Treatment Of Cytokine Release Syndrome Research Articles

Abstract 4114505: Cardiovascular Adverse Events After Anti-BCMA CAR-T (Ide-Cel and Cilta-Cel) for Relapsed/ Refractory Multiple Myeloma

Introduction: Idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-cel) are novel CAR-T therapies targeting B-cell maturation antigen (BCMA) and approved for relapsed and refractory multiple myeloma (RRMM). While cardiovascular adverse events (CVAE) are relatively common with CD-19 CAR-T, the incidence of CVAE in the real-world setting for anti-BCMA CAR-T in RRMM is largely unknown. This study aims to determine the incidence of CVAE and its associated risk factors in patients treated with ide-cel and cilta-cel. Method: This single-center retrospective cohort study evaluated RRMM patients treated with ide-cel and cilta-cel from May 2021 to December 2023. We assessed baseline cardiac and oncologic characteristics and clinical outcomes post-CAR-T. Cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome (ICANS) grading followed ASTCT consensus guidelines. Result: A total of 164 RRMM patients treated with ide-cel (N=109) or cilta-cel (N=55) with at least 6 months follow-up were included. The average age was 63 years, and 57% were male. Advanced RRMM stage (R-ISS III) was present in 17% with a median of 6 prior lines of therapy. CRS grade equal or greater than 2 occurred in 22%, and ICANS grade equal or greater than 3 in 6.7%. Twenty patients (12.2%) experienced CVAE, including atrial fibrillation (7.9%), non-sustained ventricular arrhythmia (3.0%), heart failure (3.7%), and cardiovascular death (0.6%). R-ISS III was associated with increased CVAE (52.9% vs. 11.5%; P=0.001). Patients with CVAE had higher baseline ferritin and CRP levels and a higher incidence of CRS grade ≥ 2 (60% vs. 16.7%; P<0.001) and ICANS grade ≥ 3 (20% vs 4.9%; P=0.001). Treatment with tocilizumab, steroids, or anakinra was more common in patients with CVAE. Conclusion: CVAE occurred relatively frequently following BCMA CAR-T therapy, with high-grade CRS identified as a consistent risk factor. Most CVAEs were manageable with appropriate supportive care, including careful observation and active treatment of CRS.

Siltuximab for chimeric antigen receptor T-cell therapy–related CRS and ICANS: a multicenter retrospective analysis

AbstractChimeric antigen receptor T-cell (CAR-T) therapies are effective in many hematologic malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) can affect a significant number of patients. Those who develop refractory CRS or ICANS have few treatment options. Siltuximab, a monoclonal antibody binding circulating interleukin-6, has been proposed to have clinical activity in both CRS and ICANS. We conducted a multicenter retrospective analysis of siltuximab treatment for CRS and ICANS after CAR-T therapy in a real-world cohort from 6 academic centers. Fifty-four patients were evaluated. Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Of the patients with CRS at the time of siltuximab, 75% had improvement in CRS grade. Of the patients with ICANS at the time of siltuximab, 60% had improvement in ICANS grade. To our knowledge, this is the largest cohort of patients treated with siltuximab for CRS and/or ICANS after CAR-T therapies. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.

Cytokine Storms and Anaphylaxis Following COVID-19 mRNA-LNP Vaccination: Mechanisms and Therapeutic Approaches.

Acute adverse reactions to COVID-19 mRNA vaccines are a major concern, as autopsy reports indicate that deaths most commonly occur on the same day of or one day following vaccination. These acute reactions may be due to cytokine storms triggered by lipid nanoparticles (LNPs) and anaphylaxis induced by polyethene glycol (PEG), both of which are vital constituents of the mRNA-LNP vaccines. Kounis syndrome, in which anaphylaxis triggers acute coronary syndrome (ACS), may also be responsible for these cardiovascular events. Furthermore, COVID-19 mRNA-LNP vaccines encompass adjuvants, such as LNPs, which trigger inflammatory cytokines, including interleukin (IL)-1β and IL-6. These vaccines also produce spike proteins which facilitate the release of inflammatory cytokines. Apart from this, histamine released from mast cells during allergic reactions plays a critical role in IL-6 secretion, which intensifies inflammatory responses. In light of these events, early reduction of IL-1β and IL-6 is imperative for managing post-vaccine cytokine storms, ACS, and myocarditis. Corticosteroids can restrict inflammatory cytokines and mitigate allergic responses, while colchicine, known for its IL-1β-reducing capabilities, could also prove effective. The anti-IL-6 antibody tocilizumab also displays promising treatment of cytokine release syndrome. Aside from its significance for treating anaphylaxis, epinephrine can induce coronary artery spasms and myocardial ischemia in Kounis syndrome, making accurate diagnosis essential. The upcoming self-amplifying COVID-19 mRNA-LNP vaccines also contain LNPs. Given that these vaccines can cause a cytokine storm and allergic reactions post vaccination, it is crucial to consider corticosteroids and measure IL-6 levels for effective management.

Cytokine release syndrome associated with immune checkpoint inhibitors: a pharmacovigilance study based on spontaneous reports in FAERS

ABSTRACT Objective To describe cytokine release syndrome (CRS) associated with immune checkpoint inhibitors (ICIs) reported in the FDA Adverse Event Reporting System (FAERS). Methods We obtained ICIs adverse event (AE) reports from January 2011 to September 2023 from the FAERS database. The preferred term (PT) ‘cytokine release syndrome’ from the Medical Dictionary for Regulatory Activities (MedDRA) 26.1 was used to identify cases with ICIs-related CRS. The reporting odds ratio (ROR) of the disproportionality method was performed to quantify the association between CRS and ICIs treatment strategy. Results Three hundred and ninety-five cases were gathered. 42.03% of the patients were aged 18 to 65. Male patients outnumbered female patients (53.67% vs. 34.94%). The prevalent potential cancer types were lung cancer (33.42%) and skin cancer (20.51%). Japanese were responsible for the majority of ICIs-related CRS cases (176 cases). The combination of nivolumab and ipilimumab resulted in the most CRS cases (138 cases), and the ICIs combination therapy had the highest ROR signal value (ROR = 11.95 [10.14–14.06]). ICIs-related CRS had a median time to onset of 14 days (interquartile range [IQR] 7–43.25). Conclusions ICIs-related CRS is an increasingly important immune-related AE. Our study provided helpful information to help medical professionals learn more about ICIs-related CRS.

Efficacy of sarilumab and dexamethasone co-administration for lowering multiple blood biomarkers in the treatment of cytokine release syndrome in hospitalized COVID-19 patients.

The current study was planned to explore the potential synergistic role of the co-administration of sarilumab and dexamethasone in reducing blood biomarkers associated with cytokine release syndrome in hospitalised patients of coronavirus disease-2019. The sample comprised 22 patients hospitalised with severe and critical severity levels and who were treated with sarilumab and dexamethasone. Positive responses were seen in blood biomarkers, including decreased interleukin-6 alpha levels and improved oxygen saturation. Tumour necrosis factor, Ddimer, C-reactive protein, ferritin and lymphocyte count also showed positive responses in patients who survived than those who died. Lactate dehydrogenase levels fluctuated with improvement among the survivors, but had limited effectiveness in those who died. The findings suggested promising avenues for future treatment strategies in patients with severe coronavirus disease-2019 and cytokine release syndrome.

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

Tebentafusp in the treatment of metastatic uveal melanoma - the first patient treated in the Czech Republic.

Uveal melanoma is a rare cancer, in which metastases occur in approximately one half of cases. In metastatic disease, the prognosis is unfavorable and the median of survival does not exceed 6 months. Effective treatment options were very limited up to date. Tebentafusp is a bispecific fusion protein, which as the first drug proved efficacy in uveal melanoma. The patient was referred for suspected uveal melanoma of the left eye. She was treated for Hodgkin's disease in the past. Primarily, the tumor was treated by radiosurgery with radiotherapy of a small lesion of the vertebral body. However, later the patient had to undergo bulbus enucleation with confirmation of a large tumor category pT4b. PET/CT revealed metastases of the bones and the liver; simultaneously, haplotype A*02: 01 was confirmed. The patient underwent radiotherapy of the sternum and later, after confirmation of payment from the health insurance company, she started treatment with tebentafusp. The first three doses were administered during admission to the hospital, with a need to treat cytokine release syndrome by corticosteroids. Later, the administration was performed in an out-patient regimen, without complications, except for a transient elevation of transaminases. The first CT restaging confirmed stable disease; however, the second restaging confirmed a new osteolytic lesion in the processus of Th11. Because of progression, the treatment with tebentafusp was withdrawn after 6 months. Unfortunately, the lesion could not be treated by radiotherapy. Two months later, the patient was urgently admitted to the hospital because of right-sided hemiplegia; MRI revealed bleeding metastatic lesion in the brain stem. In this case report, we present the case of the first patient treated with this drug in the Czech Republic.

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 has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the 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 January 2020 and May 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 up-regulated 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.

Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy

AbstractBispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb–related toxicities.

Evaluation of Siltuximab and Tocilizumab Analytical Interference on Interleukin 6 Measurements

Abstract Background Interleukin 6 (IL-6) plays important roles in both innate and adaptive immunity, while dysregulated persistent production of IL-6 is involved in pathological development of various diseases associated with inflammation. Targeting the IL-6 pathway has led to many innovative treatment approaches. Siltuximab and Tocilizumab are monoclonal antibodies targeting IL-6 and IL-6 receptors respectively and have been FDA-approved for treatment of Castleman disease (Siltuximab), a rare lymphoproliferative disorder characterized by hyperproduction of IL-6 with an unknown prevalence, autoimmune diseases such as rheumatoid arthritis (Tocilizumab), and both shown potential as treatment for cytokine release syndrome in hospitalized COVID-19 patients. However, the presence of siltuximab can interfere with IL-6 assays, leading to the use of C-reactive protein (CRP) as a surrogate marker to monitor its efficacy. Aim To evaluate potential Siltuximab and Tocilizumab antibody interference on IL-6 measurements in three different IL-6 protein immunoassays. Method: Serum or EDTA plasma sample pools with different IL-6 concentrations ranging from low (2.3 – 11.1 pg/mL, around the reference interval cut-off for each assay) to high (18.5 – 1142 pg/mL), above reference interval cut-off for each assay) were utilized. Various concentrations of Siltuximab or Tocilizumab were spiked into the sample pools (at 10% of total volume) to achieve final concentrations up to 600 µg/mL and up to 300 µg/mL, respectively. Sample spiked with 10% saline were used as no-drug control. Three assays were used to measure IL-6 concentration: Beckman Access IL-6 assay on UniCel DxI 800 (Beckman Coulter), V-PLEX Plus human IL-6 assay on QuickPlex SQ120 (Meso Scale Diagnostics), and a Luminex cytokine panel assay developed in house (R&amp;D systems) with upper reference interval limits of 6.4,1.8 and 5 pg/mL respectively. Results Siltuximab interfered with the measurement of IL-6 for all three assays. A significant interference (&amp;gt; 20% reduction) was observed at even a very low siltuximab concentrations in all three assays (0.05 µg/mL). In the presence of 5 µg/mL or greater Siltuximab, a maximum reduction of 93%, 83%, and 40% was observed for Beckman Access, R&amp;D Luminex assay, and V-PLEX Plus Mesoscale assay, respectively. Tocilizumab did not interfere with the measurement of IL-6 in the three assays when serum was spiked with up to 300 µg/mL of the drug. Conclusion Siltuximab falsely reduce the measured IL-6 concentration on all three immunoassays tested in this study to differing degrees, whereas Tocilizumab does not. Consider the therapeutic range of Siltuximab (84 to 332 µg/mL) for treatment of Castleman disease, and a half-life of 20.6 days, measurement of IL-6 may not be useful in Siltuximab treated patients for an extended time-period.

Cytokine Release Syndrome: The Patient, Caregiver and Healthcare Professional Experience

Background: Cytokine release syndrome (CRS) is a supraphysiologic response to T-cell engaging immunotherapy that can negatively impact the treatment experience of patients with non-Hodgkin lymphoma (NHL) and other blood cancers. We explored patient, caregiver and healthcare professional (HCP) perspectives on key burdens and unmet needs associated with CRS. Methods: Existing insights from disease-level patient journeys (follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma [MM]) and reports from focus groups with a CRS patient working group from the USA, UK, Canada, and Belgium were assessed to identify key questions. Further interviews were conducted (November 2022-January 2023) in the USA, UK, Germany, and Austria to address these questions with patients, caregivers and HCPs. HCP insights were collected via 60-minute virtual interviews; patient and caregiver insights were collected via video homework tasks and 60-minute virtual interviews. Outputs were validated by the working group, consisting of patients with CRS experience and representatives of patient organizations. Results: A total of 34 HCPs (hemato-oncologists, n=24; nurses, n=10; Tables 1 &amp; 2) with varying degrees of experience of managing CRS were interviewed, along with 9 patients and 3 caregivers (associated diagnoses: NHL, n=6; MM, n=5; acute lymphocytic leukemia, n=1). All patients had experienced CRS (Grade 1-3) as a result of CAR T-cell (n=6) or bispecific antibody (n=3) therapy. Insights were based on five focus areas: 1) patient education and information; 2) CRS diagnosis and management; 3) CRS in different healthcare archetypes; 4) digital literacy and the role of technology in mitigating/monitoring/managing CRS; and 5) the caregiver perspective. CRS education was a primary unmet need, but overall awareness and knowledge of CRS was strong among the patient sample. Patients noted the life-threatening potential of CRS, but preferred to be on active treatment. HCP communication to patients focused on CRS being an expected occurrence rather than a marker of treatment failure, the need for in-patient admission in some cases and/or close monitoring, and the critical role of caregivers. Generally, HCPs were familiar with CRS and the procedures for its monitoring and management, but the variability in time to onset, severity of symptoms, and potential impact on quality of life (QOL) warranted caution. Logistics emerged as a common barrier, with CRS treatment often administered at major hospitals, as local, community-based clinics do not currently have the required capacity/capability to manage CRS; this could be achieved via the provision of training and support. Uncertainty remains regarding the broader roll out of bispecific antibodies, given the variability in CRS treatment between countries. Patients, HCPs and caregivers were aligned on their preferences for remote monitoring for CRS. All three groups expressed the need for simple, easy-to-use solutions that integrate seamlessly with existing systems and do not cause undue concern with false alarms, complex technical set-up and patient user experience. Patients emphasized the need for prompt and assured access to their medical team in case of an emergency. HCPs expressed a range of opinions on the feasibility of adopting such solutions. Some were open to using new tools and saw the potential for alleviating resource challenges. Others had reservations about interoperability and questions around over-informing patients with detailed data. Patients were open to adopting new technologies, if they added tangible benefit to their QOL, avoided additional logistical burden and improved their experience. Conclusions: There is strong awareness among patients, caregivers, and HCPs of the risks associated with CRS and the potential impact on QOL. HCPs with experience in administering cellular immunotherapies are confident in monitoring and managing CRS; however, its unpredictability and logistical burden need to be addressed. There is value in adopting digital solutions for CRS monitoring and management. Concerns remain around interoperability, data stewardship, and integration and validation within current hospital systems. Patients' concerns regarding the useability of such digital solutions and assured data privacy also need to be addressed as part of solution development in the CRS space.

Real-World Outcomes of Brexucabtagene Autoleucel (brexu-cel) for Relapsed or Refractory (R/R) Adult B-Cell Acute Lymphoblastic Leukemia (B-cell ALL): Evidence from the CIBMTR Registry

Background Brexu-cel is a CD19 CAR T therapy first approved by the FDA in 2021 for adult patients (pts) with R/R B-cell ALL. In the pivotal phase II ZUMA-3 single arm trial, brexu-cel achieved a high rate (71%) of complete remission or complete remission with incomplete hematological recovery (CR/CRi) with a manageable safety profile. Here, we report outcomes of brexu-cel in a broad real-world patient population. Methods A total of 197 pts with B-cell ALL were infused with brexu-cel and prospectively enrolled between July 2021 and May 2023 in the CIBMTR registry across 67 centers in the US. In this analysis, we included 138 pts with at least one scheduled follow-up at Day 100 and evaluable safety and effectiveness outcomes. Descriptive statistics, Kaplan-Meier estimator and cumulative incidence functions were used to summarize outcomes. Results Median age was 43 years (range, 19.4-79.4; 19% were age ≥60 years) and 52% were males. Pts had a diverse ethnic background: 50% non-Hispanic White, 28% Hispanic, 11% non-Hispanic Black and 7% non-Hispanic Asian. More than half (55%) of pts had poor cytogenic risk score at diagnosis. Prior to lymphodepletion (LD), the majority of pts had: ECOG performance status of 0 or 1 (80%); at least one clinically significant comorbidity (79%); and Ph-negative disease (64%). Furthermore, 44% had evidence of ≤5% bone marrow blasts; of these (n=49), 65% were MRD negative. Extramedullary disease and CNS involvement was observed in 22% and 10% of pts prior to LD, respectively. As such, based on adapted criteria available in the registry data, 91% of pts in this cohort would have been ineligible for ZUMA-3. Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab. One third (35%) had prior allogeneic (allo) stem cell transplant (SCT). Moreover, 41% of pts received bridging therapy prior to LD. Median time from leukapheresis to brexu-cel infusion was 32 days (inter-quartile range [IQR] 27-42)) and median follow-up time was 5.9 months (95% CI: 5.1-6.1) (Table 1). Overall CR/CRi rate by Day 100 post infusion was 76%; 70% were still in remission at 6 months post initial response (95% CI: 55-80). For those who were not in response before LD, 63% of them converted into a CR/CRi. Relapse free survival at 6 months was 53% (95% CI: 42-62). The overall survival rate at 6 months was 78% (95% CI: 69-84); primary causes of death were primary disease (n=13/32, 41%) and infection (n=7/32, 22%). About one third (31%) of responders received a subsequent allo SCT. High response rates were observed in all pts regardless of age, prior exposure to blinatumomab, allo SCT, or presence of extramedullary disease prior to LD. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT consensus) occurred in 9% and 24% of pts, respectively (Table 2). Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%). Most of these adverse events were resolved within 3 weeks of infusion (CRS, 94%; ICANS, 80%). Prolonged cytopenia and neutropenia 30 days post infusion was experienced by 42% and 33% of pts, respectively. Conclusion In this largest-to-date real-world evidence study of brexu-cel in adult pts with B-cell ALL, response and safety outcomes were consistent with findings from ZUMA-3, even with 91% of patients not meeting ZUMA-3 eligibility criteria. Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors

Efficacy of Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Toxicities - a Multicenter Retrospective Analysis

Background: Chimeric Antigen Receptor T-Cell therapies (CAR-T) are effective in a variety of hematologic (hem) malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can affect a significant number of patients (pts). Tocilizumab, a monoclonal antibody (mAb) binding the interleukin-6 (IL-6) receptor, is the standard of care for managing CRS, but is ineffective for ICANS. Corticosteroids remain the standard of care for managing ICANS. Pts who develop refractory CRS or ICANS have few treatment options. Siltuximab, a mAb binding circulating IL-6, has been proposed to have clinical activity in both CRS and ICANS (Patel, ASH, 2022; Narkhede, TCT, 2023). This study assesses the efficacy of siltuximab for managing CRS and ICANS in a real-world cohort from six academic medical centers. Methods: We conducted a multicenter retrospective review of adult pts with hem malignancies treated with CAR-T therapy who received siltuximab for treatment of CRS and/or ICANS. Siltuximab administration occurred between January 2020 and August 2022. Pts who died within 48 hours of siltuximab administration (n=2) were excluded from this analysis. The co-primary endpoints were the percentage of pts who had improvement in CRS or ICANS after receiving siltuximab. Secondary endpoints included time to improvement of CRS or ICANS and overall survival (OS) from the date of CAR-T infusion. Time to event endpoints were evaluated by Kaplan-Meier methodology. Results: Fifty-two pts were eligible and evaluated. The median age was 60 years (range 23-81). Diffuse large B-cell lymphoma was the most common hem malignancy (52%). Axicabtagene ciloleucel (42%) was the most common cellular therapy product. Table 1 describes disease subtypes and cell therapy products in detail. Fifty-one pts (98%) developed CRS with median time to onset of 2 days (range 0-9). Max CRS grade prior to siltuximab administration was grade 1-2 in 83% and grade 3-4 in 15%. ICANS occurred in 65% with median time to onset of 6 days (range 0-16). Max ICANS grade prior to siltuximab administration was grade 1-2 in 29% and grade 3-4 in 37%. Prior to siltuximab, 52% of pts received tocilizumab with the majority (59%) receiving more than 1 dose, 69% of pts received corticosteroids, and 10 pts received additional treatments: anakinra (7/10 pts), LP with intrathecal (IT) chemo (3/10 pts), LP with IT steroids (2/10 pts), ruxolitinib (1/10 pt). Reasons for siltuximab administration included steroid refractory ICANS in 17 pts (33%), tocilizumab refractory CRS in 8 pts (15%), tocilizumab shortage in 26 pts (50%), and non-steroid refractory grade 4 ICANS in 1 pt (2%). At the time of siltuximab administration, 42 pts (81%) had evidence of CRS (10% grade 3-4 CRS) and 28 pts (54%) had evidence of ICANS (31% grade 3-4 ICANS). 18 pts (35%) had concurrent CRS and ICANS. Thirty-six pts (86%) had improved CRS grade following siltuximab treatment. The median time to CRS resolution after siltuximab was 1.5 days (range 0-18). Twelve pts with CRS received more than 1 dose of siltuximab. 4/8 pts (50%) with tocilizumab refractory CRS had improved CRS grade after siltuximab. Nineteen pts (68%) had improved ICANS grade following siltuximab treatment. The median time to ICANS resolution after siltuximab was 5 days (range 1-40). Nine pts with ICANS received more than 1 dose of siltuximab. 13/17 pts (76%) with steroid refractory ICANS had improved ICANS grade after siltuximab. The median time to discharge after siltuximab administration was 14 days (range 7-90). CAR-T therapy objective response rate was 73% and complete response rate was 48%. Twenty-one pts had died at the time of data collection; 4 deaths were deemed secondary to CAR-T toxicity. The median OS was 13.8 months (95% CI 9.6-NR) and was not statistically different based on indication of CAR-T therapy, Figure 1. Conclusions: To our knowledge, this is the largest cohort of pts treated with siltuximab for CRS and/or ICANS following CAR-T therapy. Half of the pts had CRS or ICANS refractory to tocilizumab and/or steroids. Siltuximab appeared to be effective for both CRS and ICANS, including refractory toxicities. These data support the use of siltuximab for refractory CRS and ICANS and warrant further investigation of siltuximab in earlier lines of therapy for CRS and ICANS management.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

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.

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Rates of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) data on US subjects (SUBJ) with lymphoma following chimeric antigen receptor T cell therapy (CAR-T).

7528 Background: The engineered T-cell products axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel) are FDA approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), respectively. This study investigated real-world rates of CRS and ICANS following CAR-T. Methods: This study analyzed CIBMTR data of US SUBJ receiving axi-cel or brexu-cel for any indication from Oct 2020–Dec 2021 with ≥1 follow-up visit. CRS and ICANS were graded per American Society for Transplantation and Cellular Therapy consensus guidelines. Results: 927 SUBJ (median age, 63 y; men, 65%) from 87 centers were analyzed. Most received axi-cel (76%), 83% of whom had DLBCL or transformed follicular lymphoma (tFL); 24% received brexu-cel (MCL). Most SUBJ had Ann Arbor stage III/IV (63%), no active central nervous system disease (84%), and refractory disease at CAR-T infusion (66%). Among all 589 SUBJ with DLBCL/tFL who received axi-cel, 54% achieved complete response, 17% partial response, and 6% stable disease. 89/715 SUBJ with available data received treatment for CRS prevention, mostly tocilizumab alone (80% [71/89]) or in combination (3% [3/89]). Overall, 766 SUBJ (83%) developed CRS (grade ≥3, 64 [8%]; Table). Of the 89 SUBJ who received CRS prevention treatment, 78% developed CRS, with 3% (3/89) having grade ≥3. 77% of SUBJ with CRS received CRS treatment, 97% of whom received tocilizumab (alone or in combination [eg, with corticosteroids]). Most (64%) SUBJ with grade 1 CRS received treatment, 63% of whom received tocilizumab alone. ICANS occurred in 424/876 SUBJ with ICANS data (48%; Table), of whom 205 (48%) had grade ≥3. ICANS treatment was reported and administered to 86% of SUBJ with ICANS, 92% of whom received corticosteroids. Conclusions: CRS and ICANS incidence rates were consistent with previously published literature and highlight potential burdens of CAR-T. In addition, the treatment landscape for CRS is changing; SUBJ with grade 1 CRS often received treatment. These data will inform the design of future studies aimed at preventing and treating CAR-T toxicities. [Table: see text]

Tocilizumab for Cytokine Release Syndrome Management After Haploidentical Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis

Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR]=3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR=2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% confidence interval [CI]=0.28-1.06, P=.08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR=0.56; 95% CI=0.25-1.22, P=.19). Cumulative incidences of day 100 acute GvHD grades II-IV (P=.97) and grades III-IV (P=.47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P=.05). Rates of NRM (P=.66), relapse (P=.83), disease-free survival (P=.86), and overall survival (P=.73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P=.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P=.039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P=.02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Improved efficacy with early tocilizumab in the prophylaxis and treatment of cytokine release syndrome of chimeric antigen receptor T cell (CAR-T) therapy for diffuse large B-cell lymphoma than acute lymphoblastic leukemia

BackgroundTocilizumab is a well-practiced strategy to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy. However, varied efficiency in CRS mitigation by tocilizumab has been reported to highlight affecting variables such as tumor types and timing of the administration. ObjectiveThe objective of this study is to identify different curative effect between diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) by early use of tocilizumab for prophylaxis and treatment of CRS. MethodsBy retrospectively summarizing our institution's experience with a CAR-T clinical trial targeting CD19, 11 cases were analyzed: 5 DLBCL, and 6 ALL. The two groups were compared with patient characteristics, CRS information and clinical outcomes. 3 patients were pretreated with tocilizumab for prophylaxis and the rest were treated with tocilizumab at CRS diagnosis. ResultsCRS occurred in 81.8% of patients (9/11), grade 3 or higher occurred in 55.6% of the CRS patients (5/9). The two group were similar in patient characteristics, CAR-T and CRS profile. However, tocilizumab produced much better efficacy against CRS in DLBCL group compared with ALL group (80% versus 16.7%, P ​= ​0.08). ConclusionsDespite the statistical was non-significant, possibly due to small case pool and bias was unavoidable, our analysis suggested that early use of tocilizumab was more effective for DLBCL than ALL in the prophylaxis and treatment of CRS. A treatment algorithm for management of CRS with regard to DLBCL and ALL is proposed, which may extend to other local or systemic malignancies and warrant further investigation.