Hemophagocytic lymphohistiocytosis‐like toxicity (carHLH) after CD19‐specific CAR T‐cell therapy

Hines, Melissa; Keenan, Camille; Maron, Gabriela; Cheng, Cheng; Zhou, Yinmei; Sharma, Akshay; Hurley, Caitlin; Nichols, Kim E.; Talleur, Aimee C

doi:10.1111/bjh.17662

Cited by 70 publications

(71 citation statements)

References 18 publications

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“…Importantly, patients with carHLH did have a higher number of infections in the late post CAR T cell therapy period. This is likely since carHLH often occurs later than CRS and may require treatment with immunosuppressive agents such as anakinra and steroids (18,29), as we saw in our patient population. The use of immunomodulatory agents to treat CAR-mediated side effects, the inflammatory response with elevated cytokines and/or the intensive supportive management in the ICU may all contribute to risk of infections in these patients (30)(31)(32).…”

Section: Discussionmentioning

confidence: 79%

“…Additionally, a subset of patients (n=6) received repeat CD19-CAR T cell infusion(s) of the same product due to recurrent malignancy or early loss of BCA. The clinical outcomes with a focus on disease response to CAR T cell therapy ( 22 , 23 ), carHLH ( 18 ), and epigenetic reprograming of CAR T cells ( 24 ), have been reported elsewhere for a subset of these patients.…”

Section: Resultsmentioning

confidence: 99%

“…Patients treated on trial all received Flu/Cy (cumulative doses: 75mg/m 2 and 900mg/m 2 ), while patients treated with tisagenlecleucel received Flu/Cy (cumulative doses: 120mg/m 2 and 1000mg/m 2 , or 75mg/m 2 and 900mg/m 2 ) or Flu/Cy (cumulative doses: 75mg/m 2 and 900mg/m 2 ) with an additional agent (etoposide 500mg/m 2 or cytarabine cumulative dose, 4000mg). Presence and severity of CAR T cell related immune side effects [CRS, neurotoxicity and CAR-associated hemophagocytic lymphohistiocytosis (carHLH) ( 18 )] were documented, as well as receipt of immunomodulating agents (steroids, tocilizumab, siltuximab, anakinra, and/or ruxolitinib). Available post treatment ANC, ALC and IgG results were collected for up to 90 days post infusion.…”

Section: Methodsmentioning

confidence: 99%

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Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

et al. 2022

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“… 9 CAR-T cell therapies have associated severe toxicities including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), 10 and CAR-associated hemophagocytic lymphohistiocytosis. 11 All Food and Drug Administration-approved CAR-T cell therapies originate from autologous hematopoietic starting material. The manufacturing of patient-derived T-cell products in the setting of a highly proliferative disease can be challenging.…”

Section: Introductionmentioning

confidence: 99%

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities

Christodoulou

Marple

et al. 2021

J Immunother Cancer

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BackgroundThe prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence.MethodsWe characterized in detail NK-cell populations expressing a panel of AML (CD123)-specific CARs and/or IL-15 in vitro and in AML xenograft models.ResultsCARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ Chimeric Antigen Receptor (CAR)-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK-cell persistence. Transgenic expression of secretory interleukin (sIL)-15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK-cell subsets. 2B4.ζ/sIL-15 CAR and sIL-15 NK cells maintained an overall activated NK-cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK-cell groups. In vivo, 2B4.ζ/sIL-15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL-15 CAR and sIL-15 NK cells induced lethal toxicity in a second model.ConclusionTransgenic expression of CD123-CARs and sIL-15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early-phase clinical testing.

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“…Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment option, offering high chance of remission for a historically incurable patient population, particularly those with relapsed or refractory leukemia (22)(23)(24)(25). However, CAR-T therapy comes with the risk of severe acute complications due to systemic inflammatory responses (including cytokine release syndrome [CRS], immune effector cell-associated neurotoxicity [ICANS], and CAR-T associated hemophagocytic lymphohistiocytosis [carHLH]), rapid tumor cell death, and infection, which can lead to cardiac and/or respiratory failure (22,(26)(27)(28)(29). While to our knowledge, there has been no reports of ECMO for post CAR-T therapy complications in pediatrics, Stoner, et al, reported a case of successful veno-arterial ECMO use in a pediatric patient with septic shock as a bridge to CAR-T (30).…”

Section: Introductionmentioning

confidence: 99%

Extracorporeal Membrane Oxygenation Candidacy in Pediatric Patients Treated With Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy: An International Survey

et al. 2021

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IntroductionPediatric patients who undergo hematopoietic cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at high risk for complications leading to organ failure and the need for critical care resources. Extracorporeal membrane oxygenation (ECMO) is a supportive modality that is used for cardiac and respiratory failure refractory to conventional therapies. While the use of ECMO is increasing for patients who receive HCT, candidacy for these patients remains controversial. We therefore surveyed pediatric critical care and HCT providers across North America and Europe to evaluate current provider opinions and decision-making and institutional practices regarding ECMO use for patients treated with HCT or CAR-T.MethodsAn electronic twenty-eight question survey was distributed to pediatric critical care and HCT providers practicing in North America (United States and Canada) and Europe through the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and individual emails. Responses to the survey were recorded in a REDCap® database.ResultsTwo-hundred and ten participants completed the survey. Of these, 159 (76%) identified themselves as pediatric critical care physicians and 47 (22%) as pediatric HCT physicians or oncologists. The majority (99.5%) of survey respondents stated that they would consider patients treated with HCT or CAR-T therapy as candidates for ECMO support. However, pediatric critical care physicians identified more absolute and relative contraindications for ECMO than non-pediatric critical care physicians. While only 0.5% of respondents reported that they consider HCT as an absolute contraindication for ECMO, 6% of respondents stated that ECMO is contraindicated in HCT patients within their institution and only 23% have an institutional protocol or policy to guide the evaluation for ECMO candidacy of these patients. Almost half (49.1%) of respondents would accept a survival to hospital discharge of 20-30% for pediatric HCT patients requiring ECMO as adequate.ConclusionsECMO use for pediatric patients treated with HCT and CAR-T therapy is generally acceptable amongst physicians. However, there are differences in the evaluation and decision-making regarding ECMO candidacy amongst providers across medical specialties and institutions. Therefore, multidisciplinary collaboration is an essential component in establishing practice guidelines and advancing ECMO outcomes for these patients.

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Hemophagocytic lymphohistiocytosis‐like toxicity (carHLH) after CD19‐specific CAR T‐cell therapy

Cited by 70 publications

References 18 publications

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities

Extracorporeal Membrane Oxygenation Candidacy in Pediatric Patients Treated With Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy: An International Survey

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