Received Chimeric Antigen Receptor T-cell Therapy Research Articles

Early and Consistent CRS Detection Using Wearable Device for Remote Patient Monitoring Following CAR-T Therapy in Relapsed/Refractory Multiple Myeloma (RRMM): Early Results of an Investigator-Initiated Trial

The administration of Chimeric Antigen Receptor T-cell (CAR-T) therapy for relapsed refractory multiple myeloma (RRMM) predominantly takes place in the inpatient setting to monitor for adverse effects like cytokine release syndrome (CRS) and neurotoxicity leading to increased healthcare utilization, infection risk and patient discomfort. Shifting the administration model to the outpatient setting may improve patient experience, optimize hospital bed utilization and decrease costs, but requires an objective and reliable method for CRS detection to monitor patients remotely and safely. The feasibility of using a wearable device for detecting CRS following CAR-T therapy in RRMM was compared to standard of care (SoC) nursing-recorded vital signs in this investigator initiated clinical trial (IIT). Patients wore a wearable device that collected continuous measures of temperature, pulse, respiratory rate, and O2 saturation in addition to SoC while receiving CAR-T therapy from the day infusion to discharge. Changes in vital signs captured by the device were analyzed based on 2 thresholds: (i) CRS timestamps were tagged in wearable data when pt's temperature breached a fixed threshold of 38 0C ( Tf) defined as fever by the American Society of Transplantation and Cellular Therapy (ASTCT), and (ii) when pt's temperature breached an individualized threshold of 2 standard deviations above their baseline temperature ( Ti) [see Figure 1]. Outcomes were time to first detection of CRS in wearable data vs. SoC. Wearable adherence was the duration pts wore the device over the total monitoring period. To date, 34 pts were screened, 28 enrolled (82.3% uptake), 1 was excluded from the dataset because of concurrent COVID-19, and 2 pts with CRS were excluded from time to detection comparison because of wearable adherence <50% during high-risk windows (defined as the time period where CRS is expected per known data for the CAR-T product). Max CRS grades were 1 (17 pts), 2 (1 pt), 3 (2 pts), and 4 (1 pt); 5 pts did not have clinical CRS. Patients wore the device for a median of 13 (12-15) days out of a median of 15.5 (14-17) days of inpatient admission for CAR-T infusion. Median individualized temperature threshold was 37.4 (37-37.6) C. Wearable adherence was 64 (51 - 77) % and 72 (57 - 87) % for the overall monitoring and high-risk periods, respectively. The wearable detected the initial CRS events at a median of 22 (-43 - 113.5) min earlier than SoC with Tf and a median of 184 (53 - 312) mins earlier than SoC with Ti method. In the no CRS subgroup, false CRS detection occurred in 1 pt with the Tf and 2 pts with the Ti method. Preliminary results suggest that time to CRS detection by the wearable device preceded SoC detection by a median of 103 minutes corroborated by both threshold methods. Temperature thresholds calibrated to the baseline temperature of individual patients facilitate earlier detection of CRS than fixed thresholds per clinical/ASTCT criteria. While the low false detection rate in is encouraging, these may also potentially be attributed to subclinical events. Both pts who had “false positive” triggers breached their individualized temperature thresholds via device readings while only recording low-grade temperatures that did not meet clinical CRS criteria per ASTCT, indicating possible capture of subclinical events. The study showcases the utility of continuous remote patient vital signs monitoring by wearable devices in efficiently capturing CRS, including subclinical events, earlier than SoC. Objective and reliable CRS monitoring may help safely transition workflows to outpatient CAR-T administration models. Analysis of trends in cytokine biomarkers for early CRS detection signal(s) is currently underway. Cytokine signals, alone and in combination with device data, are planned to be incorporated into machine learning models to build a CRS prediction index in future analyses. Figure 1: Snapshot in time of the continuous temperature data generated by the wearable device after CAR-T infusion showing capture of cytokine release syndrome. – Ti (solid line) represents the median baseline temperature of the patient over the entire duration of the data capture by the wearable device – Tf (dotted line) represents the temperature threshold of 38 0C, the clinical definition of fever as per ASTCT – Black diamond: clinical CRS event, when temperature >38 0C as recorded by nursing

Clinical Outcomes of Subsequent Therapies in Patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody (BsAb) targeting G protein-coupled receptor family C group 5 member D. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of >71%, which were durable, and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous (SC) tal, 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), in patients (pts) with relapsed/refractory multiple myeloma. Data with tal also demonstrated preservation of B cells throughout treatment, contributing to relatively few severe infections. To date, there is a paucity of data describing pt outcomes after T-cell redirection therapies. Here, we report outcomes for pts who received subsequent antimyeloma therapies (SATs) after discontinuing tal in MonumenTAL-1, including pts who went on to receive subsequent T-cell redirection therapies. Methods: Pts eligible for MonumenTAL-1 were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 anti-CD38 monoclonal antibody (mAb) (phase 2). Pts received step-up doses and the QW or Q2W RP2Ds of SC tal until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Following tal discontinuation, SAT, start/end date of SAT, best response to SAT, and date of PD on SAT were recorded, if available. Data are pooled for the QW and Q2W RP2D cohorts. Response to SAT is based on investigator-reported assessment. Efficacy is presented for first SAT received post tal discontinuation. Results: As of 17 Jan, 2023, 288 pts with no prior exposure to T-cell redirection therapies received tal at the RP2Ds (0.4 mg/kg QW [n=143] or 0.8 mg/kg Q2W [n=145]). Median prior LOT was 5. In the QW and Q2W cohorts, respectively, 74.1% and 69.0% were triple-class refractory, 29.4% and 23.4% were penta-drug refractory, and 15.4% and 11.0% had prior belantamab mafodotin exposure. Overall, 135 pts received ≥1 SAT post tal discontinuation: chemotherapy-based regimens (n=60 [44.4%]), a PI-, IMiD-, or other anti-neoplastic-containing regimen (n=40 [29.6%]), anti-CD38 mAb-containing regimens (n=36 [26.7%]), BsAbs (mostly monotherapy, n=23 [17.1%]: n=18 [13.3%] anti-B-cell maturation antigen [BCMA]; n=5 [3.7%] anti-Fc receptor-like protein 5 [FcRH5]), chimeric antigen receptor T-cell (CAR-T) therapy (n=20 [14.8%]; of whom n=18 [13.3%] were reported as receiving anti-BCMA-targeting CAR-T therapy), or anti-BCMA antibody-drug conjugates (n=13 [9.6%]). Time from tal discontinuation to the start of first SAT was generally similar across all drug classes (median, 1.1 months [range, 0.1-7.4]), including T-cell redirection therapies and bridging therapy in pts receiving CAR-T therapy: 1.5 months (range, 0.1-7.4) with CAR-T, 1.7 months (range, 1.0-3.5) with anti-BCMA BsAbs, and 1.0 month (range, 1.0-2.3) with anti-FcRH5 BsAbs. Best responses for each treatment class are shown in the Table. Pts had deep responses to CAR-T therapy as the first SAT post tal discontinuation with an ORR of 66.7% (8/12) (Table). ORR was 33.3% (2/6) in pts treated with anti-BCMA BsAbs as the first SAT post tal and 66.6% (2/3) with subsequent anti-FcRH5 BsAb therapy. Conclusions: Pts from MonumenTAL-1 who discontinued tal were effectively treated with several classes of therapy. Subsequent treatment with T-cell redirection therapies appears feasible, with 25.0% of pts achieving a complete response or better with CAR-T therapy post tal. Further investigation in larger pt populations is warranted to better understand the sequencing of T-cell redirecting therapies after tal to optimize outcomes.

Real-World Incidence, Characteristics and Management of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cell Therapy across Hematologic Malignancies

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. CRS occurs with varying frequency and severity, depending on the underlying disease and immunotherapy used, such as chimeric antigen receptor T-cell (CAR-T) therapy or off-the-shelf T-cell engaging bispecific antibodies. Limited research exists on the diagnosis and management of CRS in the real world. This study describes the real-world incidence, severity and clinical management of CRS induced by commercially available CAR-T therapies for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and multiple myeloma (MM). Methods: Real-world data (RWD) were obtained from the Flatiron Health, US, nationwide electronic health record (EHR)-derived, de-identified database of cancer patients within a network comprised primarily of community cancer practices. The Flatiron Health network also includes practices designated as academic sites by the National Cancer Institute; however, relative proportions of community/academic practices may vary depending on the study cohort. Data as of August 31, 2022, on CAR-T therapy, clinical characteristics and disease outcomes specific to CAR-T therapy, as well as CRS and its clinical management, were abstracted from unstructured documents in EHRs (in addition to routinely available structured data), in a cohort of patients receiving commercial CAR-T therapy. Specifically, data for CRS including treatments and resolution were abstracted based on explicit mention of and attribution to CRS in charts. Results: Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (<15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL. Highest incidence of Grade ≥2 CRS was observed among MCL patients, whereas Grade ≥3 CRS was most commonly observed among FL patients. Time to onset of CRS ranged from 0 to 16 days, with median onset between 3-4 days among lymphoma patients and earlier median onset of 1 day for MM patients. Median time to CRS resolution ranged from 2 to 6 days across indications. While 81-95% of patients received CAR-T therapy at an academic center, 5-14% received CAR-T therapy at a community center. Tocilizumab and corticosteroids were the most commonly used treatments for CRS, including 37-48% use of tocilizumab for Grade 1 CRS (Table 2). Discussion: This study uniquely summarizes RWD on CRS following the use of commercially available CAR-T therapies across multiple hematologic malignancies, based on information from clinical notes abstracted retrospectively from EHRs. Consistent with the timing of approval of commercially available CAR-T therapies, the sample size for MM was limited compared with other malignancies. Safety events are typically under-reported in RWD sources, specifically for CRS when relying on information documented in patients' EHRs, compared with other published literature. In accordance with other RWD on CRS, grading criteria for CRS as well as vasopressor and oxygen use were not consistently reported in patients' EHRs. CAR-T treatments were predominantly administered in academic centers. Limited use in community practices was also observed; however, further information to accurately characterize the size and capabilities of community centers was not available in this database. Data also showed considerable use of tocilizumab to treat low-grade CRS, suggesting the need for additional evidence on its role to treat CRS beyond its current regulatory approval. Increased evidence generation, specifically from usual clinical practice, can contribute to increased awareness and knowledge about CRS diagnosis and management, and in turn realize the maximum potential of T-cell therapeutics.

Standardization of Outpatient Care after CAR-T Therapy across a Large Cell Therapy Network- through Technology and Decentralized Virtual Nurses: Preliminary Results

Introduction: Shifting Chimeric Antigen Receptor T-cell (CAR-T) therapy to the outpatient setting may increase patient satisfaction and inpatient capacity, and reduce infection risk. Outpatient protocols require resources for patient management outside of clinic hours to be safe and effective. Our Transplant and Cellular Therapy Network (TCTN) leveraged wearable technology and decentralized nurses in four outpatient CAR-T programs. We sought to characterize patient adherence, time spent on patient monitoring, and clinical outcomes. Methods: Patients were deemed eligible for outpatient therapy if they were adults (18+ years), lived within 30-60 minutes of the treating hospital, had a 24/7 caregiver, and received CAR-T with known risks of developing cytokine release syndrome (CRS). The outpatient CAR-T program included enrollment into an FDA-cleared virtual care platform, daily engagement with virtual nurses for the duration of the program, and in-person clinic visits during the highest risk period (Days 1-14). The remote monitoring kit included a wearable device that continuously transmitted vital signs (pulse, respiratory rate, O 2 saturation and skin temperature), a tablet, axillary temperature patch and blood pressure (BP) cuff. Patients were asked to always wear the device outside of clinic visits, take a BP reading 3x/day, and complete surveys via the tablet. A multidisciplinary taskforce established clinical pathways for remote monitoring across sites and developed parameters for alarms, virtual nurse check-ins, and escalation of care to ER/clinic. Virtual nurses contacted patients based on vital sign trends, responded to patient concerns, and triaged in accordance with clinical pathways, escalating as appropriate. The virtual care platform, video and phone call logs with the virtual nurses, and clinical data were extracted for 40 patients between 2/20/23 and 6/15/2023. Inpatient admission, patient adherence, alarms, calls, and clinical metrics were summarized. Non-parametric measures were reported as median (IQR). Metrics for specific windows of time were reported for a subset of variables: wearable adherence (day vs. night) and alarms/calls during clinic hours (weekdays 8 am - 5 pm) vs. non- clinic hours. Adherence was derived from tasks/wear time completed vs. prescribed. Results: Forty patients (66 ± 12 years, 24 male) with diagnoses of Non-Hodgkin Lymphoma (75%), Plasma Cell Disorder (20%), or Acute Lymphoblastic Leukemia (5%) received CAR-T therapy [axi-cel (40%), liso-cel (25%), cilta-cel (20%), brexu-cel (12.5%), tisa-cel (2.5%)] and completed the outpatient CAR-T program. The median length of monitoring on the platform was 14.7 (10.4 - 27.6) days. Overall wearable adherence was 79 (67.7 - 87.9) %; 67 (48.7 - 83.4) % in the day and 89.1 (79.8 - 92.8) % at night. Median survey completion was 50 (7.7 - 80) % and BP compliance was 95 (69.8-100) %. Out of 717 patient days, 68.4% had 100% BP compliance (3 readings/day). There was a total of 780 alarms; 67% operational and 86% clinical alarms occurred during non-clinic hours (Table 1). The operational alarm rate was 0.5 and the clinical alarm rate was 0.6 per patient-day. 75% of patients triggered at least one operational and clinical alarm during their program. The virtual nurses engaged in 1102 calls through the tablet or phone (3.5 ± 3.4 mins). More than half of the calls were during non-clinic hours (63%) and 70% of calls were with a patient/care giver. Calls about a clinical alarm or clinical concern were 3x and 6.8x higher, respectively, during non-clinic hours. Twenty-seven patients required some level of hospital observation service and/or admission to the hospital; 25 patients developed CRS. Median duration from infusion to admission/observation was 5 (1-11) days. Median days to discharge was 5 (1-26). Of those admitted,10 patients were admitted to the ICU with a median stay of 5.5 (1-21) days. Conclusion: Our TCTN established a successful, integrated outpatient management process to ensure patient safety within the first 30 days post CAR T-Cell therapy. The virtual care platform and decentralized virtual nurses have enabled patients to recover safely with more time at home rather than in hospital. Future research will address patient and provider experiences and continue to expand on the safety and resource utilization of this integrated program.

Efficacy and Safety of Glofitamab in Patients with R/R DLBCL in Real Life Setting - a Retrospective Study

Introduction - Glofitamab is a CD20-directed CD3 T-cell engager that has recently been approved by the FDA for relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL). The approval was based on a pivotal phase II study including 154 patients with a median of 3 lines of treatment (a third post chimeric antigen receptor T (CAR-T) cell therapy) demonstrating an overall response rate (ORR) and complete response (CR) rate of 52% and 39%, respectively 1. However real-life data is still lacking. The present study was aimed to determine the efficacy and safety of glofitamab in real-life settings. Methods -A retrospective multicenter study including consecutive patients aged 18 years and older with R/R DLBCL, treated through a national compassionate program with at least 1 dose of glofitamab, after failing at least three lines of therapy. The first patient was recruited in September 2020 till January 2023. Outcomes included ORR and CR, defined by the Lugano criteria; progression free survival (PFS) and overall survival (OS), defined from the day of obinutuzimab infusion until event; cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) were defined by the ASTCT consensus 2019. Risk factors for PFS and OS were identified by univariate and multivariate analyses, using logistic regression. Results - A total of 35 patients treated in 6 Israeli centers, were included. Median age at the time of initiation of glofitamab was 67 years (59-74) and 66% of the patients were males. The median number of previous therapies was 5 (IQR, 4-6) and 83% received more than 3 previous lines of therapy. 43% were primary refractory, all but 3 received CAR-T cell therapy (91%) and 23% underwent autologous stem cell transplantation (Table 1). Median follow up was 34 months (IQR, 18-57). Outcomes: 34% achieved ORR with 14% achieving CR. Median PFS and OS was 2 (IQR, 1-6) and 4 months (IQR, 2-10), respectively (Figure 1). At the end of follow up - 12 (34%) patients survived, 21 died and 2 patients were lost to follow- up. Causes of death included disease progression in 15 patients and infections in 6. Treatment was discontinued earlier than 12 cycles in 86%, mostly due to progressive disease (76%), and 24% due to infections (3 - COVID-19; 3- bacterial). Adverse events included CRS in 37% - all grade 1-2. 2 patients developed grade 1 ICANS. In a multivariate analysis including age, male, bulky disease, elevated LDH and CRS, only male sex was found to be significant risk factor for PFS and OS (p=0.02, p=0.04 respectively). Conclusions - In this real-life cohort of R/R DLBCL, glofitamab showed less efficacy than in the pivotal study. This might be due to the more heavily pretreated patients in our series with nearly all patients post CAR-T. Nevertheless, toxicity in our real-life analysis was better than reported in the pivotal study, supporting the role of glofitamab in R/R DLBCL patients. References- 1. Dickinson et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. NEJM 2022;387:2220-31

Impact of Sarcopenia and Subsequent Muscle Loss on Post-CAR T-Cell Outcomes in Relapsed/Refractory Large B-Cell Lymphoma

Background: Sarcopenia is a hallmark of cachexia commonly found in cancer patients that is caused by immune and metabolic mediators of catabolism. Chimeric antigen receptor (CAR) T-cell therapy is used to treat cancer and is characterized by the release of inflammatory cytokines and other potentially catabolic mediators. Previously, we showed that baseline sarcopenia and other immuno-nutritional scores were associated with poor outcomes after CD19-directed CAR T-cell therapies in patients with R/R LBCL (Rejeski et al. Cancer Immunol. Res. 2023). Here we examined the relationship between body composition and serum metabolite levels over time after CAR T-cell infusion. Methods: This is a single-center retrospective study of N=83 patients with R/R LBCL who received CAR T-cell therapy. The median clinical follow-up was 18.4 months. Muscle and adipose tissue distribution were calculated from clinical pre-lymphodepletion, day (d) 30, and day (d) 90 CT imaging using Slice-O-Matic software (v5.0, Tomovision). Baseline sarcopenia status was determined using established criteria (SMI 52.4 cm2/m2 for Males and 38.5 cm2/m2 for Females) . Immuno-nutritional scores included: GPS Score: CRP ≤ 10 mg/L = 0; CRP > 10 mg/L and albumin > 3.5 g/dL = 1; CRP > 10 mg/L and albumin < 3.5 g/dL = 2. PNI Score: Albumin (g/L) + 5 × total lymphocyte count (10^9/L). Muscle loss at d30 or d90 after CAR T-cell therapy was defined by a decrease of > 10% in their skeletal muscle index (SMI) from baseline. Patients who had relapsed, died or had missing scans were censored during the analysis. Univariate and multivariable Cox regression models using LASSO regularization assessed the association between various factors and survival outcomes. Serum metabolites were profiled at baseline and at regular time points up to 4 weeks after CAR T cell therapy (n=55) as previously described (Fahrmann et al. Cell Rep. Medicine 2022). Results: Patients with baseline sarcopenia (n=44) had worse progression-free (PFS) and overall survival (OS) after CD19 CAR T cell therapy for R/R LBCL compared to non-sarcopenic patients (n=39) (OS: HR=2.5, 95% CI: 1.3-4.9, P=0.008; PFS: HR=1.8, 95% CI: 1.0-3.2, P=0.037). In multivariable Cox fits (MVA) for OS, male gender (HR=3.3, 95% CI: 1.3-8.8, P=0.014), and GPS score of 2 (HR=3.8, 95% CI: 1.4-10.6, P=0.011) were associated with worse OS. On MVA for PFS, a lower PNI score was mildly associated with worse outcomes (HR=0.9, 95% CI: 0.8-1.0, P=0.039). Muscle loss occurred between baseline and d30 and d90 after CAR T-cell therapy in 34% and 32% of patients, respectively. Muscle loss correlated with concurrent adipose tissue loss and overall weight loss. Patients who had baseline sarcopenia had more pronounced muscle loss at d30 and d90 compared to patients who were non-sarcopenic at baseline. Associations with d30 muscle loss included ICANS grade 2 or higher (P=0.046) and baseline LDH (P=0.033). Further, patients with ICANS grade 2 or higher had a significantly higher d30 median muscle loss compared to patients with grade 0-1 ICANS (9.1% versus 6.4%; p=0.049). However, whether landmarked at d30 or d90, muscle loss after CAR T-cell therapy did not significantly associate with the risk of subsequent progression or death. Individual serum metabolites that significantly decreased between pre-infusion and after CAR T-cell infusion included those potentially associated with gut microbiome alterations (indole-3-acetate and xanthosine). Pathway analysis revealed changes in purine and pyrimidine metabolism over time after CAR T-cell therapy. Subgroup analyses comparing metabolites over time in sarcopenia versus non-sarcopenia, as well as based on muscle loss are in progress. Conclusions: Sarcopenia is highly prevalent (53%) in R/R DLBCL patients presenting for CAR-T and approximately 1/3 of patients lose muscle mass during the course of therapy, with the greatest risk noted in those with baseline sarcopenia. High immuno-nutritional scores are associated with inferior outcomes. Muscle loss was associated with a higher disease burden and higher-grade toxicities. Further study is needed to understand the association between antibiotics use and clinical factors for microbiome-related metabolites that change over time after CAR T-cell infusion. Interventional approaches to improve functional and nutritional reserve to optimize outcomes are warranted.

Risk of Bleeding and Thrombosis with CAR T-Cell Therapy: A Scoping Review

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is emerging as a novel and revolutionary therapy in the treatment of relapsed or refractory lymphoma and other hematological malignancies. Patients with hematological malignancies are at risk of bleeding and thrombosis due to multiple risks factors. As there is an ongoing exploration of the incidence and characteristics of bleeding and thrombosis after CAR T-cell therapy, there is no existing published data that incorporates both peer-reviewed and non-peer-reviewed literature. Aim: Assess the risk of bleeding and thrombosis in CAR T-cell recipients for hematological malignancies. Method: We conducted a systematic literature search in MEDLINE, EMBASE, and CENTRAL electronic databases from inception to October 2022 using a combination of subject headings and text words. We included studies that assessed thrombotic and bleeding complications in patients eighteen or older who underwent CAR T-cell therapy for a hematologic malignancy. Our search strategy yielded 14 studies in the form of abstracts and full-text articles. The review process consisted of two levels of screening: (1) a title and abstract review and (2) a full-text review. Result: Of 3354 records, we included 14 studies based on our inclusion criteria [figure 1]. Majorities of the studies were retrospective. Most of the patients in these studies received CAR T-cell therapy for refractory diffuse large B-cell lymphoma. Patients received at least 2 lines of therapy or more before CAR T-cell treatment. Different types of CAR T-cell therapy were used. Based on the included studies, the risk of bleeding was higher than thrombosis [figure 2]. Bleeding sites were variable, but gastrointestinal (GI) bleeding was predominant. In Ma et al, GI bleeding occurred in 11 (42.3%) patients. In Qi et al and Johnsrud et al, bleeding occurred in 44 (11%) and 12 (9.4%) patients respectively. Variable sites of thrombosis were noticed. In Hashmi et al incidence of thrombosis was 10.8%. Although there are some risk factors associated with bleeding and thrombosis in this population, the exact mechanism is still unknown. We think future studies to determine the exact mechanism of this toxicity and to assess the underlying risk factors would be crucial to decrease morbidity and mortality in this population and to develop risk assessment tools.

Infection epidemiology in relation to different therapy phases in patients with haematological malignancies receiving CAR T-cell therapy.

We described the real-life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T-cells directed towards CD19+ or BCMA+ cells. All consecutive patients receiving CAR T-cell therapy at our institution were prospectively followed-up. We performed various comparative analyses of all patients and subgroups with and without infections. Ninety-one adults mainly received CAR T-cell therapy for acute leukaemia (53%) and lymphoma (33%). We documented a total of 77 infections in 47 (52%) patients, 37 (48%) during the initial neutropenic phase and 40 (52%) during the non-neutropenic phase. Infections during the neutropenic phase were mainly due to bacterial (29, 78%): catheter infections (11 [38%] cases), endogenous source (5 [17%]), and Clostridioides difficile (5 [17%]). Patients receiving corticosteroids after CAR T-cell therapy had a higher risk of endogenous infection (100% vs. 16%; p = .006). During the non-neutropenic phase, bacterial infections remained very frequent (24, 60%), mainly with catheter source (8, 33%). Respiratory tract infections were common (17, 43%). Infections after CAR T-cell therapy were frequent. During the neutropenic phase, it is essential to prevent nosocomial infections and balance the use of antibiotics to lower endogenous bacteraemia and Clostridial infection rates.

Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30-5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15-4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS.

Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

Mathematical Model of Leukemia Treatment with Chimeric Antigen Receptor (CAR) T Cell Therapy

Leukemia, a type of blood cancer that originates in the bone marrow, is characterized by the uncontrolled growth of abnormal blood cells, which disrupt the normal functioning of blood cells. Chimeric antigen receptor (CAR) T-cell treatment, a form of immunotherapy, utilizes genetically modified T cells to specifically target and eliminate cancer cells. This treatment has shown promising results for leukemia patients who are unresponsive to chemotherapy or other therapies, as well as those who experience relapses. In this study, we develop a mathematical model of leukemia that incorporates chimeric antigen receptor (CAR) T-cell therapy. The model takes into account the logistic intrinsic growth rate of leukemia cells, which gradually declines over time due to limited resources within the body. There are four compartments in this model: susceptible blood cells, infected blood cells, leukemia cells, and immune cells. We have analyzed the equilibrium points and their local stability, determined the basic reproduction number, and conducted a sensitivity analysis. Through numerical simulations, we observed that prior to treatment, the number of leukemia cells in the blood escalated rapidly towards endemic conditions. However, after receiving CAR T-cell therapy through external infusion, the leukemia cells either became extinct or took a significant amount of time to reach endemic levels in the blood. Sensitivity analysis revealed that the growth rate of cancer cells (r) and the death rate of immune cells (significantly contribute to the increase in the basic reproduction number (.

Chimeric antigen receptor T-cell treatment patterns in relapsed or refractory large B-cell lymphoma.

Aim: To investigate real-world chimeric antigen receptor (CAR) T-cell therapy treatment patterns. Patient & methods: Relapsed/refractory large B-cell lymphomapatients who received CAR T-cell therapy were identified. Patient characteristics, setting of CAR T-cell infusion, incidence of CAR T-cell therapy-associated adverse eventsand healthcare resource utilization were assessed. Results: Of 1175 patients, 83% were infused inpatient. Within threedays postinfusion, inpatient-infused patients had a significantly higher risk of CAR T-associated adverse events (hazard ratio: 2.67; 95% CI: 2.09-3.42) compared with outpatient-infused patients. By day 30, 67% of outpatient-infused patients were hospitalized at least once. Conclusion: These findings suggest that physicians were able to select lower-risk patients for outpatient infusion, but postinfusion hospitalizations still occur.

Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma

AbstractThe emergence of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for diffuse large B-cell lymphoma (DLBCL); however, real-world experience reporting outcomes among older patients treated with CAR T-cell therapy is limited. We leveraged the 100% Medicare fee-for-service claims database and analyzed outcomes and cost associated with CAR T-cell therapy in 551 older patients (aged ≥65 years) with DLBCL who received CAR T-cell therapy between 2018 and 2020. CAR T-cell therapy was used in third line and beyond in 19% of patients aged 65 to 69 years and 22% among those aged 70 to 74 years, compared with 13% of patients aged ≥75 years. Most patients received CAR T-cell therapy in an inpatient setting (83%), with an average length of stay of 21 days. The median event-free survival (EFS) following CAR T-cell therapy was 7.2 months. Patients aged ≥75 years had significantly shorter EFS compared with patients aged 65 to 69 and 70 to 74 years, with 12-month EFS estimates of 34%, 43%, and 52%, respectively (P = .002). The median overall survival was 17.1 months, and there was no significant difference by age groups. The median total health care cost during the 90-day follow-up was $352 572 and was similar across all age groups. CAR T-cell therapy was associated with favorable effectiveness, but the CAR T-cell therapy use in older patients was low, especially in patients aged ≥75 years, and this age group had a lower rate of EFS, which illustrates the unmet need for more accessible, effective, and tolerable therapy in older patients, especially those aged ≥75 years.

Chimeric antigen receptor T-cell therapy in a dialysis patient with lymphoma

Chimeric antigen receptor T-cell (CAR-T) therapy has become a revolutionary cancer therapy for multiple subtypes of hematologic malignancies. Despite this progress, CAR-T use in End Stage Kidney Disease (ESKD) patients is limited. We describe the successful administration of CAR-T therapy in a patient with ESKD who had developed diffuse large B-cell lymphoma (DLBCL) from an underlying chronic lymphocytic leukemia. The patient received CAR-T therapy, preceded by lymphodepleting chemotherapy with dose-reduced fludarabine and cyclophosphamide, followed by intermittent hemodialysis on a modified basis. The treatment course was complicated by pancytopenia and Grade 2 cytokine release syndrome, managed with tocilizumab. The patient underwent an initial disease response assessment, which showed a complete response, and remains in remission 12 months after CAR-T infusion. This case report highlights the importance of individualized hemodialysis schedules and lymphodepleting chemotherapy dose adjustments in ESKD patients for a successful administration of CAR-T therapy.

Hypoxia-specific imaging in patients with lymphoma undergoing CAR-T therapy.

Intratumoral hypoxia in non-Hodgkin's Lymphoma (NHL) may interfere with chimeric antigen receptor T-cell (CAR-T) function. We conducted a single-center pilot study (clinicaltrials.gov ID NCT04409314) of [18F]fluoroazomycin arabinoside, a hypoxia-specific radiotracer abbreviated as [18F]FAZA, to assess the feasibility of this positron emission tomography (PET) imaging modality in this population. Patients with relapsed NHL being evaluated for CAR-T therapy received a one-time [18F]FAZA PET scan before pre-CAR-T lymphodepletion. A tumor to mediastinum (T/M) ratio of 1.2 or higher with regard to [18F]FAZA uptake was defined as positive for intratumoral hypoxia. We planned to enroll 30 patients with an interim futility analysis after 16 scans. Of 16 scanned patients, 3 had no evidence of disease by standard [18F]fluorodeoxyglucose PET imaging before CAR-T therapy. Six patients (38%) had any [18F]FAZA uptake above background. Using a T/M cutoff of 1.20, only one patient (a 68-year-old male with relapsed diffuse large B-cell lymphoma) demonstrated intratumoral hypoxia in an extranodal chest wall lesion (T/M 1.35). Interestingly, of all 16 scanned patients, he was the only patient with progressive disease within 1month of CAR-T therapy. However, because of our low overall proportion of positive scans, our study was stopped for futility. Our pilot study identified low-level [18F]FAZA uptake in a small number of patients with NHL receiving CAR-T therapy. The only patient who met our pre-specified threshold for intratumoral hypoxia was also the only patient with early CAR-T failure. Future plans include exploration of [18F]FAZA in a more selected patient population.

REAL‐WORLD OUTCOMES OF INTRAVENOUS IMMUNOGLOBULIN FOR HYPOGAMMAGLOBULINEMIA AFTER CHIMERIC ANTIGEN RECEPTOR T‐CELL THERAPY IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is a treatment for patients with diffuse large B-cell lymphoma (DLBCL) and is associated with toxicities, including hypogammaglobulinemia (HGG). Intravenous immunoglobulin (IVIG) is often used to manage HGG and prevent recurrent infections after CAR-T therapy, but more real-world evidence is needed to support this. Aim: To describe the real-world incidence of HGG and the effectiveness of IVIG after CAR-T therapy in patients with DLBCL. Methods: This observational cohort study used de-identified data from the nationwide (US-based) electronic health record (EHR)-derived Flatiron Health database. Patients were aged ≥18 years, diagnosed with DLBCL, had ≥2 visits in the Flatiron network on/after 1-Jan-11 and had received CAR-T therapy (tisagenlecleucel or axicabtagene ciloleucel) in any treatment line after 1-Jan-18. Baseline characteristics were identified in the 60 days prior to the index date (date of first CAR-T therapy administration). Outcomes, including HGG, were measured from index date until patient death or end of data availability (cut-off: 30-Apr-21). In this ad-hoc analysis, the primary objectives were to evaluate HGG incidence and IVIG use in patients with DLBCL who received CAR-T therapy. Exploratory objectives were to describe overall survival (OS) and progression-free survival (PFS) by IVIG treatment. Proportions and medians were used for patient characteristics. The Kaplan–Meier method was used for clinical outcomes. Results: Overall, 91 patients were included. During follow-up, 14 patients (15.4%) developed HGG, of which six cases were ‘directly attributed’ and one case ‘possibly attributed’ to CAR-T therapy; attribution was not documented for seven patients. Among these 14 patients, eight received treatment for HGG and six had no documented record of treatment. In total, 14/91 patients received IVIG (IVIG cohort). The IVIG cohort was younger (median [range] age 59 [32–67] vs 63 [28–83] years), had more females (50.0% vs 37.7%), had more patients with an Eastern Cooperative Oncology Group score of 2 (14.3% vs 6.5%) and was more frequently treated in a community setting (64.3% vs 49.4%) than the non-IVIG cohort. In the IVIG and non-IVIG cohorts, median (95% confidence interval [CI]) OS was not reached (NR; 5.6–NR) and 18.3 (9.1–NR) months, respectively and median (95% CI) PFS was NR (2.3–NR) and 3.0 (2.7–7.4) months, respectively. Conclusions: In this real-world study, half of the 14 HGG cases in patients with DLBCL were directly/possibly attributed to CAR-T therapy. This may be an underestimate because HGG is primarily assessed using laboratory data but here it was identified using EHRs. Despite a small sample size, the hypothesis-generating analyses of IVIG effectiveness and management outcomes support further evaluation of IVIG for the treatment of HGG in patients with DLBCL after CAR-T therapy. The research was funded by: Takeda Development Center Americas, Inc. Writing support was funded by: Takeda Pharmaceuticals International AG. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Immunotherapy Conflicts of interests pertinent to the abstract D. S. Chun Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda Y. Yin Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda C. Anderson-Smits Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda

Association of frailty and high-risk immuno-nutritional score with outcomes in patients with relapsed and refractory multiple myeloma treated with chimeric antigen receptor T-cells.

12052 Background: Multiple myeloma is a disease of older adults with a median age at diagnosis of 68 years (y). Patients (pts) receiving chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory MM (RRMM) often experience detrimental effects due to frailty, comorbidity, and cumulative toxicities. In this study, we evaluated the prevalence and impact of frailty, defined by the simplified frailty score, (SFS; Facon et al, Leukemia 2020), and immuno-nutritional status, using Glasgow-prognostic score (GPS; Proctor et al, Br J Cancer 2011) in a real-world cohort of pts receiving CAR-T therapy for RRMM. Methods: We included all pts treated with commercial CAR-T therapy for RRMM between 2021 - 2023 at Moffitt Cancer Center. The SFS and GPS (CRP &gt; 10 mg/dL, 1 point; albumin &lt; 3.5, 1 point) were calculated for all pts at lymphodepletion. Primary endpoints included overall survival (OS) and progression free survival (PFS). Pearson’s chi-squared tests or Fisher’s exact tests were used to compare association between categorical variables. OS and PFS were estimated used using Kaplan-Meier methods; the log-rank test was used to compare OS and PFS, and a cox-proportional model was used for multivariable analysis (MVA). Results: A total of 139 pts were included, with a median follow up of 6.3 months (m; range, 0.2 to 20.3 m). Median age was 66 y (IQR, 58-72 y); 38% were ≥70 y. Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). Around 1/3rd of pts had features of high-risk disease [high disease burden, 30%; high-risk cytogenetics (HR-Cyto), 37%; extramedullary disease (EMD), 37%]. Overall, 30% of pts were categorized as frail and 14% were classified as high-risk GPS (score = 2). There were no significant differences in GPS between older (≥70 y) and younger pts ( &lt; 70 y; p= 0.8). Median OS in the cohort was not reached (NR) and median PFS was 11.7 m. Both frailty and high-risk GPS were associated with inferior PFS (frail vs non-frail, HR 2.0, p= 0.03, high GPS vs low/int, HR 1.7 p = 0.009) and OS (frail vs non-frail, HR 3.0, p = 0.006, high GPS vs low/intermediate, HR 2.1 p = &lt; 0.001). The association of GPS with OS remained significant in a MVA, even after adjusting for high-risk disease factors (high disease burden, HR-Cyto and EMD) and frailty. Pts categorized as frail had a lower median PFS of 5.4 m (vs 12.7m non-frail group, p= 0.025), and inferior median OS of 9.7 m (vs NR in non-frail, p= 0.0039). Conclusions: In a real-world setting, frailty affects almost a third of pts with RRMM receiving CAR-T therapy and is associated with inferior PFS and OS. The GPS, a simple immuno-nutritional score, is highly predictive of survival even after adjusting for the presence of high-risk disease. Studies looking at role of pre-habilitation and other modalities to reduce inflammatory burden prior to CAR-T therapy are warranted.

RADIATION THERAPY AS A BRIDGING AND SALVAGE STRATEGY IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA UNDERGOING BCMA‐TARGETED CAR T‐CELL THERAPY

Introduction: Radiation therapy (RT) may be a useful bridging and/or salvage approach prior to and following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory multiple myeloma (MM). Thus, we sought to report our early experience evaluating the potential role of RT in bridging and salvage settings in MM patients undergoing CAR T-cell therapy. Methods: A multi-institutional retrospective study was conducted for consecutive MM patients who received CAR T-cell therapy between 2018 and 2022. Patients who were administered bridging RT pre-CAR T and salvage RT post-CAR T failure were identified and analyzed using descriptive and statistical analysis. Results: We retrospectively reviewed 13 patients who have been treated with RT pre- and/or post-CAR T-cell therapy infusion at two tertiary care centers [5 patients received bridging RT pre-CAR T, 4 patients received salvage RT post-CAR T failure, and 4 patients received both bridging and salvage RT]. A total of 17 sites were treated with bridging-RT with a median dose of 20 Gy (range, 4–24 Gy) and a median of 5 fractions (range, 1–12 fractions). Twelve sites were treated with salvage RT with a median dose/fractionation of 20 Gy (range, 4–30 Gy) and 5 fractions (range, 1–12 fractions). No worsening in CAR T-related toxicities occurred among the patients who were treated with bridging RT, and no significant RT-related toxicities were observed post-bridging or salvage RT. For the entire cohort, the median overall survival was 16.2 months (95% CI: 8.6 months-not reached), and the median progression-free survival was 4.1 months (95% CI: 1.07 months-not reached). The local control rate for patients receiving bridging RT and/or salvage RT was 100%, with a median follow-up after each RT course of 7.3 months. Conclusion: Our findings suggest that using RT as a bridging and salvage strategy is safe and feasible, and offers excellent local control among relapsed/refractory MM patients treated with CAR T-cell therapy infusion. Future larger studies with translational correlatives are required to assess the optimal role of RT in these settings. Keywords: Cellular therapies, Multiple Myeloma No conflicts of interests pertinent to the abstract.

Treatment patterns for extramedullary multiple myeloma and outcomes with CAR-T therapy and bispecific antibodies.

8022 Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p &lt;0.0001) months for &lt;PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with &lt;PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p&lt;0.001] for &lt;PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]

Circulating tumor DNA and association with CAR-T cell therapy response in gastric and pancreatic cancer patients.

4053 Background: Circulating tumor DNA (ctDNA) is a form of cell free DNA that can be used to detect and measure cancer molecular residual disease (MRD) before and after systemic therapy. There are no data pertaining to the assessment of MRD in patients with solid tumors treated with chimeric antigen receptor T-cell (CAR-T) therapy. Here, we evaluated a tumor-informed ctDNA assay in the setting of gastric and pancreatic malignancies treated with claudin18.2 (CT041)-targeted CAR-T cell therapy (NCT04404595). Methods: A single-center review between 7/1/2021 – 1/1/2023 identified 10 patients with pancreatic or gastric carcinoma who received CAR-T CT041 cell therapy. Eight patients were ctDNA positive prior to treatment and had blood samples serially drawn before and after CAR-T cell therapy. Banked plasma was analyzed for ctDNA using a tumor-informed Signatera, mPCR-NGS ctDNA assay (Natera, Inc.). The correlative prognostic value of ctDNA to predict response after CAR-T cell therapy was analyzed by RECIST 1.1 criteria. Results: Pre- and post-treatment serial ctDNA was available for 8 of 10 (3/5 gastric and 5/5 pancreatic cancer) patients and all 8 were ctDNA positive prior to CAR-T CT041 cell therapy. The median nadir of ctDNA was on day 14 after CT041 infusion.Of the 8 patients with detectable ctDNA, 5 (62.5%) became undetectable at some time after CT041 therapy, while 3 (37.5%)remained ctDNA positive throughout treatment. The disease control rate (DCR) was 80% for anytime negative ctDNA patients (4/5). Of patients with responsive disease after CT041 CAR-T, 2/3 (67%) achieved undetectable ctDNA and 1/3 (33%) had a ctDNA reduction by 95%. Both patients with stable disease developed undetectable ctDNA. In those patients with progressive disease, 1/3 (33%) had a negative anytime ctDNA. One patient with a complete response had undetectable ctDNA and target lesion response, then later developed progressive disease detectable by ctDNA 3 months prior to radiography. Overall survival was higher (9.1 months vs. 3.7 months) in those who achieved anytime undetectable ctDNA. Conclusions: Tumor-informed ctDNA correlates with response to CAR-T cell therapy in gastrointestinal malignancies. Ongoing clinical trials of CT041 CAR-T cell therapy will continue ctDNA analysis prospectively. Characteristics of initially ctDNA positive patients receiving CAR-T therapy. Clinical trial information: NCT04404595 . [Table: see text]