Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells

Park, Jae H.; Romero, Fabián Andrés Rosas; Taur, Ying; Sadelain, Michel; Brentjens, Renier J.; Hohl, Tobias M.; Seo, Susan K.

doi:10.1093/cid/ciy152

Cited by 226 publications

(351 citation statements)

References 32 publications

Supporting

Mentioning

330

Contrasting

Unclassified

Order By: Relevance

“…In a study using multivariable modelling, CRS severity was the only significant risk factor for infection (Hill et al , ). Supporting this, another study using a different CD19 CAR‐T cell product also demonstrated an increase in infections, particularly bloodstream infections with severe CRS (Park et al , 2018b).…”

Section: Clinical Presentation Of Crsmentioning

confidence: 78%

Cytokine release syndrome and neurotoxicity afterCD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

2018

View full text Add to dashboard Cite

Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

show abstract

Section: Clinical Presentation Of Crsmentioning

confidence: 78%

Cytokine release syndrome and neurotoxicity afterCD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

2018

View full text Add to dashboard Cite

show abstract

“…Most infections are caused by bacteria typical for patients with hematologic malignancies undergoing chemotherapy and occur early after CAR‐T cell infusion, during periods of neutropenia, following the onset of CRS . The incidence of life‐threatening or fatal infections is low . In a study at our institution, patients with ALL, more prior antitumor treatment regimens, a higher CAR‐T cell dose, and more severe CRS were at increased risk of infection .…”

Section: Other Toxicities Of Cd19 Car‐t Cell Immunotherapymentioning

confidence: 96%

“…Patients receiving CAR‐T cell therapies may be at risk of infection due to underlying immune suppression, the effects of lymphodepletion, or the consequence of on‐target, off‐tumor toxicity resulting in B cell depletion in the case of CD19 CAR‐T cells. Most infections are caused by bacteria typical for patients with hematologic malignancies undergoing chemotherapy and occur early after CAR‐T cell infusion, during periods of neutropenia, following the onset of CRS . The incidence of life‐threatening or fatal infections is low .…”

Section: Other Toxicities Of Cd19 Car‐t Cell Immunotherapymentioning

confidence: 99%

Toxicities of CD19 CAR‐T cell immunotherapy

2019

View full text Add to dashboard Cite

CD19‐targeted chimeric antigen receptor (CAR)‐modified T (CAR‐T) cell immunotherapy has demonstrated impressive results in B‐cell malignancies, and CAR‐T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life‐threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR‐T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR‐T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.

show abstract

“…Most treatment-related death was due to these two adverse events [27]. In addition, the persistence of in vivo CAR-T cells usually contributes to prolonged B cell aplasia [22,28,29], which can potentially lead to infectious complications [30,31].…”

Section: Introductionmentioning

confidence: 99%

Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy

et al. 2019

View full text Add to dashboard Cite

The CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has been widely proved effective on relapsed and refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Meanwhile, CAR-T therapy-related toxicities, including cytokine release syndrome (CRS) and neurological toxicities, are drawing researchers' attention. In addition, our research team notices that coagulopathy and even disseminated intravascular coagulation (DIC) are common problems during CAR-T therapy. In our phase 1/2 clinical trial (NCT02965092), 53 r/r B-ALL patients underwent leukapheresis on day − 11 and received lymphodepleting chemotherapy on day − 7 to day − 5. Finally, they received split infusions of anti-CD19 CAR-T cells on day 0 to day 2. Plasma concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1) were also measured to identify the mechanism of coagulation disorders. The overall 1-month remission rate of the 53 patients was 88.7%. During the treatment course, 19 patients experienced grade 3-4 CRS, 8 patients developed grade 2-3 neurological toxicities. Beyond that, 30 patients (30/53, 56.6%) suffered from coagulation disorders, and half of them should be diagnosed as DIC. Benefiting from replacement and anticoagulant therapy, 14 patients successfully got out of the conditions of DIC. Remarkably, the severity of coagulopathy was positively correlated with CRS grade. What is more, plasma TF and PECAM-1 levels indicated that vascular endothelial factors played key roles in the process of CRS-related coagulopathy. To conclude, coagulation disorders frequently happen during CAR-T therapy. TF and PECAM-1 are of great importance in the etiology and pathogenesis of coagulation problems. Early and proper interventions targeted at CRS-related coagulopathy contribute a lot to the control of side effects in CAR-T therapy.

show abstract

Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells

Abstract: NCT01044069.

Cited by 226 publications

References 32 publications

Cytokine release syndrome and neurotoxicity afterCD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

Cytokine release syndrome and neurotoxicity afterCD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

Toxicities of CD19 CAR‐T cell immunotherapy

Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy

Contact Info

Product

Resources

About