Abstract Patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary central nervous system (CNS) lymphoma (SCNSL) face a dismal prognosis. They have been excluded from most clinical CAR T‐cell trials as investigators feared an increased risk for severe immune effector cell‐associated neurotoxicity (ICANS). To investigate the potential of anti‐CD19 CAR T‐cell therapy (CART) in such patients, we analyzed data of 100 patients with CNS manifestation treated with CART between January 2018 and July 2023 and reported to European Society for Blood and Marrow Transplantation. Median age was 62 years. Of patients, 58% had failed ≥3 treatment lines, and 40% had received autologous stem‐cell transplantation before CART. Fifty‐nine patients received axicabtagene ciloleucel, 38 patients were treated with tisagenlecleucel, three patients received other products. At the time of CART, 67 patients had active CNS disease. Overall and progression‐free survival (PFS) at 24 months were 37% and 28%. Relapse incidence (RI) at 24 months was 59%, whereas non‐relapse mortality at 1 year was 7%. Cytokine release syndrome (CRS) and ICANS of any grade occurred in 83% and 42% of patients, respectively. CRS grade 3 occurred in 11 and ICANS grades 3–4 in 17 patients. Two patients died of neurotoxicity. Elevated lactate dehydrogenase was an independent risk factor for RI and PFS (hazard ratio [HR] 2.4, p = 0.003; HR: 1.9, p = 0.016). Patients with ECOG 2–3 had a significantly increased risk for the development of ICANS (HR 2.68, p = 0.002). These data support the implementation of CART as treatment for patients with r/r PCNSL and SCNSL.

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy has demonstrated exceptional efficacy in treating hematologic malignancies. However, clinical outcomes can be limited by factors such as suboptimal expansion and persistence of adoptively transferred CAR-T cells, antigen-negative relapses, and the immunosuppressive tumor microenvironment. In our previous work, we engineered CD19CAR-T cells to secrete a PD-1Ab21 fusion protein, which combines an anti-PD-1 single-chain antibody with IL-21 (PD-1Ab21-CD19CAR-T). This investigator-initiated clinical trial aims to evaluate the safety and therapeutic potential of these novel CAR-T cells in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). Methods: The study has recruited 9 patients with r/r B-NHL, with additional patient enrollment ongoing. All patients received fludarabine and cyclophosphamide before a single infusion of PD-1Ab21-CD19CAR-T cells, with escalating dose ranging from 0.3×106 to 3×106 cells/kg. Patients were monitored for adverse events, clinical responses, and immune cell kinetics, including the expansion of CAR-T cells and CD8+ T cells. Results: Nine patients were enrolled, with a median age of 61 years (range: 38-73). One patient had follicular lymphoma (FL), and the remaining eight were diagnosed with diffuse large B-cell lymphoma (DLBCL), two of whom had bone marrow involvement. The overall response rate (ORR) was 77.8% (7/9), with 66.7% (6/9) achieving complete remission (CR). Cytokine release syndrome (CRS) occurred in 55.6% (5/9) of patients, but all cases were very mild (grade ≤1). No treatment-related neurotoxicity or deaths were reported. The first patient, diagnosed with DLBCL and presenting with paraplegia, achieved CR three months after CAR-T infusion, which has been sustained for over two years, resulting in a progression-free survival (PFS) greater than two years. After CAR-T infusion, we observed a rapid increase in CAR-CD8+ T cell proportion, which remained above 50% even after the decline of CAR-T cells. Conclusion: These preliminary findings suggest that PD-1Ab21-CD19CAR-T cells have promising clinical efficacy in r/r B-NHL, with a high ORR and sustained CR. The mild nature of CRS (grade ≤1) indicates that this treatment can be well tolerated. Further studies are necessary to confirm these results and assess long-term outcomes. Citation Format: Yu Jing, Ying Li, Meng Li, Shengjuan Zhang, Baocai Zhao, Yueyi An, Hang Li, Jitao Zhao, Liping Dou, Shengdian Wang. Phase I investigator-initiated clinical trial of CD19CAR -T cells secreting PD-1-targeted IL-21 in relapsed/refractory B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT144.

Abstract Tarlatamab is a DLL3/CD3 bispecific T-cell engager (TCE) recently approved by the FDA for the treatment of extensive-stage small cell lung cancer (ES-SCLC). The dosing follows a step-up regimen for the first cycle, with 1 mg given on day 1, and 10 mg given on days 8 and 15. A similar step-up dosing regimen, but with 100 mg instead of 10 mg, was also tested in a pivotal phase 2 trial (Ahn et al. N Engl J Med. 2023 Nov 30;389(22):2063-2075). The alternative step-up dose or step-up regimen were not investigated in the study. The aim of our work was to explore the alternative step-up regimens of tarlatamab, predicting trimer (complex of TCE with target receptors) kinetics in the tumor using quantitative systems pharmacology (QSP) modeling. The QSP model integrated pharmacokinetics of tarlatamab, its distribution into the tumor of patients with ES-SCLC, binding with CD3 expressed by T-cells and DLL3 expressed by cancer cells, formation of trimer in the immunological synapse between T-cell and cancer cell, turnover of free and bound receptors, trimer internalization. Predicted peak trimer levels in the tumor are associated with cytokine release syndrome (CRS) incidence following tarlatamab administration. Higher peak levels of trimer are predicted for the doses and regimens causing more frequent CRS events. The model showed that 1 mg is the optimal step-up dose for the regimens tested in clinical trials since lower doses led to a higher peak trimer level after second dose (10 mg given on day 8). However, split dosing of the 1st or 2nd doses and a longer step-up schedule decreased the peak trimer levels following tarlatamab administration. Splitting the first dose in the approved regimen resulted in a reduction of peak trimer by 30-40%, thus mitigating CRS incidence. Administration of the 0.5 mg on day 1 and 0.5 mg on day 4 also caused a minor decrease of peak trimer level after administration of 10 mg on day 8. A substantial reduction of the maximal level of the trimer after the second dose was predicted for the step-up regimen with 100 mg if the second dose given on day 8 is 3 mg instead of 100 mg. This dose optimization might lower the probability of CRS grade 3 events observed in patients treated with 100 mg. Split-dose regimens and regimens with more than one step-up dose allow for minimizing CRS incidence without compromising the efficacy of TCEs. QSP modeling is a useful tool to investigate various doses and regimens of bispecific and multispecific antibodies. Citation Format: Oleg Demin Jr, Galina Kolesova, Dmitry Shchelokov. Optimization of tarlatamab step-up dosing regimen to mitigate cytokine release syndrome using quantitative systems pharmacology modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2130.

Non-viral engineering can ease CAR-T cell production and reduce regulatory and cost requirements. We utilized Sleeping Beauty transposon to engineer donor-derived anti-CD19.CD28.OX40.CD3zeta T cells differentiated in cytokine-induced killer (CARCIK-CD19) for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (alloHSCT). We report the results of CARCIK-CD19 observed in 36 patients (4 children and 32 adults) treated according to the final recommended dose. Cytokine release syndrome of grade 2 or lower occurred in 15 patients, ICANS grade 2 in 1 patient, and late-onset peripheral neurotoxicity of grade 3 in 2 patients. GVHD never occurred after treatment with allogeneic CARCIK-CD19. Complete remission was achieved by 30 out of 36 patients (83.3%), with MRD negativity in 89% of responders. With a median follow-up of 2.2 years, the 1-year overall survival was 57.0%, and event-free survival was 32.0%. The median duration of response at 1 year was 38.6%. CAR-T cells expanded rapidly after infusion and remained detectable for over 2 years. Integration site analysis after infusion showed a high clonal diversity. These data demonstrated that SB-engineered CAR-T cells are safe and induce durable remission in heavily pretreated patients with BCP-ALL relapsed after alloHSCT. Trial registration: The phase 1/2 and phase II trials are registered at www.clinicaltrials.gov as NCT#03389035 and NCT#05252403.

Safety of tarlatamab with 6-8-h outpatient versus 48-h inpatient monitoring during cycle 1: DeLLphi-300 phase 1 substudy.

Pulmonary function tests (PFTs) are recommended for hematopoietic cell transplantation (HCT) evaluation. However, their prognostic value in chimeric antigen receptor T-cell (CAR-T) therapy remains unclear. We assessed the predictive significance of PFTs and pulmonary comorbidity classifications, per the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in patients with B-cell lymphoma undergoing autologous CD19 CAR-T therapy. Single-center retrospective analysis encompassing 192 patients with relapsed/refractory B-cell lymphoma (BCL), treated with commercial and point-of-care CD19-directed CAR-T therapy. Pretherapy PFTs were conducted, and patients were stratified into 3 HCT-CI-based pulmonary comorbidity grades, using forced expiratory volume in 1 second (FEV1) and single-breath diffusing capacity for carbon monoxide (DLCO). Outcomes and toxicities were evaluated using univariate and multivariable Cox regression, logistic regression, Kaplan-Meier method, and spline models. Pulmonary comorbidity measures were not correlated with overall response rates or immune toxicities, including cytokine release syndrome grade >2 and immune effector cell-associated neurotoxicity grade >2. Categorical FEV1, DLCO, and pulmonary comorbidity level did not correlate with overall survival (OS; P=.3, P=.4, P=.6, respectively) or progression-free survival (PFS; P=.058, P > .9, P=.2, respectively). FEV1 as a continuous measure was associated with reduced PFS in a multivariable model (hazard ratio, 0.87; 95% confidence interval, 0.78-0.96; P=.007). Spline modeling demonstrated a linear correlation between FEV1 and PFS. Categorical FEV1, DLCO, and pulmonary comorbidity level failed to predict therapy efficacy or toxicity. FEV1 as a continuous measure was the sole PFT measure associated with PFS, independent of OS or severe toxicities.

Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome in Haploidentical Transplantation

To evaluate brain MRI findings in children and young adults after chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoid leukemia (B-ALL) and associate results with clinical and neurological symptoms. We reviewed pre- and post-CAR-T cell therapy brain MRIs of B-ALL patients aged 25 years or younger who underwent therapy between April 2015 and October 2023 at a single institution. MRI abnormalities were categorized as no change, exacerbation of preexisting lesion, or newly developed lesion. Clinical CAR-mediated toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) grades, were recorded. Patients were grouped into those with and without 'exacerbated/new lesion,' and clinical and neurological symptoms were compared using Fisher's exact test. Sixteen patients with pre- and post-CAR brain MRIs (median age 16 years [interquartile range, 11-21]; 9 males, 7 females) were included in the analysis. Post-CAR brain abnormalities were observed in 81% (13/16) of patients, including white matter (WM) signal changes (12/16), leptomeningeal enhancement (1/16), and cerebellar embolic infarction (1/16). Of the post-CARWM lesions, 50% (6/12) were exacerbated, 33% (4/12) were newly developed, and 17% (2/12) remained unchangedcompared to pre-CAR brain MRI. No difference in CRS (p = 0.079) or ICANS grades (p > 0.99) was observed between patients with and without 'exacerbated/new lesions'. Children and young adults with B-ALL can develop brain MRI abnormalities after CAR T-cell therapy, predominantly WM signal changes. These brain abnormalities did not show an association with higher CRS or ICANS grade. Question Brain MRI findings after chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoid leukemia (B-ALL) and their association with clinical and neurological symptoms are not well understood. Findings Brain MRI abnormalities, mostly white matter changes, were seen in 81% of patients but were not associated with CAR-mediated toxicities. Clinical relevance Brain MRI abnormalities, commonly observed post-CAR T-cell therapy, do not correlate with the severity of CAR-related toxicities, aiding in the clinical management and monitoring of these patients.

Itacitinib for the prevention of IEC therapy-associated CRS: results from the 2-part phase 2 INCB 39110-211 study.

We investigated B-cell maturation antigen-directed chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed or refractory multiple myeloma (MM) and central nervous system (CNS) involvement. Ten patients received either idecabtagene vicleucel (n=6) or ciltacabtagene autoleucel (n = 4), where brain/cranial nerve and/or spinal cord involvement/leptomeningeal disease were evident on either magnetic resonance imaging (100%) and/or cerebrospinal fluid (40%). Eight patients had their CNS diagnosis before CAR-T therapy, and two were diagnosed within 14 days post-infusion. Seven received CNS-directed therapy during bridging before CAR-T therapy. There were no excess toxicities: no cytokine release syndrome grade ≥3; 10% immune effector cell-associated neurotoxicity syndrome (ICANS) grade 3; and no ICANS grade 4. Two patients experienced delayed but treatable neurotoxicity, with no reported parkinsonian side effects. The best overall response rate was 80% (≥70% very good partial response) and a 100% CNS response. With a median follow-up of 381 days, patients with CNS myeloma diagnosed before CAR-T therapy (n = 8) had a median overall survival and progression-free survival (PFS) of 13.3 and 6.3months, respectively. Best outcomes were observed in 4 patients who had a response to bridging therapy, suggesting that optimizing pre-CAR-T therapy may be key for improved outcomes. Our study suggests that CAR-T therapy in patients with CNS MM is safe and feasible, and screening for CNS involvement before CAR-T therapy could be warranted in high-risk patients. The excellent initial response but relatively short PFS suggests consideration for post-CAR-T maintenance. Larger studies are needed to confirm these findings.

128 Background: T-cell engaging bsAbs and CAR T-cell therapy have shown exceptional success in treating multiple hematologic malignancies. More recently, bsAbs have been FDA-approved to treat uveal melanoma and small cell lung cancer, demonstrating proof-of-concept for immune therapies beyond checkpoint inhibition to effectively treat solid tumors. bsAbs and CAR-T therapies are presently undergoing evaluation in trials for patients with mCRPC. Despite early successes with these classes of therapy, there are multiple ongoing challenges including dose-limiting toxicity, ‘on-target, off-tumor’ toxicity, and immune-effector cell related toxicity. This systematic review analyzes publicly available safety derived from ongoing clinical trials. Methods: An electronic systematic search through PubMed, CINHAL, Scopus, and Ovid was done to identify phase I/II clinical trials evaluating bsAbs or CAR-T therapy in patients with mCRPC reported prior to 9/30/2024. Treatment-related adverse events (TRAE) were collected, focusing on prevalence in bsAbs versus CAR-T. A random effects model was used for analysis. Results: Eleven trials with 511 patients evaluated bsAbs, and 5 trials with 55 patents studied CAR-T therapies. Mean patient age was 67 years [95% CI: 63, 71]. Cytokine release syndrome (CRS) occurred in 49% [24, 75] of patients; 53% [17, 86] on bsAbs compared to 43% [28, 59] on CAR-T. Only 4% [2, 7] of patients had CRS grade ≥3; 14% [2, 43] on CAR-T compared to 3% [2, 6] on bsAbs (p=0.05). Neurologic TRAEs occurred in 11% [3, 31] of patients; 39% [22, 60] on CAR-T compared to 5% [2, 13] on bsAbs (p= <0.01). Hematologic TRAEs occurred in 38% [14, 71] of patients; 34% [8, 75] on CAR-T compared to 43% [9, 86] on bsAbs. Hepatic TRAEs occurred in 31% [12, 59] of patients; 25% [12, 44] on CAR-T compared to 39% [9, 81] on bsAbs (p= 0.55). However, 8% of patients [3, 20] had grade ≥3 hepatic TRAEs, with 21% [5, 51] on CAR-T versus 5% [2, 10] on bsAbs (p=0.03). Musculoskeletal/dermatologic TRAEs were seen in 30% of patients [24, 37]; 30% [24, 38] on bsAbs and 29% [8, 58] on CAR-T (p=0.89). Renal TRAEs occurred in 15% [10, 23] of patients; 21% [5, 51] on CAR-T compared to 14% [8, 24] on bsAbs (p= 0.50). Gastrointestinal TRAEs were reported in 18% [10, 33] of patients; 14% [2, 42] on CAR-T compared to 19% [9, 36] on bsAbs (p= 0.69). Conclusions: In patients with mCRPC, bsAbs and CAR-T therapies produce similar hematological, musculoskeletal/dermatologic, renal and gastrointestinal TRAE rates. However, significantly higher rates of all-grade neurologic, grade ≥3 CRS and grade ≥3 hepatic TRAEs are reported with CAR-T therapy. These data highlight the need to appreciate the differences in toxicity profiles for these two classes of therapy and to practice appropriate vigilance during treatment.

Immune effector cell-associated hematotoxicity (ICAHT) is associated with morbidity and mortality after chimeric antigen receptor (CAR) T-cell therapy. To date, the factors associated with ICAHT are poorly characterized, and there is no validated predictive model of ICAHT as defined by current consensus criteria. Therefore, we performed comprehensive univariate analyses to identify factors associated with severe (grade 3-4) early ICAHT (eICAHT) in 691 patients who received commercial or investigational CAR T-cell therapy for hematologic malignancies. In univariate logistic regression, preinfusion factors associated with severe eICAHT included disease type (acute lymphoblastic leukemia), prelymphodepletion (pre-LD) blood counts including absolute neutrophil count (ANC), lactate dehydrogenase (LDH), and inflammatory (C-reactive protein [CRP], ferritin, and interleukin-6 [IL-6]) and coagulopathy biomarkers (D-dimer). Postinfusion laboratory markers associated with severe eICAHT included early and peak levels of inflammatory biomarkers (CRP, ferritin, and IL-6), coagulopathy biomarkers (D-dimer), peak cytokine release syndrome grade, and peak neurotoxicity grade. We trained (n=483) and validated (n=208) 2 eICAHT prediction models (eIPMs): eIPMPre including preinfusion factors only (disease type and pre-LD ANC, platelet count, LDH, and ferritin) and eIPMPost containing both preinfusion (disease type and pre-LD ANC, platelet count, and LDH) and early postinfusion (day+3 ferritin) factors. Both models generated calibrated predictions and high discrimination (area under the receiver operating characteristic curve in test set, 0.87 for eIPMPre and 0.88 for eIPMPost), with higher net benefit in decision curve analysis for eIPMPost. Individualized predictions of severe eICAHT can be generated from both eIPMs using our online tool (available at https://eipm.fredhutch.org).

465 Background: Gastric cancer (GC) is associated with significant mortality due to the limited efficacy of current conventional treatments, necessitating the need for novel therapies. In this systematic review and meta-analysis, we aim to explore the potential role and outcomes of bi-specific antibodies and chimeric antigen receptor T-cell (CAR-T) immunotherapy in treating GC. Methods: Using PRISMA guidelines, searches were conducted on PubMed, Cochrane, and Clinicaltrial.gov for 'Gastric cancers', 'bispecific antibodies', and 'CAR-T therapy' as of March 30, 2024. Out of 35 studies, 9 were selected for pooled analysis in R (v4.3.3) using the Der Simonian-Laird Estimator, calculating inter-study variance and extracting data with 95% CI. Results: 138 gastric cancer (GC) patients from 2 phase I (22.22%), 3 phase Ib (33.33%), 3 phase II (33.33%), and 1 case report (11.11%). Median age was 57 (28-77) years, and 76% (31/41) were male. Bispecific antibodies were MCLA-128 (25/138), catumaxomab (15/138), AK104 PD-1/CTLA-4 (16/138), ABL 001 DLL4VEGFA (19/138), and KN026 (25/138) while CART therapy was CT041 (38/138). The pooled overall response (OR), partial response (PR), and complete response (CR) for bispecific antibodies was 37% (95% CI, 0.12-0.71, I2=76%, n=100, p <0.01), 21% (95% CI,0.05-0.55, I2=73%, n=85, p<0.01), and 11%(95% CI, 0.02-0.38, I2=63%, n=85, p=0.03) respectively, while the pooled OR, PR, and CR for CART was 56% (95% CI, 0.40-0.71, I2=0%, n=38, p=0.41), 53%(95% CI, 0.36-0.69, I2=0%, n=38, p=0.38, ), and 12% (95% CI, 0.02-0.42, I2=38%, n=38 p=0.2), respectively. The pooled disease control rate was 75% (95%CI,0.46-0.92, I2=79%, n=80, p < 0.01) for bispecific antibodies and 27% (95% CI,0.16-0.40, I2=0%, n=65, p=0.37) had the stable disease while pooled incidence of progressive disease was 18% (95% CI,0.09-0.31, I2=0%, n=55, p=0.53). The median progressive free survival was 6.74 months, with a median overall survival of 14.75 months. Common adverse effects included anemia, diarrhea, fatigue, and cytokine release syndrome grades 1 or 2. Conclusions: This analysis shows promising results in GC patients using bi-specific antibodies and CAR-T cell therapy. However, further clinical trials are needed to fully explore their potential.

BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.

CD7 chimeric antigen receptor T-cell (CAR-T cell) therapy is an emerging method for treating hematological malignancies, and is another breakthrough in CAR-T cell therapy. This study summarizes the currently published clinical research results on CD7 CAR-T cells and evaluates the safety and effectiveness of CD7 CAR-T cell therapy. Among the 13 studies included in this study, a total of 200 patients received CD7 CAR-T cell therapy, including 88 patients who received autologous CAR-T cells, 112 patients who received donor derived CAR-T cells. 87% (80% -94%, I2 =29.65%) of patients achieved complete remission. The incidence of cytokine release syndrome (CRS) was 94% (88% -98%, I2 =32.71%, p=0.12), while the incidence of severe CRS (grade ≥ 3) was 12% (5% -20%, I2 =41.04%, p=0.06). As for the incidence of immune effector cell-associated neurotoxicity syndrome (ICANS), it is 4% (1% -7%, I2 =0, p=0.72). Through analysis of the key clinical issues, we found that consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T cell therapy can significantly improve survival and avoid recurrence. Therefore, we believe that the consolidation allo-HSCT after CD7 CAR-T cell therapy should be advocated. And patients who received CD7 CAR-T cell therapy without gene editing had significantly longer overall survival than those who received CD7 CAR-T cell therapy with gene editing. This suggests that gene edited CD7 CAR-T cells may pose some potential risks that limit the long-term survival of patients. Our study confirms the efficacy and safety of CD7 CAR-T cells and provides research directions for the subsequent treatment. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=502896, identifier CRD42024502896.

IntroductionThe development of robust predictive models for high-grade cytokine release syndrome (CRS) in CAR-T recipients remains limited by sparse clinical trial data.MethodsWe analyzed of 496 COVID-19 patients revealed that CRS plays a pivotal role in disease progression and serves as a valuable data source for understanding CRS progression. Building on this insight, we evaluated and compared the predictive performance of three machine learning models, with the ultimate goal of developing a predictive model for high-grade CRS in patients receiving CAR-T therapy.ResultsAmong evaluated algorithms (XGBoost, Random Forest, Logistic Regression), XGBoost demonstrated superior performance in high-grade CRS prediction. Feature importance analysis identified SpO2, D-dimer, diastolic blood pressure, and INR as key predictors, enabling development of a validated riskassessment algorithm. In an independent CAR-T cohort (n=45), the algorithm achieved impressive predictive performance for high-grade CRS prediction.DiscussionUsing machine learning, we identified key clinical biomarkers strongly associated with high-grade CRS. This tool efficiently predicts progression to high-grade CRS post-onset and shows significant potential for clinical deployment in CAR-T therapy.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel (n = 162) versus cilta-cel (n = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel (p < 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; p < 0.001), with complete response at Day 30 of 48% versus 26% (p < 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel (p < 0.001 and p = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3-4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; p < 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel (p = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM.

ObjectiveTo develop a novel prognostic scoring system for severe cytokine release syndrome (CRS) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 chimeric antigen receptor (CAR)-T-cell therapy, aiming to optimize risk mitigation strategies and improve clinical management.MethodsThis single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023. These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data, documented CRS grading, and at least 3 months of follow-up. Data on patient demographics, treatment history, laboratory parameters, CAR-T-cell characteristics, safety, and efficacy endpoints were collected. CRS severity was graded according to the 2019 ASTCT consensus criteria. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity, and a prognostic model was constructed.ResultsThe overall incidence of CRS was 67.2%, with 13.6% having grade ≥ 3 (severe) CRS. Higher baseline and post-lymphodepletion minimal residual disease (MRD) levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS. Inflammatory markers (CRP, ferritin, and IL-6) and coagulation dysfunction (APTT) on day 7 post-infusion were also predictive of CRS severity. The prognostic model incorporating these factors demonstrated robust discriminatory ability, with an area under the ROC curve of 0.875.ConclusionThis study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy. The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS. Further validation in larger, prospective cohorts is warranted.

To investigate the clinical characteristics of cytokine release syndrome (CRS) in children with thalassemia major (TM) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and their prognosis. A retrospective analysis was performed for the clinical data of 280 children with TM who underwent haplo-HSCT in the Department of Hematology and Oncology, Shenzhen Children's Hospital, from January 2019 to December 2021. According to the CRS criteria, they were divided into two groups: CRS grade <3 (260 children) and CRS grade ≥3 (20 children). The children with TM were analyzed in terms of clinical characteristics of CRS after haplo-HSCT and their prognosis. There were significant differences between the two groups in neutrophil engraftment time, clinical manifestations of CRS, and the rate of use of glucocorticoids within 4 days after haplo-HSCT (P=0.012, 0.040, and <0.001 respectively). For the CRS grade <3 group, the incidence rate of acute graft-versus-host disease (aGVHD) was 9.6% within 3 months after transplantation, while no aGVHD was observed in the CRS grade ≥3 group within 3 months after transplantation, but there was no significant difference in the incidence of aGVHD between the two groups within 3 months after transplantation (P=0.146). No transplantation-related death was observed in either group within 3 months after haplo-HSCT. The children with CRS grade≥3 have an early neutrophil engraftment time, severe and diverse clinical manifestations of CRS, and a high rate of use of glucocorticoids within 4 days after haplo-HSCT. For these children, early use of low-dose glucocorticoids after transplantation may alleviate CRS response and reduce the incidence of aGVHD, thereby bringing more benefits to the children. CRS after haplo-HSCT has no significant impact on the prognosis of the children.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD-19 utilizes ex-vivo engineered T-cells to treat refractory malignancies. Widespread CAR-T adoption is limited by resource utilization and cost, and CAR-T has also been associated with adverse cardiovascular events. Limited data exist exploring the relationship between CAR-T-associated cardiovascular events and resource utilization events (RUE). Objective: To evaluate whether CAR-T-associated cardiovascular events are associated with RUE. Methods: Records of patients treated with an FDA-approved CAR-T product between 2018 and 2022 at a single institution were reviewed. Cardiovascular events post-CAR-T were defined as arrhythmia, acute coronary syndrome, stroke, cardiovascular death, new cardiomyopathy, heart failure, or pericarditis. RUE was a composite of intensive care unit (ICU) transfer, prolonged length of stay (LOS; &gt;75th cohort percentile), and unplanned 6-month readmission. Results: Of 117 patients, 30 (26%) experienced cardiovascular events over a median 16 (IQR 7-34) months follow-up. RUE occurred in 65 patients (56%): 28 (24%) ICU transfers, 23 (20%) prolonged LOS, and 48 (41%) readmissions. Those with RUE experienced subsequent higher mortality (62% vs. 21%, p≤0.001). Among patients who experienced cardiovascular events, 24 (80%) experienced RUEs. In a Cox model, cardiovascular events (HR 2.3, 95% CI 1.3-4.1) and high cancer burden (HR 2.1, 95% CI 1.3-3.5) were independently associated with increased RUE rate, after adjusting for age, Cytokine Release Syndrome grade ≥2, atrial fibrillation history, and CAR-T costimulatory domain. Conclusion: CAR-T recipients who experience cardiovascular events also experience increased resource utilization events. Further prospective studies are needed to assess whether post-CAR-T cardiovascular event management and/or pre-therapy assessment may reduce resource utilization burden.