Cytokine Release Syndrome Grade Research Articles

The degree of HLA matching determines the incidence of cytokine release syndrome and associated nonrelapse mortality in matched related and unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide

Cytokine release syndrome (CRS) occurs frequently after haplo-identical allogeneic stem cell transplantation (alloSCT) with post-transplant cyclophosphamide (PTCy), increasing nonrelapse mortality (NRM) and decreasing survival. Data on CRS in HLA-matched alloSCT are limited and effects of specific HLA-mismatches on CRS development unknown. We hypothesized that in HLA-matched alloSCT increasing degrees of HLA-mismatching influence CRS incidence, NRM and survival. Retrospective analysis of 126 HLA-matched PTCy-alloSCT patients showed that higher degrees of HLA-mismatching significantly increased CRS incidence (26%, 75% and 90% CRS with 12/12, 10/10 and 9/10 matched donors, respectively). Maximum temperature during CRS increased with higher HLA-mismatch. Specific associations between HLA-mismatches and CRS could be determined. Grade 2 CRS and CRS-induced grade 3 fever were associated with significantly increased NRM (p < 0.001 and p = 0.003, respectively) and inferior survival (p < 0.001 and p = 0.005, respectively). NRM was mainly caused by disease conditions that may be considered CRS-induced inflammatory responses (encephalopathy, cryptogenic organizing pneumonia and multi-organ failure).

Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia

Chimeric antigen receptor T-cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 88 infections. Nine patients experienced nine infections during lymphodepletion chemotherapy, 35 experienced 41 infections during the early phase (days 0–+ 30 after infusion), and 29 experienced 38 infections during the late phase (day + 31–+ 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. In a univariate analysis, there were ten factors associated with infection, including tumor load, lymphodepleting chemotherapy, neutrophil deficiency and lymphocyte reduction, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), etc. In a multivariate analysis, CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08–5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.

Abstract CT244: HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II)

Abstract Background: HR001 is a CD19-targeted CAR-T cell for patients with relapsed and refractory non-Hodgkin's (R/R NHL). Here, we report the primary results of the phase 2 study (HRAIN01-NHL01-II). Methods: HRAIN01-NHL01-II is an open-label, single-arm, and multicenter (17 centers) study in China. It enrolled R/R NHL patients treated with at least two lines of therapy (must-have anthracycline and CD20-targeted agents) or after autologous hematopoietic stem cell transplantation. All patients received a single infusion of HR001 at the 2.0 × 106 CAR+T cells/kg dose. The disease response was evaluated by the independent review committee with Lugano response criteria [2014]. Results: As of May 16th, 2023, 81 R/R NHL patients with ECOG 0-1 at baseline received the infusion HR001 from the Jinshan manufacturing facility [51.9% male; median age 53.4 years (range 23~74); 3.7% CD19 negative; 91.4% diffuse large B-cell lymphoma; 79.0% III-IV of Ann Arbor classification or Lugano] with a median follow-up of 160 days (range 7 to 454). The median time to best response was 30 days (range 28-358). The 3-month, 6 month and best objective response rate (ORR) was 53.1%(95% CI: 41.7-64.3), 45.7%(95% CI: 34.6-57.1) and 74.1% (95% CI: 63.1-83.2) respectively. The 3-month, 6 month and best complete response rate (CRR) was 32.1%(95% CI: 22.2-43.4), 29.6%(95% CI: 20.0-40.8) and 49.4%(95% CI: 38.1-60.7) respectively. Median duration of response (DOR) and progression-free survival (PFS) were 339 days (95% CI: 149-NE) and 176 days (95% CI: 91-NE) respectively. The overall survival (OS) was not reached. The most common treatment-related adverse events (AEs) happened in the hematologic system. The cytokine release syndrome (CRS) occurred in 95.1% of patients, with ≥3 grade CRS observed in 3.7% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) happened in 8.6% of patients, without any ≥ 3 grade ICANS reported. The treatment-related mortality was 1.2%. The median time to CAR T-cell peak expansion was 240 hours (120~672) after infusion, median maximum expansion (Cmax) was 17413.9 copies/μg DNA (124.9~136382.2), and median AUC0-28d was 3201014.0 copies/μg DNA (205082.8~18400016.2). Positive tests for the anti-drug antibody (ADA) were noted in 14.8% of patients, while neutralizing antibody (Nab) tests were positive in 3.7% of patients. Among Nab-positive patients, the complete response was maintained until follow-up. Conclusions: Patients with R/R NHL could benefit from the HR001 treatment with satisfactory objective response, durable remission, and favorable safety profile. Citation Format: Yian Zhang, Yuhua Li, Kai Hu, Wuping Li, Hongwei Xue, Qi Deng, Zheng Ge, Liangquan Geng, Xianmin Song, Kang Yu, Hongmei Jing, Bing Chen, Xin Li, Zhimin Zhai, Jianping Shen, Jiang Cao, Qingming Wang, Peng Liu. HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT244.

Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies.

Chimeric antigen receptor (CAR-) T cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that is thus far considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR-T cell therapy between 01/2020 and 05/2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet, DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose dependent manner (r = -0.44, p = 0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, p < 0.001). We thus hypothesize that fibrinogen synthesis in CRS is upregulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR-T cell therapy and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study

AimsChimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy.MethodsPatients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers.ResultsIncidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01).ConclusionsThere is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.Graphical

Exploring the efficacy and safety of anti-BCMA chimeric antigen receptor T-cell therapy for multiple myeloma: Systematic review and meta-analysis.

Multiple myeloma (MM) is a bone marrow cancer that profoundly affects plasma cells involved in the immune response. Myeloma cells alter the average production of cells in the bone marrow. Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy allows genetic modifications of an individual's T-cells to increase the expression of CARs used to identify and attach BCMA proteins to the malignant cells. Our main objective is to perform a systematic review and meta-analysis to explore the efficacy and safety of anti-BCMA CAR T-cell therapy for MM. We searched five databases, PubMed, CNKI, EMBASE, Cochrane, Web of Science, and CNKI, for studies published on anti-BCMA,CAR-T-cell treatment for MM. Inclusion criteria involved prospective single-arm studies either single or multi-center, in various MM phases and studies that reported anti-BCMA,CAR-T-cell treatment for MM. We excluded non-English publications and conference papers. All statistical analyses were performed in R software and Review Manager 5.4.1. Thirteen articles were included in the analysis. We found that the overall response survival complete response increase was statistically significant. Similarly, the reduction in cytokine release syndrome grades 3 and 4 and neurotoxicity after follow-up was statistically significant. However, the reduction in minimal residual disease negativity (MRDN) was not statistically significant. Using anti-BCMA CAR T-cell therapy in MM was highly efficacious and safe in lowering the adverse outcomes and improving the survival outcomes, complete response, and overall response.

18F]FDG PET/CT for prognosis and toxicity prediction of diffuse large B-cell lymphoma patients with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has been confirmed to benefit patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). It is important to provide precise and timely predictions of the efficacy and toxicity of CAR T-cell therapy. In this study, we evaluated the value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) combining with clinical indices and laboratory indicators in predicting outcomes and toxicity of anti-CD19 CAR T-cell therapy for DLBCL patients. Thirty-eight DLBCL patients who received CAR T-cell therapy and underwent [18F]FDG PET/CT within 3 months before (pre-infusion) and 1 month after CAR T-cell infusion (M1) were retrospectively reviewed and regularly followed up. Maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), clinical indices, and laboratory indicators were recorded at pre-infusion and M1 time points, and changes in these indices were calculated. Progression-free survival (PFS) and overall survival (OS) were as endpoints. Based on the multivariate Cox regression analysis, two predictive models for PFS and OS were developed and evaluated the efficiency. Pre-infusion indices were subjected to predict the grade of cytokine release syndrome (CRS) resulting from toxic reactions. For survival analysis at a median follow-up time of 18.2 months, patients with values of international prognostic index (IPI), SUVmax at M1, and TLG at M1 above their optimal thresholds had a shorter PFS (median PFS: 8.1 months [IPI ≥ 2] vs. 26.2 months [IPI < 2], P = 0.025; 3.1 months [SUVmax ≥ 5.69] vs. 26.8 months [SUVmax < 5.69], P < 0.001; and 3.1 months [TLG ≥ 23.79] vs. 26.8 months [TLG < 23.79], P < 0.001). In addition, patients with values of SUVmax at M1 and ∆SUVmax% above their optimal thresholds had a shorter OS (median OS: 12.6 months [SUVmax ≥ 15.93] vs. 'not reached' [SUVmax < 15.93], P < 0.001; 32.5 months [∆SUVmax% ≥ -46.76] vs. 'not reached' [∆SUVmax% < -46.76], P = 0.012). Two novel predictive models for PFS and OS were visualized using nomogram. The calibration analysis and the decision curves demonstrated good performance of the models. Spearman's rank correlation (rs) analysis revealed that the CRS grade correlated strongly with the pre-infusion SUVmax (rs = 0.806, P < 0.001) and moderately with the pre-infusion TLG (rs = 0.534, P < 0.001). Multinomial logistic regression analysis revealed that the pre-infusion value of SUVmax correlated with the risk of developing a higher grade of CRS (P < 0.001). In this group of DLBCL patients who underwent CAR T-cell therapy, SUVmax at M1, TLG at M1, and IPI were independent risk factors for PFS, and SUVmax at M1 and ∆SUVmax% for OS. Based on these indicators, two novel predictive models were established and verified the efficiency for evaluating PFS and OS. Moreover, pre-infusion SUVmax correlated with the severity of any subsequent CRS. We conclude that metabolic parameters measured using [18F]FDG PET/CT can identify DLBCL patients who will benefit most from CAR T-cell therapy, and the value before CAR T-cell infusion may predict its toxicity in advance.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51–75) in PMBCL versus 48% (95% CI: 41–57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78–95) in PMBCL versus 71% (95% CI: 64–79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta-Analysis.

B-cell maturation antigen (BCMA)-targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T-cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life-threatening. However, systematic evaluation of the risk of CRS with BCMA-targeting BsAb and CAR-T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta-analysis approach to compare the CRS profile in BCMA-targeting CAR-T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR-T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta-analysis suggests that different types of BCMA-targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit-risk profiles of these therapies.

Transient acute kidney injury after chimeric antigen receptor T-cell therapy in patients with hematological malignancies.

Acute kidney injury (AKI) occurs in 30% of patients infused with chimeric antigen receptor (CAR) T-cells. The purpose of this study was to identify risk factors and long-term outcomes after AKI in patients who received CAR T-cell therapy. Medical records of 115 adult patients with R/R hematological malignancies treated with CD19-targeted CAR T-cells at Vall d'Hebron University Hospital between July 2018 and May 2021. Baseline demographic data including age, gender, ethnicity, body mass index (BMI), and co-morbidities, as well as the type of hematological neoplasia and prior lines of therapy were collected. Laboratory parameters including serum creatinine and whole blood hemoglobin were retrospectively reviewed and values were gathered for days +1, +7, +14, +21, and +28 post-infusion. A total of 24/115 (21%) patients developed AKI related to CAR T-cell therapy; 6/24 with AKI over chronic kidney disease (CKD). Two patients had AKI in the context of lymphodepleting (LD) chemotherapy and the other 22 after CAR T-cell infusion, starting at day+1 in 3 patients, day+7 in 13 patients, day +14 in 1 patient, day+21 in 2 patients, and day+28 in 3 patients. Renal function was recovered in 19/24 (79%) patients within the first month after infusion. Male gender, CKD, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with AKI. Male gender, CKD, ICANS grade ≥3 and CRS grade ≥2 were identified as independent risk factors for AKI on multivariable analysis. In terms of the most frequent CAR T-cell related complications, CRS was observed in 95 (82%) patients and ICANS in 33 (29%) patients. Steroids were required in 34 (30%) patients and tocilizumab in 37 (32%) patients. Six (5%) patients were admitted to the intensive care unit (1 for septic shock, 4 for CRS grade ≥2 associated to ICANS grade ≥2, and 1 for CRS grade ≥3). A total of 5 (4.4%) patients died in the first 30 days after CAR T-cell infusion for reasons other than disease progression, including 4 cases of infectious complications and 1 of heart failure. Our results suggest that AKI is a frequent but mild adverse event, with fast recovery in most patients.

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

AbstractCD19 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 after 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 patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion 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 postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Efficacy and side effects of anti-CD19 CAR T-cell therapy in patients with relapsed/refractory gastrointestinal lymphoma.

Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy was approved as a very effective salvage strategy in relapsed/refractory (R/R) B cell lymphoma, the experience in R/R gastrointestinal (GI) lymphoma is still insufficient. We summarized the efficacy and side effects of anti-CD19 CAR T-cell therapy in 12 patients with R/R GI lymphoma. Based on literature, the R/R GI lymphoma patients were divided into subgroups with different characteristics: Bulky/No bulky disease, Gastric/Gastrointestinal involvement, Gastrointestinal/Combined extra-gastrointestinal lesions, Ulcer/Lumps or nodules type, With/without gastrointestinal bleeding. The objective response rate (ORR) was 66.67% in these 12 patients. The ORR was 83.33% in no bulky disease group, 80.00% in gastric involvement group, 100.00% in ulcer type group, and 80.00% in no gastrointestinal bleeding group. The CR rate was 33.33% in these 12 patients. The CR was 50.0% in no bulky disease group, 60.00% in gastric involvement group, and 80.00% in ulcer type group. The PFS and OS rate of the 12 patients at 6 months after infusion were 54.55% and 58.33%, respectively. The overall survival (OS) at 6 months was higher in no bulky disease group. There was no difference of the OS or the progression free survival (PFS) at 6 months between the other groups. The mean peak of CAR-T cells and Cytokine Release Syndrome (CRS) grade were higher in gastrointestinal lesions group. The mean peak of IFN-γ and CRS grade were higher in gastrointestinal bleeding group. Four out of six patients in group of gastrointestinal lesions group were patient with high tumor burden. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding. The ORR and CR of high tumor load, gastrointestinal involvement, lumps or nodules type and gastrointestinal bleeding group were lower. The CRS grade was higher in gastrointestinal lesions group and in gastrointestinal bleeding group. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding.

Reduced Cytokine Release Syndrome and Improved Outcomes with Earlier Immunosuppressive Therapy in Haploidentical Stem Cell Transplantation

The optimal timing of immunosuppression and post-transplantation cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is unknown. However, cytokine release syndrome (CRS) following haplo-HSCT is associated with worse transplantation outcomes, and the incidence of CRS may be affected by the timing of immunosuppression and PTCy. In this study, we compared CRS and other transplantation outcomes in 2 cohorts receiving different immunosuppression and PTCy schedules following haplo-HSCT. This was a retrospective cohort study of 91 patients who underwent haplo-HSCT at the Intermountain Health Blood and Marrow Transplant Program. The original or standard haplo-HSCT GVHD prophylaxis regimen included PTCy on days +3 and +4, with mycophenolate mofetil (MMF) and tacrolimus starting on day +5. The modified regimen adopted in November 2020 changed PTCy to days +3 and +5, with earlier introduction of tacrolimus and MMF, on day -1 and day 0, respectively. Grade ≥1 CRS occurred in 32% of patients in the modified regimen, in 82% of patients in the standard regimen (P <.0001), and 65% overall. Likewise, grade ≥2 CRS was lower with the modified regimen (16% versus 57%; P = .0002). The mean duration of CRS symptoms was longer with the standard regimen (3.14 days versus 1.44 days; P = .0003). The incidence of acute graft-versus-host disease grade III-IV or extensive chronic GVHD (cGVHD) at 1 year was lower in the modified regimen (6% versus 32%; P = .0068). No differences between the standard and modified regimens were seen in overall survival, relapse, or GVHD-free relapse-free survival (GRFS), although there appeared to be a trend toward improved GRFS with the modified regimen. Post hoc analysis comparing GRFS in patients with CRS and those without CRS found that CRS was associated with lower GRFS at 1 year (36% versus 63%; P = .0138). The duration of broad-spectrum antibiotic therapy was decreased by 7.5 days (P = .0017) and the time to hospital discharge was reduced by 7.1 days (P = .0241) with the modified regimen. This is the first analysis to evaluate and find a difference in CRS with early initiation of immunosuppressive therapy in haplo-HSCT. Our results suggest that this modified GVHD regimen benefits patients by reducing CRS and high-grade GVHD compared to the standard PTCy-based GVHD prophylaxis regimen in haplo-HSCT. Additionally, this novel regimen did not appear to negatively impact outcomes.

Clinical Impact of Cytokine Release Syndrome on Prolonged Hematotoxicity after Chimeric Antigen Receptor T Cell Therapy: KyoTox A-Score, a Novel Prediction Model

Prolonged hematotoxicity is the most common long-term adverse event in chimeric antigen receptor T cell therapy (CAR-T). To evaluate the impact on prolonged cytopenia of inflammatory status after CAR T infusion, we performed a single-center retrospective study and analyzed patients with B cell lymphomas after CAR-T. Among 90 patients analyzed at 90 days after infusion, the cumulative incidence was 57.5% for prolonged neutropenia, 36.7% for anemia, and 49.8% for thrombocytopenia. Patients who experienced cytokine release syndrome (CRS) had significantly higher incidence and longer duration of prolonged cytopenia. In addition, we found that among patients with grade 1 CRS, those with a longer duration of CRS-related symptoms (>5 days; grade 1b in modified CRS grading [m-CRS]) had a significantly higher incidence and longer duration of prolonged cytopenia than those whose CRS-related symptoms resolved within 5 days (grade 1a m-CRS). Multivariate analysis revealed that a higher m-CRS grade (grade 1b or 2; hazard ratio [HR], 2.42), higher peak CRP (≥10 mg/dL; HR, 1.66), longer duration of elevated CRP (≥10 days; HR, 1.83), and a decrease in serum inorganic phosphorus concentration (≥30% from baseline; HR, 1.95) were associated with significantly higher cumulative incidence of prolonged neutropenia, as well as anemia and thrombocytopenia. Using these factors, we developed a new predictive scoring model for prolonged hematotoxicity, the KyoTox a-score, which can successfully stratify the incidence and duration of cytopenia independent of the existing model, CAR-HEMATOTOX, which is based on laboratory data at lymphodepletion. Thus, this newly developed post-CAR-T inflammation-dependent score is accurate and useful for predicting prolonged hematotoxicity.

Persistent Cytopenia After CD19 CAR T Therapy in Relapsed/Refractory DLBCL Patients Could Be a Predictor of Efficacy and Side Effects.

Hematological toxicity is a severe adverse event (AE) in anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, the pathophysiological mechanism underlying prolonged cytopenia and the relationship between persistent cytopenia, efficacy, and AEs after anti-CD19 CAR T cell therapy are unknown. Therefore, this study explored whether persistent cytopenia after anti-CD19 CAR T cell therapy in patients with R/R DLBCL can predict therapeutic efficacy and AEs. Thirty-eight patients with R/R DLBCL were enrolled in an anti-CD19 CAR T cell therapy clinical trial. Patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide before CAR T cell therapy. The degree and duration of cytopenia, clinical response, proportion of CAR T cells, interleukin-6 (IL-6) levels, AEs, and follow-up were observed after therapy. Grades 3-4 persistent cytopenia occurred in 14 patients with R/R DLBCL, who recovered 8-18 weeks after CAR T cell infusion. These patients achieved an objective response rate (ORR) for anti-CD19 CAR T cell therapy. In patients who achieved ORR, the incidence of Grades 3-4 persistent cytopenia was higher in patients with a high tumor load than in those without a high tumor load. The mean peaks of IL-6 and anti-CD19 CAR T cells and the cytokine release syndrome grade in patients with Grades 3-4 persistent cytopenia were higher than those in patients without persistent cytopenia. Anti-CD19 CAR T cells were observed 21 and 28 days after infusion, and patients had Grades 3-4 persistent cytopenia. Progression-free and overall survival were higher in patients with Grades 3-4 persistent cytopenia than in those without cytopenia. Therefore, persistent cytopenia after anti-CD19 CAR T cell therapy in patients with R/R DLBCL can predict therapeutic efficacy and AEs, allowing clinicians to determine the efficiency of CD-19 CAR T cell therapy and the associated AEs.

Axicabtagene Ciloleucel versus Tisagenlecleucel for Relapsed or Refractory Large B Cell Lymphoma: A Systematic Review and Meta-Analysis

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Significant costs and complex manufacturing underscore the importance of evidence-based counseling regarding the outcomes of these treatments. With the aim of examining the efficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for response, progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta-analysis and meta-regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P < .001) and was associated with higher odds for PFS at 1 year after infusion (OR, .60; P < .001). OS appeared to be improved with axi-cel (OR, .84; 95% CI, .68 to 1.02; P = .08), whereas the cumulative incidence of nonrelapse mortality (NRM) was 11.5% for axi-cel versus 3.7% for tisa-cel (P = .002). The main predictors for survival were lactate dehydrogenase level, Eastern Cooperative Oncology Group Performance Status, and response to bridging, and axi-cel maintained superior efficacy even in elderly patients. In terms of safety, axi-cel was associated with significantly higher odds of any-grade CRS (OR, 3.23; P < .001), but not of grade ≥3 CRS (P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade ≥3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit.

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

Effect of early tocilizumab intervention on patients with cytokine release syndrome following chimeric antigen receptor T cell therapy

Objective: This study aimed to evaluate the effect of early tocilizumab intervention to relieve cytokine release syndrome (CRS) following chimeric antigen receptor T cell (CAR-T) therapy. Methods: Twenty-two patients with acute lymphoblastic leukemia who received tocilizumab to relieve CRS response after CAR-T cell infusion in our research center from October 2015 to July 2021 were retrospectively analyzed. According to the timing of tocilizumab intervention, patients were divided into the conventional and early intervention groups. Patients who received tocilizumab treatment after sustained high fever for 4 h were included in the early intervention group. The clinical data, CRS grade, and event-free survival (EFS) between the two groups were evaluated. Results: Compared with patients who used tocilizumab after severe CRS, no patients in the early intervention group died from CRS, and there was no increased risk of neurotoxicity. Eleven patients (84.62%) achieved complete remission with minimal residual lesions. The median EFS of patients in the early intervention and conventional groups was 2 (95% CI 0-5) and 7 (95% CI 3-11) months, respectively. Conclusion: Early tocilizumab intervention in patients with CRS reduces severe CRS and provides a more optimized therapeutic strategy for CRS caused by CAR-T cell therapy.

Tocilizumab Administration in CAR-T Cell Associated Cytokine Release Syndrome Induces Hypofibrinogenemia

Introduction Chimeric antigen receptor (CAR)-T cell therapy is considered a therapeutic breakthrough in cancer immunotherapy with high and sustained remission rates. However, it can cause serious side effects such as cytokine release syndrome (CRS). CRS is characterized by systemic hyper-inflammation leading to hypotension, hypoxia, and progressive organ failure. Management of CRS commonly requires administration of the Interleukin-6 receptor antagonist (IL6-RA) tocilizumab. CRS-related coagulopathy is considered the result of disseminated intravascular coagulation (DIC) and concomitant progressive liver dysfunction. Overall, coagulopathy is observed in about every second patient after CAR-T cell therapy with a disproportional rate of hypofibrinogenemia. In this study, we investigated the incidence, dynamics, and possible causes of hypofibrinogenemia after CAR-T cell therapy. Methods We included all patients (n=41) with hematological malignancies receiving CAR-T cell therapies at the University Hospital Regensburg between 2020 and May 2023. All patients were followed up until death or 07/31/2023. Median age was 69 (range: 38-83) years, half of the patients were female and 73% had diffuse large cell B-cell lymphoma. Results 93% of patients developed CRS (12% ≥ grade 3), 71% received tocilizumab and 34% high-dose corticosteroids. While DIC and liver dysfunction almost exclusively occurred in CRS grade 3 or higher, 38% of patients with CRS grade 1 and 90% with CRS grade 2 developed de novo hypofibrinogenemia. Hypofibrinogenemia was severe or life-threatening (CTCEA ≥ grade 3) in 39% of cases and frequently required substitution. Median day of fibrinogen recovery (&amp;gt; lower limit of normal) was day 52 after CAR-T cell therapy. Patients with de novo hypofibrinogenemia initially displayed rising fibrinogen levels alongside development of CRS and rapidly declined in fibrinogen levels shortly after the first administration of tocilizumab. Minimum fibrinogen levels and duration of hypofibrinogenemia further correlated to tocilizumab dosing (r=-0.44 p=0.004 and r=0.7 p&amp;lt;0.001, respectively). Resolution of hypofibrinogenemia was associated to normalization of suppressed C-reactive protein (CRP) after tocilizumab treatment. In contrast, patients with CRS grades 1 and 2 who did not receive tocilizumab (7/13 and 2/20, respectively) had increased fibrinogen levels throughout the course and until resolution of CRS. Logistic regression showed that administration of tocilizumab was the most important, independent risk factor for development of hypofibrinogenemia (OR = 517, p&amp;lt;0.001). Conclusions In summary, hypofibrinogenemia is a frequent complication of CAR-T cell therapy and tocilizumab administration. We conclude that fibrinogen synthesis in CRS is upregulated in an IL-6-dependent acute phase reaction compensating for CRS-induced consumptive coagulopathy. IL-6RA tocilizumab inhibits fibrinogen upregulation and thereby causes protracted hypofibrinogenemia. These observations provide novel insights into the emergence and pathophysiology of hypofibrinogenemia after CAR-T cell therapy and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Real-World Treatment Outcomes of Teclistamab Under an Outpatient Model for Step-up Dosing Administration

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.