment are uncommon, and other causes should be considered. T-cell lymphoma (TCL) after CART is an extremely rare event and not necessarily related to CAR transgene. Myeloid neoplasm is not rare post-CART, but unclear causality given heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm.ConclusionCART19 is associated with clinically significant long-term effects such as prolonged cytopenia, hypogammaglobulinemia, and infections that warrant clinical surveillance, but they are mostly manageable with a low risk of non-relapse mortality. The risk of subsequent malignancies post-CART19 seems low, and the relationship with CART19 and/or prior therapies is unclear; but regardless of the possible causality, this should not impact the current benefit–risk ratio of CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

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Section: Resultsmentioning

confidence: 99%

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma

Cordeiro,

Durisek,

Batista

et al. 2024

Front. Oncol.

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“…Recent reports have linked prolonged post-infusion cytopenias to diminished CAR-T efficacy ( 56 , 57 ). However, our study indicates that qualitative differences in cytopenia (e.g., biphasic versus monophasic) likely provide critical context for any observed survival differences.…”

Section: Discussionmentioning

confidence: 99%

Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion

Rejeski,

Perez,

Iacoboni

et al. 2023

Sci. Adv.

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Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with “intermittent” neutrophil recovery (e.g., recurrent neutrophil dips) compared to either “quick” or “aplastic” recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.

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Chimeric Antigen Receptor T-Cell Therapy and Hematopoiesis

Reinhardt

Lee

Sasine

2023

Cells

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Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment option for patients suffering from B-cell- and plasma cell-derived hematologic malignancies and is being adapted for the treatment of solid cancers. However, CAR T is associated with frequently severe toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome (MAS), and prolonged cytopenias—a reduction in the number of mature blood cells of one or more lineage. Although we understand some drivers of these toxicities, their mechanisms remain under investigation. Since the CAR T regimen is a complex, multi-step process with frequent adverse events, ways to improve the benefit-to-risk ratio are needed. In this review, we discuss a variety of potential solutions being investigated to address the limitations of CAR T. First, we discuss the incidence and characteristics of CAR T-related cytopenias and their association with reduced CAR T-cell efficacy. We review approaches to managing or mitigating cytopenias during the CAR T regimen—including the use of growth factors, allogeneic rescue, autologous hematopoietic stem cell infusion, and alternative conditioning regimens. Finally, we introduce novel methods to improve CAR T-cell-infusion products and the implications of CAR T and clonal hematopoiesis.

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Diminished durability of chimeric antigen receptor T‐cell efficacy with severe or prolonged postinfusion cytopenias

Cited by 3 publications

References 11 publications

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma

Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion

Chimeric Antigen Receptor T-Cell Therapy and Hematopoiesis

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