JAK1 Inhibition during CAR T-Cell Treatment Does Not Affect CAR T-Cell Proliferation, Persistence, or Function

Pratta, Michael A.; Burke, Lea; DiPersio, John F.; Maziarz, Richard T.; Feldman, Patricia; Brodeur, Teresa; Timmers, Cynthia; Ivanova, Olga; Barbour, April M.; Morariu-Zamfir, Rodica; Frigault, Matthew J.

doi:10.1182/blood-2022-169382

Cited by 8 publications

(4 citation statements)

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“…Approaches are underway to develop risk-mitigation strategies for individuals at high risk of developing CAR T cell–associated neurotoxicity. 31 , 32 , 33 These strategies include the prophylactic use of steroids or anakinra and the use of Janus kinase inhibitors or dasatinib. 33 , 34 , 35 Because severe ICANS also varies among CAR T-cell products, the use of alternative CAR T-cell constructs to treat MCL are being investigated.…”

Section: Discussionmentioning

confidence: 99%

“… 31 , 32 , 33 These strategies include the prophylactic use of steroids or anakinra and the use of Janus kinase inhibitors or dasatinib. 33 , 34 , 35 Because severe ICANS also varies among CAR T-cell products, the use of alternative CAR T-cell constructs to treat MCL are being investigated. Notably, in patients with MCL treated with lisocabtagene maraleucel or a CD19-CD20 CAR T-cell therapy, severe ICANS was reported in 9% and 0% of patients, respectively, significantly lower than that observed for breu-xel.…”

Section: Discussionmentioning

confidence: 99%

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Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma

Nie,

Su,

Baird

et al. 2024

Blood Advances

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CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma

Nie,

Su,

Baird

et al. 2024

Blood Advances

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“…54 Such inflammatory stressors may in turn modulate the subsequent CAR T-cell expansion that is required to efficiently eradicate lymphoma cells. 55 Considering that an increased CAR-HEMATOTOX score may fundamentally reflect underlying disease 'aggressiveness' and immune dysregulation, HT high patients may represent attractive candidates to explore anticipatory anti-inflammatory measures such as JAK inhibitors (NCT05757219) 56 or concurrent BTK inhibition. 22 This study has several pertinent limitations: it was retrospective, uncontrolled, and follow-up remains short.…”

Section: Discussionmentioning

confidence: 99%

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

et al. 2023

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CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu‐cel. Furthermore, we report associations between the baseline CAR‐HEMATOTOX (HT) score and toxicity events, non‐relapse mortality (NRM), and progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90‐day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not‐reached, p < .0001), and OS (median 26 months vs. not‐reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu‐cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

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“… Randomized phase 2 (itacitinib vs placebo) underway, treating DLBCL/FL with axi-cel. Pratta et al 33 NCT04071366 axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; FL, follicular lymphoma; MCL, mantle cell lymphoma; NA, not available; prophy, prophylactic; toci, tocilizumab; tisa-cel, tisagenlecleucel. ∗ None of the comparisons are randomized and instead provide information as compared with nonrandomized cohorts, cross-trial comparisons, and retrospective cohorts.…”

Section: Introductionmentioning

confidence: 99%

How I Treat Refractory CRS and ICANS Following CAR T-cell Therapy

Jain

Smith

Shah

2023

Blood

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The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly due to expanding indications for standard of care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential to facilitating the widespread use. Pre-emptive interventions to prevent more severe toxicities has improved safety, facilitating CAR T-cell therapy in medically frail populations and those at high-risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic, as it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk-factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.

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JAK1 Inhibition during CAR T-Cell Treatment Does Not Affect CAR T-Cell Proliferation, Persistence, or Function

Cited by 8 publications

References 0 publications

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

How I Treat Refractory CRS and ICANS Following CAR T-cell Therapy

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