Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR-T-cell treatment

Inflammation plays an important role in CAR-T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR-T-cell treatment is currently widely unknown. We longitudinally evaluated the prevalence of CHIP, using a targeted deep sequencing approach in a cohort of patients with r/r B-NHL before and after CAR-T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34 %) before CAR-T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR-T-cell treatment but had an improved OS (not reached vs. 265 days, p=0.003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic usage of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (except ferritin) or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR-T-cell therapy and is not associated with an inferior outcome.

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Quality of life (QOL) in patients undergoing CAR-T therapy versus stem cell transplant (SCT).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.6594 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 6594-6594 ◽

Cited By ~ 3

Author(s):

Surbhi Sidana ◽

Amylou C. Dueck ◽

Michelle Burtis ◽

Joan M. Griffin ◽

Gita Thanarajasingam ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Cell Transplant ◽

Short Term ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Significant Difference ◽

Car T

6594 Background: Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients in addition to efficacy, compared with established forms of cellular therapy like SCT. Methods: QOL was evaluated prospectively in patients undergoing CAR-T therapy, autoSCT & alloSCT for hematologic malignancies. QOL was assessed with FACT-G at baseline, 2 weeks and monthly for 6 months thereafter. Functional well-being (FWB), physical WB (PWB) emotional WB (EWB) & social WB (SWB) and change over time were compared across groups. Results: 45 patients were recruited (CAR-T: 10; Auto SCT: 22; Allo SCT: 13) with follow up for 2 weeks & 1 month available for 23 &15 patients, respectively (Table). There was no statistically significant difference in baseline total QOL scores (p=0.13), though scores were lower in the alloSCT group (85,84,68). EWB &FWB were numerically higher in the CAR-T group, followed by autoSCT group. At 2 weeks, overall QOL decreased by only 2 points in CAR-T group vs. 22 & 18 points in auto & alloSCT groups (p=0.09). Change in PWB vs. baseline was less pronounced in the CAR-T group (-1, -9, -13, p=0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in auto & alloSCT groups, respectively (p=0.34). Importantly, PWB had at least returned to baseline in the CAR-T group. Conclusions: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant decline in QOL compared with auto & allo SCT, and may experience fewer physical side effects in the short-term. Accrual & follow-up are ongoing. [Table: see text]

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Reactions Related to CAR-T Cell Therapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.663201 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lele Miao ◽

Zhengchao Zhang ◽

Zhijian Ren ◽

Yumin Li

Keyword(s):

T Cell ◽

Cell Therapy ◽

Adverse Reactions ◽

Tumor Lysis Syndrome ◽

T Cell Therapy ◽

Immune Effector ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Life Threatening

The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.

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Infectious Complications Following Chimeric Antigen Receptor T-Cell Therapy for Hematologic Malignancy

Blood ◽

10.1182/blood-2021-154476 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2831-2831

Author(s):

Yingnan Li ◽

Heng Mei ◽

Mengyi Du ◽

Chenggong Li ◽

Yinqiang Zhang ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

Cell Therapy ◽

Bacterial Infections ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Significant Difference ◽

Car T ◽

Grade 3

Abstract Background CAR T-cell therapy has shown remarkable efficacy for the treatment of hematologic malignancy. However, this novel adoptive cell therapy is associated with toxicities such as cytokine release syndrome (CRS), CAR-T related encephalopathy syndrome (CRES/ICANS) and infection. While as one of the most common toxicities after CAR T-cell therapy in the first month, infectious complications have not been systematically studied. we aim to explore the incidence, clinical and microbiological characteristics and identify high risk factors for infection in patients with ALL, NHL, and MM. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-OIC-17011180; ChiCTR1800018143). Methods 72 patients with ALL, 56 patients with NHL and 42 patients with MM from January 2016 to December 2020 are involved in the cohort and the baseline data and the clinical characteristics of infection are retrospectively analyzed within 28 days. Infections were defined as a microbiologic, histopathologic, corroborating laboratory, radiographic or clinical diagnosis, and classified as bacterial (bacteremia or site infection), viral (respiratory or other), or fungal (proven or probable). Infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al.Biol Blood Marrow Transplant 2016; 22:359-70.)CRS was graded by ASTCT. We used univariate and stepwise multivariable Poisson regression to identify associations between baseline clinical characteristics and infection density, and Cox proportional hazards regression to assess high-risk factors for infection. Results Among 170 patients, a total of 119 infections occurred in 99 patients within 28 days, with a cumulative infection rate of 58.2%. The incidence of infection in ALL patients is higher than that of MM and NHL patients. Among 72 ALL patients, 46 (63.9%) patients developed infections, and among 42 MM patients, 24 patients (53.1%) developed infections. The difference in infections between these two groups of patients was statistically significant (Chi-Square test, P=0.038<0.05). There was no significant difference in infection between the ALL and NHL groups, and the MM patients and NHL groups had no significant difference in infection (Chi-square test: ALL vs NHL P=0.168; NHL vs MM P=0.497) . 78 patients had 98 bacterial infections and the cumulative incidence of bacterial infection was 45.9%. The cumulative incidence of viral infection was 8.24%, and fungal infection was 4.12%. Bacterial infections are the main types of infections in patients with different tumors, followed by viral infections, and finally fungal infections. There was no statistic significant difference in the severity of infection among different tumors, whether it was the number of patients or events (Kruskal-Wallis test, P=0.646 ,P=0.605） 75 infection events occurred in patients who were agranulocytosis, and 90% of patients with bloodstream infections had neutropenia at the time of infection. When agranulocytosis lasted for 28 days, the cumulative infection rate was 38.8%. 91 patients had both CRS and infection. The cumulative incidence of CRS and infection was 68.8% and 58.2%, respectively. Among patients with grade 3-4 CRS, 18 of 30 infections (60%) occurred after the peak of CRS. The adjusted baseline characteristic model showed that ALL patients, previous 30 days of infection history, refractory disease, ANC<0.5×10 9/L before infusion and≥4 prior antitumor treatment regimens had a higher infection density within 28 days; Grade 3 or 4 CRS was the only high-risk factor related to infection after infusion in the multivariate analysis. Conclusions Infection is one of the common complications of CAR-T cell therapy in patients with hematological malignancy. Bacterial infections occur in most patients regardless of the type of disease. ALL patients, previous 30 days of infection history，refractory disease, ANC<0.5×10 9/L before infusion and Grade 3 or 4 CRS are risk factors for infection. Keywords：chimeric antigen receptor t cell；hematological malignancy； bacterial infection Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Neurotoxicity—CAR T-cell therapy: what the neurologist needs to know

Practical Neurology ◽

10.1136/practneurol-2020-002550 ◽

2020 ◽

Vol 20 (4) ◽

pp. 285-293 ◽

Cited By ~ 2

Author(s):

Lorna Neill ◽

Jeremy Rees ◽

Claire Roddie

Keyword(s):

T Cell ◽

Cell Therapy ◽

Cerebral Oedema ◽

T Cell Therapy ◽

Immune Effector ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Innovative Therapies ◽

Infection Disease

Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed.A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

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Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy

10.1101/2021.05.10.21256634 ◽

2021 ◽

Author(s):

Carla S. Walti ◽

Andrea N Loes ◽

Kiel Shuey ◽

Elizabeth M. Krantz ◽

Jim Boonyaratanakornkit ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

B Cell ◽

Antibody Responses ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Before And After ◽

Time Point

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B-cell aplasia. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients.

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How I treat adverse effects of CAR-T cell therapy

ESMO Open ◽

10.1136/esmoopen-2020-000746 ◽

2020 ◽

Vol 4 (Suppl 4) ◽

pp. e000746 ◽

Cited By ~ 1

Author(s):

Lucrecia Yáñez ◽

Ana Alarcón ◽

Miriam Sánchez-Escamilla ◽

Miguel-Angel Perales

Keyword(s):

T Cell ◽

Cell Therapy ◽

Early Recognition ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

T Cell Therapy ◽

Immune Effector ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Chimeric antigenreceptor (CAR) T cell therapy has demonstrated efficacy in B cell malignancies, particularly for acute lymphoblastic leukaemia (ALL) and non‑Hodgkin lymphomas. However, this regimen is not harmless and, in some patients, can lead to a multi organ failure. For this reason, the knowledge and the early recognition and management of the side effects related to CAR-T cell therapy for the staff is mandatory. In this review, we have summarised the current recommendations for the identification, gradation and management of the cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, as well as infections, and related to CAR-T cell therapy.

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655 Concordance between healthcare providers and expert consensus recommendations in the management, monitoring, and mitigation of adverse events associated with CAR T-cell therapy: an updated analysis

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0655 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A692-A692

Author(s):

Matthew Frigault ◽

Megan Cartwright ◽

Krista Marcello ◽

Timothy Quill ◽

Daniel DeAngelo ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Healthcare Providers ◽

T Cell Therapy ◽

Online Tool ◽

Immune Effector ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Expert Recommendations

BackgroundChimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies. These therapies are associated with unique and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity (ICANS), that require vigilance, prompt recognition, and appropriate management to ensure patient safety and optimal therapeutic benefit. We developed an online tool to give healthcare providers (HCPs) case-specific, evidence-based expert guidance on the management of adverse events (AEs) from CAR T-cell therapy. Here, we report an updated analysis comparing CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations.1MethodsIn March 2019, 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients considering or receiving CAR T-cell therapy. This information was used to build the interactive online tool. To use this tool, HCPs enter the AE of interest, the severity of the event,2 and their planned management approach. The HCPs were then shown the expert recommendation for that specific scenario. After viewing the expert recommendation, HCPs were asked if it affected their intended approach.ResultsBetween May 2019 and July 2020, 282 HCPs entered 431 unique case scenarios into the tool. Of the entered cases, 56% were HCPs seeking expert recommendations on pretreatment screening and prophylaxis/monitoring strategies for patients not yet experiencing an AE. Of 188 cases entered for patients who received CAR T-cell therapy and experienced an AE, 67% were CRS and 33% were neurotoxicity/ICANS. Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 57% of cases, with a similar rate of concordance for both CRS and ICANS events. There was no significant difference in concordance rates with expert recommendations by toxicity severity (figure 1) nor among HCPs who indicated they practiced at authorized centers vs those who did not (P = 0.7184). Among HCPs who answered the optional survey on the impact of the tool on their management plan, 30% indicated that the expert recommendations changed their approach.Abstract 655 Figure 1Planned management of HCPs compared with expert recommendations, by gradeConclusionsThese data suggest that many HCPs are challenged to optimally manage CAR T-cell therapy toxicities in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool including planned management vs expert recommendations for each toxicity and grade will be presented.ReferencesFrigault MJ, Cartwright M, Marcello K, Quill T, DeAngelo DJ, Galinsky IA, Paul S, Park JH. Management of CAR T-Cell toxicities: concordance and divergence between healthcare providers and expert recommendations. Blood 2019:134:2199.Lee DW, Santomasso BD, Lock FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625–638.

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