Occurrence Of Cytokine Release Syndrome Research Articles

The occurrence of cytokine release syndrome and its impact on the prognosis of patients with relapsed and refractory multiple myeloma following chimeric antigen receptor T-cell therapy

Objective: To analyze the incidence of cytokine release syndrome (CRS) and its impact on the prognosis of patients with relapsed and refractory multiple myeloma (RRMM) following treatment with chimeric antigen receptor T-cell (CAR-T) therapy. Methods: A retrospective collection was conducted of the clinical data of 91 patients with RRMM who underwent CAR-T therapy at the Affiliated Hospital of Xuzhou Medical University from January 2020 to October 2022. Before CAR-T cell infusion, the patient underwent pretreatment with the fludarabine plus cyclophosphamide (FC) regimen. On day 0 (d0), the patient received a dose of 1×106 cells/kg of CAR-T. The occurrence of CRS was recorded post-treatment and graded accordingly, with grades 1 to 2 indicating mild CRS and grade≥3 indicating severe CRS. The follow-up cut-off date was February 14, 2023, with a median follow-up time [M (Q1, Q3)] of 14.1 (3.1, 37.7) months. Kaplan-Meier survival curve analysis assessed the progression-free survival (PFS) and overall survival (OS) of Grade 1 and Grade 2 CRS patients. Furthermore, univariate logistic regression analysis was conducted to identify factors associated with the development of severe CRS. Results: In a cohort of 91 patients diagnosed with RRMM, there were 51 male and 40 female individuals, with a median age [M (Q1,Q3)] of 57 (31, 73) years. All 91 cases (100%) experienced CRS, with 82 cases (90%) classified as mild (grades 1-2) CRS and 9 cases (10%) classified as severe (grades 3-5) CRS. In a study involving 9 patients with severe CRS, 8 cases resulted in mortality. The Kaplan-Meier survival curve analysis revealed that among grade 1 CRS patients, neither the median PFS nor the median OS was achieved. For grade 2 CRS patients, the median PFS was 12 months (95%CI: 4-not achieved), and the median OS was 21 months (95%CI: 4-not achieved). The progression-free survival and overall survival rates of grade 2 CRS patients were both lower than those of grade 1 CRS patients (both P<0.05). Single-factor logistic regression analysis revealed that a high tumor burden (OR=1.025, 95%CI: 1.002-1.049, P=0.031), a prolonged duration of CRS onset (OR=0.809, 95%CI: 0.646-0.971, P=0.037) and persistence (OR=1.758, 95%CI: 1.349-2.481, P=0.001) were identified as significant factors associated with severe CRS in patients with RRMM. Conclusions: Patients with RRMM who undergoes CAR-T therapy have a high incidence of CRS, with a higher mortality rate among those experiencing severe CRS. Furthermore, patients with grade 2 CRS exhibit lower rates of progression-free survival and overall survival compared to those with grade 1 CRS. Factors associated with the development of severe CRS in RRMM patients include high tumor burden and prolonged duration and onset of CRS.

The Immunotherapy of Acute Myeloid Leukemia: A Clinical Point of View.

The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody-drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20-37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33-59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds.

Correlative biomarker analyses for optimal therapeutic dose determination of ABBV-383, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM).

7532 Background: ABBV-383 is a BCMA x CD3 bispecific antibody with 2 high-affinity BCMA-binding domains and a low-affinity CD3 engaging arm that has been shown to decrease the negative impact of soluble BCMA (sBCMA) and drive sustained T-cell activation with reduced cytokine release in preclinical models of MM. Here, we describe correlative biomarker results of baseline and longitudinal sBCMA levels and immune profiles in the ongoing first-in-human trial that supports 60 mg Q4W as the optimal therapeutic dose of ABBV-383 monotherapy. Methods: Peripheral blood and serum samples from patients with RRMM enrolled in the phase 1 open-label, dose-expansion study (NCT03933735) who received ABBV-383 at 20, 40, or 60 mg Q3W or 60 mg Q4W were collected at baseline (post-dexamethasone, pre–ABBV-383), on treatment, and at disease progression. Samples were analyzed by flow cytometry for immune cell populations, Luminex for cytokines, and electrochemiluminescence ligand binding for sBCMA. Results: Median sBCMA levels at baseline were highly variable among patients, but did not associate with clinical response (≥ partial response [PR]) to ABBV-383 at the selected optimal dose level of 60 mg Q4W (&lt;PR: 244.7 ng/mL; ≥PR: 52.2 ng/mL; P=0.13). Reduction in sBCMA levels over time associated with clinical response (Cmin at cycle 5: &lt;PR, 244.7 ng/mL; ≥PR, 4.7 ng/mL; P=0.04). ABBV-383 treatment led to a rapid and transient increase of proinflammatory cytokines, including IL-6, IL-8, IL-10, TNF-α (Cmax within cycle 1: 29, 349.5, 1375, 456.5 pg/mL, respectively), and promoted T-cell redistribution (89% reduction of CD8+ T cells from periphery), activation (1.9-fold increase in CD69+CD8+ T cells), and proliferation (2-fold increase in Ki67+CD8+ T cells) within cycle 1 in 60-mg Q4W-treated patients. The frequency of baseline CD8+ T-cell exhaustion (PD-1/TIM3) did not impact clinical response at the optimal dose level of 60 mg Q4W ABBV-383 (&lt;PR: 3.5%; ≥PR: 3.9%; P=0.9). Peak induction levels of proinflammatory cytokines during cycle 1 correlated with occurrence of cytokine release syndrome (≥G1) as well as clinical response across dose levels. Conclusions: High-avidity BCMA binding coupled to low-affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383. Responses to 60 mg Q4W ABBV-383 were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation, indicating that the optimal dose of ABBV-383 maximizes its clinical potential as a convenient, safe, and effective therapy for MM. Clinical trial information: NCT03933735 .

Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.

The influence of CRS and ICANS on the efficacy of anti-CD19 CAR-T treatment for B-cell acute lymphoblastic leukemia.

Chimeric antigen receptor T-cell (CAR-T) therapy has offered new opportunities for patients with relapsed/refractory B-cell lymphoblastic leukemia (r/r B-ALL). However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most common toxicities following CAR-T cell therapy. At present, whether the occurrence of CRS and ICANS will impact CAR-T activity remains unknown; this affects the therapeutic efficacy of CAR-T. In this multicenter retrospective study, we enrolled 93 patients with r/r B-ALL receiving anti-CD19 CAR-T cell therapy at four medical centers. We evaluated their complete response (CR) rates, minimal residual disease (MRD)-negative CR rates, and survival outcomes. Among the included patients, 76 (81.7%) developed CRS and 16 (5.3%) developed ICANS. Fifteen patients experienced concurrent CRS and ICANS. However, no significant differences were noted in CR or MRD-negative CR rates between patients with and without CRS/ICANS. Furthermore, no significant difference was noted in leukemia-free survival (LFS) (p = 0.869 for CRS and p = 0.276 for ICANS) or overall survival (OS) (p = 0.677 for CRS and p = 0.326 for ICANS) between patients with and without CRS/ICANS. Similarly, patients with concurrent CRS and ICANS exhibited no differences in OS and LFS when compared with other patients. Multivariate analysis showed that the development of CRS and ICANS was not associated with any difference in OS and LFS. Patients with CRS/ICANS experience similar clinical outcomes compared with those without CRS/ICANS following anti-CD19 CAR-T therapy.

Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.

Efficacy and Tolerance of Brexucabtagene Autoleucel in Adults with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia : A Graall Study from the Descar-T Registry

Background : Brexucabtagene autoleucel (brexu-cel) was recently approved for adult patients with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on the results of the ZUMA-3 phase 2 study. After a median follow-up of 39 months, brexu-cel showed a complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival of 26 months (Shah B, et al. ASCO 2023). In the present study, we aimed at investigating the efficacy and safety of brexu-cel in a real-life cohort of adult BCP-ALL patients included in the French early access program. Methods : In this Group for Research on Adult Acute Lymphoblastic leukemia (GRAALL) study, we performed an analysis of the DESCAR-T registry which collects real-life data of patients treated with CAR T-cells since July 2018 in France. All patients who underwent a leukapheresis with an intent to manufacture brexu-cel were included (N=80). Efficacy and safety analyses were performed in the 64/66 infused patients with available response assessment after infusion. The data cut-off was June 2023. The present study reports on best overall response, overall survival (OS), relapse-free survival (RFS), as well as immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (according to ASTCT Consensus). Results : Between May 2019 and February 2023, 80 adults with R/R BCP-ALL from 22 French centers had a leukapheresis for brexu-cel. Among them, 14 patients (18%) were not infused because of death (8 pts), progression (1 pt), manufacturing failure (2 pts), or other causes (3 pts). Among the 64 infused patients with available response assessment, median age was 43.5 yrs (range, 22-69). A Philadelphia(Ph)-chromosome was found in 20/64 (31%). Patients had received a median of 3 (range, 1-6) prior lines of treatment including blinatumomab, inotuzumab ozogamicin and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 67%, 19% and 70% of patients respectively. Twelve patients (19%) had an active CNS disease (CNS2/3) prior to apheresis and 18/40 (45%) had bone marrow blasts ≥ 25% before lymphodepletion (LD). ECOG before infusion was ≥2 in 6/64 (9%) patients. All patients received fludarabine and cyclophosphamide as LD. Median time from apheresis to infusion was 40 days (range, 27-99). CRS and ICANS occurred in 48/64 (77%, grade 3+ in 6%) and 28/64 (45%, grade 3+ in 8%) of patients respectively and were reversible. A CR was achieved in 49/64 patients (77%) of whom 23/25 (92%) were MRD-negative. An older age, a prior allo-HSCT, and the occurrence of CRS were associated with significantly higher CR rates. The median follow-up was 13 months. Three patients were bridged to an allo-HSCT in continuous complete remission (second allo-HSCT for 2 of them). The median RFS and OS were 12.9 months and 15.6 months respectively (Figure). In patients who achieved a CR, median OS was 25.8 months (Figure). Patients with CNS involvement before leukapheresis had a significantly shorter RFS (HR 5.4, 95%CI 1.9-15.8, p=0.002) and OS (HR 3.3, 95%CI 1.4-8.2, p=0.008). Number of prior treatment lines, prior inotuzumab, prior blinatumomab, or pre-LD BM blast% were not associated with outcome. A better OS was observed in patients with prior allo-HSCT (HR .4, 95%CI 0.2-0.9, p=0.04). Conclusion : This multicenter real-life study confirms the efficacy and acceptable safety profile of brexu-cel in adult patients with R/R BCP-ALL. It also suggests that patients with CNS involvement, that were not eligible to ZUMA-3 study, have a limited benefit of brexu-cel when compared to other patients.

Cellular Dynamics Following CAR T Cell Therapy Are Associated with Response, Resistance and Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma

Introduction The introduction of B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). While long-term follow-up of CD19 CAR T cells demonstrated a connection between CAR T cell expansion and persistence with outcome, very little is known about persistence and effects on bystander cells of BCMA-targeting CAR T cells. Methods We analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. Pts were grouped based on their remission evaluated 100 days after infusion into responders (partial response or better, n=16) or non-responders (progressive disease, n=11). Peripheral blood (pb) was drawn at day of leukapheresis, at day of infusion/after lymphodepletion (LD, d0) and at several time points following Ide-cel infusion (d7, d14, d30 and d100). In order to reflect a comprehensive picture of the longitudinal dynamics of CAR and non-CAR T cells, we subjected pb mononuclear cells to advanced flow cytometry. Additionally, we assessed the impact of cellular dynamics on the occurrence of cytokine release syndrome (CRS), tocilizumab application and the incidence of cytopenia. Results The median number of infused CAR T cells was 430x10 6 (range: 248.8 - 489.1x10 6) with one exception (25.7x10 6). There was no correlation between the median number of infused cells and in vivo expansion of CAR T cells after infusion as well as response or the development of CRS or cytopenia. Significant differences between responders and non-responders were already detected on day of leukapheresis: While non-responders showed similar numbers of CD4+ and CD8+ T cells, responders had significantly higher CD8+ T cell counts as compared to CD4+ T cells (p&amp;lt;0.05, Figure 1). Additionally, significantly reduced percentages of effector memory CD8+ T cells were detected in responders as compared to non-responders. The latter group showed significantly increased numbers of CD3+CD8+ T cells at the day of infusion indicating a less effective LD in non-responders. Following CAR T cell infusion, peak expansion occurred two weeks after infusion and was significantly higher in responders as compared to non-responders (p&amp;lt;0.001, Figure 2). CD3+ CAR T cell compartment predominantly comprised of CD8+ T cells regardless of response (median: 85%). Analysis of the distribution of CAR and non-CAR T cells after infusion revealed that the majority of CD4+ T cells in responders and non-responders were untransfected. Similar results were detected for CD8+ T cells in non-responders. However, in responders CD8+ CAR T cells approximated CD8+ non-CAR T cells with no significant differences on d7 and d14. With regard to T cell differentiation, almost the entire CD4+ T cells exhibited either a central memory or effector memory phenotype after CAR T cell infusion. Shortly after CAR T cell infusion, effector memory CD8+ T cells outbalanced all other CD8+ T cell subtypes. Most pts had no detectable CAR T cells 100 days after infusion, regardless of remission. Overall, 22 pts (81%) developed CRS shortly after CAR T cell infusion and 7 of these (32%) required tocilizumab treatment. Whereas percentages of CD3+ CAR T cells were significantly elevated in both CRS positive groups (p&amp;lt;0.05) shortly after infusion, absolute numbers were significantly increased only in CRS positive pts without tocilizumab. Analysis of blood counts following CAR T cell infusion revealed that cytopenias persisted longer in CRS pts treated with tocilizumab, which was also reflected by significantly increased numbers of days below thresholds for all cell lines (anemia, thrombocytopenia and leukopenia, p&amp;lt;0.01). Even though the occurrence of CRS and especially the treatment with tocilizumab affected blood cell composition, it did not correlate to response. Conclusion We demonstrate that BCMA-targeting CAR T cells only transiently persist in pb after infusion. Still, initial CAR T cell expansion, predominantly caused by effector memory CD8+ CAR T cells, was linked to response and CRS in RRMM pts. A correlation between CRS and tocilizumab administration with prolonged cytopenias following CAR T cell infusion was also observed. Our data provide first evidence that responders and non-responders can early be distinguished by differential cellular composition in CAR and non-CAR T cell compartments with distinct features already present at day of apheresis.

A Phase 2 Trial of SCRI-CAR19 Demonstrates Favorable Leukemia-Free Survival (LFS), with a Pilot Study of CD19-Expressing T-Cell Antigen Presenting Cells (CD19t T-APCs) Demonstrating Safety and Tolerability

The value of CD19 directed CAR T cell therapy for relapsed, refractory B-ALL has been well established. Iterative and complementary clinical trials have identified subgroups with improved outcomes, including those with low disease burden at the time of treatment as well as those with prolonged CAR T cell in vivo persistence. PLAT-02 was a phase 1/2 study of SCRI-CAR19, a 2 nd generation murine CAR with 41BB co-stimulation. Phase 1 previously reported 1 year LFS, event-free (EFS) and overall survival (OS) of 55%, 51.2%, and 69.5%. Subjects with low CD19 antigen burden in the bone marrow (&amp;lt;15%) prior to lymphodepletion (LD) and those with a rapid contraction of CAR T cells between Day 10 and 14 (ratio ≥1.5) were at higher risk of early loss of persistence. Phase 2 of PLAT-02 was a multisite trial along with a single site pilot study, PLAT-03, to explore administration of exogenous CD19 antigen designed to boost CAR T cell engraftment in subjects at high risk of early loss of persistence. PLAT-02 (NCT02028455) enrolled subjects 1-26 years of age with relapsed, refractory CD19+ B-ALL. The primary efficacy cohort was defined as those who received fludarabine/cyclophosphamide (flu/cy) LD and were infused with CAR19. PLAT-03 (NCT03186118) was a pilot study of CD19t T-APCs (manufactured T cells with CD19 tag) administered at doses of 10x10 6/kg or flat dosing of 5x10 8 for subjects &amp;gt;25kg every 4 weeks up to 6 total doses. Cohort A included subjects with low CD19 antigen burden, and cohort B included those with rapid early contraction of CAR19. 88 subjects with B-ALL were enrolled on PLAT-02 with plans for treatment at the recommended phase 2 dose (RP2D) of 1x10 6 CAR+ T cells/kg. Eighty-six percent had at least one prior relapse and 42% had undergone prior hematopoietic cell transplant (HCT). The feasibility of manufacturing was 98%. 71 subjects were in the primary efficacy cohort with an 89% minimal residual disease negative complete remission (MRDneg CR) rate. EFS and OS probability estimates with 95% CI at 1 year following CAR19 were 0.65 (0.53, 0.75) and 0.76 (0.64, 0.84). LFS at 1 year from entering MRDneg CR was 0.71 (0.58, 0.81). Cytokine release syndrome (CRS) was grade (Gr) 1 (53%), Gr 2 (26%), Gr 3 (10%), and Gr 4 (3%). Neurotoxicity occurred in 53%: Gr 1 (24%), Gr 2 (13%), Gr 3 (15%), and Gr 5 (1%). 25 subjects were treated on PLAT-03, 10 as cohort A (10 received CAR19 on PLAT-03, 9 received T-APCs), and 11 as cohort B (5 received CAR19 on PLAT-02, 6 received CAR19 on PLAT-03, and 9 total received T-APCs). One was cohort C (retreatment) and 3 were cohort D (no T-APCs). A total of 72 infusions of T-APCs were administered, with no occurrence of CRS or neurotoxicity. Two subjects had grade 3 toxicities related to T-APCs, 1 febrile neutropenia and 1 infusion related reaction. EFS and OS probability estimates at 1 year following CAR19 were 0.67 (0.43, 0.83) and 0.95 (0.71, 0.99). Overall LFS at 1 year was 0.63 (0.38, 0.80); by cohort: cohort A, 0.44 (0.13, 0.72) and cohort B, 0.80 (0.41, 0.95). Median duration of persistence, as determined by cumulative incidence using B cell aplasia (BCA) as a surrogate, among all subjects who received RP2D of CAR19 with flu/cy LD across PLAT-02 and PLAT-03, engrafted and achieved MRDneg CR, was 12.9 months (m). For subjects who did not receive T-APCs, the median persistence was 12.1m. Impact of antigen burden prior to LD was again observed; those with &amp;gt;15% CD19 antigen burden had persistence of &amp;gt;12.1m vs. 3.9m in the low antigen burden group. For subjects treated with T-APCs, the median persistence was 16m; 9.9m in cohort A and &amp;gt;16m in cohort B. The improvement in LFS after SCRI-CAR19 in phase 2 compared to phase 1 is likely multi-factorial, with contributing factors including earlier treatment, uniform use of LD, enhanced persistence, and better allocation of patients who benefit from consolidative HCT. The use of T-APCs was well tolerated without recurrent CAR T cell mediated toxicity. Although not directly comparable, there did appear to be enhancement of CAR T cell persistence with the use of T-APCs in populations predicted to have inferior persistence, including those with low antigen burden. There was not a clear improvement of LFS in those who received T-APCs. However, subjects were not randomized to receive T-APCs and those enrolled on PLAT-03 were more heavily treated and more likely to have received a prior HCT. Further exploration of T-APCs is warranted to define and evaluate their impact on persistence and durable responses.

Phase I Clinical Study of Humanized BCMA-Single-Domain Antibodies-Targeting CAR T (BCMA-CART) in Patients with Relapsed/Refractory Multiple Myeloma

Background:The CAR structure adopted by CART-BCMA is composed of a single-domain antibody targeting BCMA, CD8 hinge region, transmembrane region, 4-1BB co-stimulatory domain, and CD3-ζ T cell activation domain. In the phase I clinical study (NCT05346198) carried out in China, the safety and efficacy of CART-BCMA were initially evaluated through the dose escalation + dose expansion design, and the recommended dose (RD dose) for follow-up studies was determined as well. Method:Enrolled patients with relapsed and/or refractory multiple myeloma (RRMM) had previously received at least 3 lines of therapy including at least one proteasome inhibitor and one immune modulator. After lymphatic preconditioning chemotherapy (program: fludarabine 30mg/m 2/d and cyclophosphamide 300mg/m 2/d, -5, -4, -3, for 3 consecutive days), all patients received a single dose of CART-BCMA at 2.5×10 6, 5×10 6 and 7.5×10 6 CAR-positive T cells/kg (subject body weight), according to the dose level in which they were enrolled. R esults :Up to June 26, 2023, a total of 15 cases of RRMM received 2.5×10 6 CAR-positive T cells/kg (n=3), 5×10 6 CAR-positive T cells/kg (n=11) or 7.5×10 6 CAR-positive T cells/kg (n=1) dose level of CART-BCMA cell infusion therapy on the basis of the dose level in which they were enrolled. The median follow-up time was 14.42 months (range: 10.2-26.6 months). The median age of the subjects was 63.0 years old (range: 36-73 years old) (Table 1), 73.3% of the subjects (n=11) had previously received ≥4 lines of multiple myeloma therapy, and the median line of treatment was 5 lines (range: 3-9 lines), among which, 2 subjects (13.3%) had previously received autologous hematopoietic stem cell transplantation, and 4 subjects (26.7%) had relapsed/refractory diseases after previous treatment with proteasome inhibitors, immune modulators and CD38 monoclonal antibodies (three-drug relapsed/refractory). Nine subjects (60.0%) had high-risk cytogenetic abnormalities according to sMART 3.0 criteria, and 6 subjects (40.0%) had extramedullary plasmacytoma. The most common grade ≥3 adverse events were hematological toxicity, including decreased neutrophil count (n=13, 86.7%), decreased white blood cell count (n=12, 80.0%), decreased lymphocyte count (n=10, 66.7%), anemia (n=8, 53.3%), decreased platelet count (n=4, 26.7%). The first patient in the 7.5×10 6 CAR-positive T cells/kg dose group had a dose-limiting toxicity (DLT) event of grade 4 platelet count decrease, and no DLT event occurred in the other low-dose groups (2.5 and 5×10 6 CAR-positive T cells/kg). All 15 patients (100.0%) developed grade 1-2 cytokine release syndrome (CRS), no grade ≥3 CRS occurred, and the median time to CRS was 2.0 days (range: 1-13 days) , with a median duration of 7.0 days (range: 2 to 17 days). After the occurrence of CRS, all patients recovered without sequelae after supportive treatment, and 6 patients (40%) received tocilizumab (3 subjects received 2 doses, 3 subjects received 1 dose), 4 patients (26.7%) used glucocorticoids. There was no event of immune effector cell-associated neurotoxicity syndrome (ICANS), and no death event occurred. The median time to the first response (TTR) of the patients was 0.953 months (range: 0.92 to 2.23 months). All 15 patients who received CART-BCMA infusion achieved remission, and the overall remission rate (ORR) ( At least achieve PR or better efficacy) was 100% (95%CI, 78.20%-100.00%), as shown in Figure 1, among which, the best response of 9 patients (60%) was strict complete remission ( sCR), 5 patients (33.3%) achieved very good partial response (VGPR), and 1 patient (6.7%) achieved PR. All sCR patients achieved MRD negativity. The ORR of 6 patients with extramedullary plasmacytoma was 100%, of which 2 achieved sCR and 4 achieved VGPR. Notably, gradual deepening of remission was observed in 12 patients (80%), of which 10 patients (66.7%) further deepened the depth of remission on days 60-90 after infusion, and 2 patients (13.3%) were assessed sCR at day 360. Conclusion:Data from this phase 1 clinical study showed that CART-BCMA is well tolerated and highly efficacious in patients with RRMM. Patients with extramedullary plasmacytoma had the comparable response to those without extramedullary diseases. Notably, 12 patients (80%) patients elicted deeper response after 3 months of CART-BCMA infusion

Practice Efficiency Associated with Epcoritamab for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma from an Institutional Perspective

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Recently approved treatment options for patients with relapsed/refractory (R/R) DLBCL include polatuzumab, tafasitamab, chimeric antigen receptor T-cell (CAR-T) therapy and two newly approved bispecific antibodies, epcoritamab and glofitamab. Epcoritamab (subcutaneous [SC]) is a CD3xCD20 bispecific antibody developed using the DuoBody ® platform. It was the first bispecific antibody approved for the treatment of R/R DLBCL patients after two or more lines of therapy and is the first in the class to be offered as a SC treatment, in contrast to glofitamab which is offered as an intravenous infusion. Given the different treatment options available, there is a need to understand their impact on clinical practice efficiency and institutional costs. Methods: A micro-costing analysis was developed to compare practice efficiency of treating patients with R/R DLBCL using epcoritamab versus comparator treatments (glofitamab, polatuzumab/bendamustine/rituximab [pola-BR], tafasitamab/lenalidomide [tafa-len], and axicabtagene ciloleucel [axi-cel]) over a time horizon of up to 1 year. Time for clinical personnel (pharmacy technician, pharmacist, and nurse) and chair time were estimated throughout treatment stages (pre-dosing, blood work, pre-medication, treatment administration) as well as time in hospital during post-treatment monitoring. Dosing schedules and time inputs were based on prescribing information (PI) of respective drugs, published studies, and clinical expert opinion. Institutional costs of clinical personnel and inpatient days were sourced from publicly available databases and presented in 2023 US dollars. Results: Over the 1-year time horizon, epcoritamab treatment required 35 hours of personnel time and 22 hours of chair time per patient (Table 1). With SC administration, epcoritamab is associated with improved practice efficiency with reduced personnel time (time saved per treated patient: 31 hours versus glofitamab, 0.4 hour versus pola-BR, 41 hours versus tafa-len, 22 hours versus axi-cel) and chair time (time saved per treated patient: 54 hours versus glofitamab, 22 hours versus pola-BR, 63 hours versus tafa-len, -2 hours versus axi-cel). The improved practice efficiency translates into savings in institutional personnel costs of $1,577 versus glofitamab, $2,443 versus tafa-len, and $1,295 versus axi-cel but is slightly higher ($189) when compared with pola-BR, which is a time-limited treatment of up to 6 cycles. Post-treatment monitoring varies across the treatments according to the PIs, based on recommended monitoring time and occurrence of cytokine release syndrome. While epcoritamab-treated patients were estimated to be monitored in the hospital for an average of 24.6 hours, glofitamab was projected to be associated with 37.9 hours of hospitalization for post infusion monitoring per patient. Patients receiving axi-cel therapy were estimated to be monitored in hospital for an average of 7 days according to clinical expert opinion. Due to reduced inpatient monitoring, epcoritamab results in savings in inpatient costs of $6,924 versus glofitamab and $19,234 versus axi-cel. The trends are consistent when looking at shorter time horizons including 6 months, 30 days, or using the median cycles of the treatments. Conclusion: Due to its unique SC administration, epcoritamab improves institutional practice efficiency despite more frequent dosing, saving personnel costs and inpatient costs. This could help to alleviate capacity constraints at infusion centers and ease patient scheduling. The resources saved (staff time, chair time, inpatient monitoring) can be redirected to other institutional needs, improving the availability and quality of healthcare services for patients.

Inflammatory Biomarkers and Outcomes in Multiple Myeloma Patients after CAR T-Cell Therapy

Introduction: CAR T-cell therapy is an effective tool for the treatment of multiple myeloma but produces a systemic inflammatory response which can manifest as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurologic toxicities, and hyperferritinemia. Understanding the factors associated with these complications can help clinicians better evaluate their patients' candidacy for CAR T-cell therapy. In this study, we assessed whether baseline values of inflammatory biomarkers were associated with outcomes after CAR T-cell therapy. Methods: We retrospectively reviewed multiple myeloma patients who underwent CAR T-cell therapy with commercial products or on clinical trials at The Mount Sinai Hospital between 2017 and 2023. We gathered data on lab parameters that we felt were indicative of patients' baseline inflammatory status including C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, absolute lymphocyte count (ALC), and absolute neutrophil count (ANC). Baseline data were collected prior to lymphodepletion. Outcomes of interest were occurrence and maximum grade of CRS and ICANS, occurrence of delayed neurotoxicity, attainment of peak ferritin ≥5000 within 30 days of infusion, progression-free survival (PFS), and overall survival (OS). Univariate logistic regression was used to assess the association between baseline labs and CRS, ICANS, delayed neurotoxicity, and peak ferritin ≥5000. Ordinal logistic regression was used to assess the baseline labs' association with maximum grade of CRS and ICANS, while proportional cox regression was used to assess their association with OS and PFS. The percentage of bone marrow plasma cells pre-CAR T, which we used as a surrogate for tumor burden, was included as a covariate on multivariable analyses. Results: A total of 101 patients treated with CAR T cells were included - 45 with ciltacabtagene autoleucel, 37 with idecabtagene vicleucel, and 19 with other products on clinical trials. Median age was 63 (range 37-82), median baseline marrow plasma cells percentage was 5% (range 0%-95%), and median follow-up was 11.9 months. Patients had a median (IQR) CRP of 4.0 mg/L (1.8, 11.8), ferritin of 174 ng/mL (68, 364), D-dimer of 0.6 mcg/L (0.4, 1.2), fibrinogen of 397.0 mg/dL (334.0, 477.5), ALC of 0.8 x10 3/µL (0.5, 1.1), and ANC of 2.7 x10 3/µL (1.9, 3.6). CRS occurred in 88.2% of patients (3.9% grade ≥3), ICANS in 15.7% (all grade &amp;lt;3), and delayed neurotoxicity in 5.9% (all grade &amp;lt;3). Increased baseline fibrinogen and ferritin were significantly associated with inferior OS even after adjusting for covariates (p-values 0.031 and 0.010, respectively). Every 143 mg/dL increase in fibrinogen increased the hazard of death by 83.7%, while every 500 ng/mL increase in ferritin increased the hazard of death by 27.5%. Patients with higher baseline CRP had a trend towards inferior OS (30.2% increased hazard of death per 20 mg/L CRP increase, p = 0.055). Baseline CRP, D-dimer, fibrinogen, ferritin, ALC, and ANC were not associated with PFS. Higher baseline ALC was associated with both increased odds of ICANS (110.2% increased odds of ICANS for every 0.5 x10 3/µL increase in ALC, p = 0.019 on multivariable analysis) and increased grade of ICANS (p = 0.023 on multivariable analysis). None of the assessed biomarkers were associated with peak ferritin ≥5000 (aside from baseline ferritin), occurrence of CRS, maximum grade of CRS, or delayed neurotoxicity. Conclusion: Although CAR T-cell therapy is a highly effective treatment option for patients with multiple myeloma, outcomes of infused patients can be highly variable. Serologic biomarkers like fibrinogen and ferritin are routinely assessed in patients undergoing CAR T-cell therapy and could offer value as predictors of outcomes. We found that higher fibrinogen and ferritin values at baseline were associated with inferior OS after CAR T-cell therapy, even after controlling for tumor burden. Higher baseline ALC was also associated with higher risk of ICANS and higher grade of ICANS, an important toxicity to consider for patients receiving CAR T. Baseline fibrinogen, ferritin, and ALC may be incorporated into assessments of the risk of CAR T-cell therapy for multiple myeloma patients.

Assessment of Activities of Daily Living (ADL)Scale Can be Used to Predict Overall Survival after CAR-T Cell Therapy in Elderly Patient(over 70 years of age) with Refractory/Relapsed B-Cell Lymphoma

Background:The advent of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for refractory/relapsed B-cell lymphoma (r/r B-NHL). However, there are limited data on outcomes in older patients (age≥65 years) treated with CAR -T-cell therapy, particularly in patients older than 70 years. Objectives:Our objective was to evaluate the efficacy of CAR -T-cell therapy in elderly patients with r/r B-NHL, including response rates, progression-free survival (PFS), and overall survival (OS), as well as factors affecting survival. Methods:As of April 1, 2023, a total of 80 patients with r/r B-NHL in the age group 65-70 years (n=57) or older than 70 years (n=23) were included. Diagnoses included DLBCL NOS (n=58) ,HGBCL(n=6) ,TFL(n=6), Richter(n=4) and Other(n=6). Baseline characteristics are described in Table 1.All patients were heavily pretreated. 71/80 (88.75%) patients were at stage III-IV. The median IPI score was 3 (range 1-5). 8/96 (10%) patients failure of prior autologous hematopoietic stem cell transplantation (HSCT). The median assessment score of ADL scale was 95 for both the 65-70 and &amp;gt; 70 age groups, and 47.5% of patients received bridging therapy(BT) prior to CAR -T cell therapy. There were no significant differences in baseline data between age groups. Prior to the study, CD19/CD22 antigen expression in tumor tissue was confirmed by pathology, and the target was selected according to antigen expression. The kinetics and function of CAR -T cells were monitored by quantitative PCR and flow cytometry. Efficacy was assessed by PET-CT every 3 months after CAR -T therapy. All p-values were two-sided values. Survival curves were calculated by the Kaplan-Meier method. Results: The number of patients who chose a CD19 target or a CD19/CD22 dual target for CAR -T therapy was 67/80 (%) and 13/80 (%), respectively. The median CAR -T cells infused dose in the 65-70 and &amp;gt; 70 age groups was 1.3 (range, 0.0485-9.5) and 1.6 (range, 0.088-3.91) (×106/Kg), respectively (P=0.9618).(Table 2).There were no differences between the 2 age groups in the occurrence of cytokine release syndrome (CRS) grade 3 or higher(P=0.6221). The proportion of patients using glucocorticoid therapy for CRS was higher in the age group &amp;gt; 70 years than in the age group 65-70 years, but there was no statistically significant difference (P=0.0957). A response occurred in 35/57 (61.4%) of patients in the 65-70 years age group and in 14/23 (60.7%) of patients in the &amp;gt; 70 years age group (P=0.9646), with a complete response in 21/57 (36.8%) and 8/23 (34.8%), respectively (P=0.8623). At a median follow-up of 8.05 months (95% CI: 10.27-15.20), 12-month overall survival(OS) was 54.6% (95%CI: 39.3%-67.6%) vs 72.1% (95%CI:43.9%-87.8%) at ages 65-70 vs &amp;gt; 70,12-month progression-free survival (PFS) was 32.8% (95%CI: 19.8%-46.5%) vs 32.9% (95%CI: 13.5%-54%), and there was no significant difference in OS (p=0.0623) and PFS(p=0.6327) by age group. In contrast, patients aged &amp;gt; 70 with ADL &amp;lt; 95 showed significantly shorter 12-m OS (0) compared to patients aged 65-70 with ADL≥95(55.2%,95%CI:35.5%-71.1%) or ADL &amp;lt; 95(40.5%, 95%CI: 14.2%-59.9%), or &amp;gt; 70 with ADL≥95(85.6%, 95%CI:52.5%-96.3%), respectively (Figure 1: P= 0.0069). The three negative factors comprising the prognostic tool OS: low ADL scores (P=0.0124), high IPI scores (P=0.0029), and presence of extranodal lesions (P=0.0143). Conclusions: Our data suggest that the safety and efficacy of CAR -T-cell therapy in &amp;gt; 70-year-old patients is not significantly different from that in 65-70-year-olds. Elderly patients with ADL scores below 95 have poor survival after CAR -T therapy, especially those over 70 years of age. However, studies on curative approaches and long-term follow-up are needed.

Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects suchas cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR.

Cytokine Release Syndrome (CRS) Is Not Required for CAR-T Cell Efficacy in Aggressive Large B-NHL

BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy for treatment of aggressive large B-cell non-Hodgkin lymphoma (B-NHL) has changed management and outcomes for this disease. Treatment with CAR T-cells is accompanied by a unique set of adverse effects, including development of cytokine release syndrome (CRS). Though rates of CRS varied in trials, the development of severe (Grade 3 or 4) CRS was rare and similar incidences have been noted in real world studies. Here, we addressed whether the development of CRS is associated with outcomes in patients with aggressive large B-NHL undergoing treatment with CAR T cells. METHODS Patients aged ≥18 years with aggressive large B-NHL who underwent apheresis between May 2018 and January 2021 for commercial CAR T-cell therapy at eight academic US medical centers were identified from the Cell Therapy Consortium (CTC) registry. Providers could prescribe either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). CRS was graded using ASTCT consensus criteria. Tumor response 90 days after CAR T-cell infusion was assessed per Lugano criteria by the treating clinician. Persistent cytopenias were defined as ANC<1000 and/or Plt<50 and evaluated at the following intervals post infusion: day 30, 3 months, 6 months, 9 months, and one year. Cox regression analysis and the Kaplan Meier method were used for survival outcomes. Logistic regression analysis was used to assess association with tumor response and persistent cytopenias. RESULTS This study included 351 patients who underwent apheresis for commercial CAR T cell therapy for aggressive large B-NHL (Table 1A). Of these, 262 (74.4%) developed CRS while 90 (25.5%) did not. The median age at apheresis was 61 (range 18-88) among patients who developed CRS and 65 (range 37-85) among those who did not (p=0.005). Of the patients included, 202 (57.6%) received axi-cel and 149 (42.5%) received tisa-cel. With median follow up of 21.6 months, there were no differences in progression free survival (PFS) or overall survival (OS) between patients who developed CRS and those who did not. Median PFS in patients who did not develop CRS was 5.99 months compared to 5.89 months (p=0.99) in those who did. Median OS in patients who did not develop CRS was 26.6 months compared to 17.5 months in patients who did (p=0.16). Exploratory analysis showed that CRS grade did not influence PFS or OS (Figure 1). Results of the multivariate analysis are summarized in Table 1. The development of CRS did not have a significant impact on PFS or OS. A peak ferritin level of greater than 5000 within 28-days following CAR T-cell infusion was associated with worse PFS (HR 2.61; CI: 1.71-3.98, p<0.001) and OS (HR 2.38; CI: 1.50-3.76, p<0.001). LDH greater than the upper limit of normal was associated with worse progression-free (HR 2.11; CI: 1.49-2.98, p<0.001) and OS (HR 2.34; CI: 1.55-3.53, p<0.001). The administration of steroids for treatment of CAR T-cell associated toxicities had no significant impact on PFS or OS. Presence of bulky disease (≥10 cm) had no impact on PFS but was associated with worse OS (HR 1.81; CI: 1.29-2.75, p=0.005). Receipt of bridging therapy was associated with worse PFS (HR 1.58; CI: 1.11-2.24, p=0.011), though not OS. At 30 days post-infusion, there was no difference in ORR (66% vs 52%, p=0.081) or CR rate (39% vs 27%, p=0.155) between patients who developed CRS and those who did not. The occurrence of CRS within 28 days of treatment was significantly associated with cytopenias at day 30 (p=0.001), but not at any other time point. Amongst patients with Grade ≥3, 63% had cytopenias at day 30, compared to 47% among patients who did not have CRS (p=0.142). Grade ≥3 CRS was not significantly associated with cytopenias beyond day 30. CONCLUSION Survival outcomes were similar in patients with aggressive large B-NHL treated with CAR T-cell therapy who did or did not develop CRS. Furthermore, the occurrence of CRS had no impact on ORRs or CR rates. Having CRS was associated with cytopenias at day 30 post infusion, though not at subsequent time points. These findings lend further support to the finding that development of CRS does not impact efficacy of CAR T-cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dynamics and Predictive Value of T-Cell Chimerism after Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Background: T-cell chimerism after allogeneic hematopoietic cell transplantation (alloHCT) is an important tool to investigate T-cell reconstitution. Haploidentical HCT (haplo-HCT) using post-transplantation cyclophosphamide (PTCy) has been increasingly applied due to readily available donors and favorable outcomes. PTCy induces immune tolerance by depleting expansion of alloreactive T-cells. However, limited clinical data exist regarding the impact of PTCy on the dynamics of T-cell chimerism. Methods: Adult patients receiving haplo-HCT with PTCy and reduced-intensity conditioning regimens were retrospectively reviewed. Patients with primary graft failure or receiving donor-lymphocyte infusion prior to +90 days were excluded. T-cell chimerism was measured from sorted CD3+ cells collected from peripheral blood or bone marrow at 1, 2, 3, 6, and 12 months. Complete chimerism was defined as < 5% donor T-cells. Patients were divided into full and partial T-cell chimerism groups based on their T-cell chimerism status at Month 1 and 3. Results: From 1/2017 to 6/2021, 34 patients underwent haplo-HCT and met inclusion criteria (Table 1). One month post HCT, 29 (85.3%) patients achieved complete T-cell chimerism; 3 months post HCT, 31 (93.9%) patients achieved complete T-cell chimerism (Figure A). In univariate logistic regression analysis, peripheral blood rather than bone marrow as the donor source, and the occurrence of cytokine-release syndrome (CRS), were significantly associated with higher incidences of full T-cell chimerism at Month 1 (Table 2). In multivariable analysis, only the occurrence of CRS was significantly associated with full T-cell chimerism at Month 1 (odds ratio 18.7, 95% confidence interval [CI] 1.30 to 641, p=0.04, Table 2). Next, we investigated whether early achievement of full T-cell chimerism would affect clinical outcomes. After a median follow up of 363 and 530 days for patients with full and partial T-cell chimerism at Month 1, respectively, there was no significant difference of progression-free survival (PFS) (median PFS not reached v.s. 367 days, hazard ratio [HR] 0.54, 95%CI 0.14 to 2.07, Figure B) or overall survival (OS) (median OS not reached vs 530 days, HR 0.41, 95%CI 0.10 to 1.69, Figure C). In contrast, patients who achieved full T-cell chimerism at Month 3 had significantly longer OS than those with partial T-cell chimerism (median OS not reached v.s. 492 days, HR 0.18, 95%CI 0.03 to 0.90; p=0.04, log-rank test; Figure E). Of note, for the two deaths in the partial T-chimerism group, 1 died from relapse and the other from sepsis in the setting of Grade 4 acute graft-versus-host disease. Moreover, patients who achieved full T-chimerism at Month 3 had a trend of improved PFS over those with partial T-chimerism, although the difference was not statistically significant (HR 0.23, 95%CI 0.05 to 1.11; p=0.07; Figure D). Lastly, achieving partial T-cell chimerism at Month 1 or Month 3 was not associated with an increased risk of bacteremia (p=0.83 for Month 1; p=0.99 for Month 3; Chi-square test) or pneumonia (p=0.31 for Month 1; p=0.38 for Month 3), compared with those with full T-cell chimerism. Conclusion: For patients receiving haplo-HCT with PTCy, the majority achieved full T-cell chimerism within the first month. The occurrence of CRS was associated with a significantly higher chance of achieving full T-cell chimerism at Month 1. Achieving a full T-cell chimerism at Month 3 was associated with significantly improved OS compared with those with partial T-cell chimerism. These data should be confirmed in a larger patient cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Short-Term Follow-up of Blinatumomab in Children with B-Cell Precursor Acute Lymphoblastic Leukemia：Study of a Single Center from China

Background: Acute lymphoblastic leukemia (ALL) is the most common hematologic disorders in children. The 5 years overall survival (OS) has reached more than 90%, but still 20% of patients relapsed. Positive of microscopic residual disease (MRD+) is the important factors for pediatric ALL. Blinatumomab is a combination of CD3 and CD19 bispecific antibody. Previous studies have shown that it has a significant advantage in improving the efficacy and survival of refractory /relapsed (R/R) ALL and MRD+ patients. Blinatumomab has been approved in China for R/R ALL indications in adults and children respectively since Aug 2021 and Apr 2022. So far, there is a lack of research data on ALL in Chinese children. This study mainly discusses the short-term efficacy and safety of Blinatumomab for R/R ALL and MRD+ of children with B-ALL in China. Methods: We collected the patients' information of children with R/R or MRD+ B-ALL treated with blinatumomab from Aug 2021 to Jun 2022 in our single institute from China. Retrospectively analyzed were carried out for the short-term efficacy and safety. Results: since Aug 2021, blinatumomab has been introduced to China. 13 cases were enrolled in this study, including R/R ALL 6 cases and MRD + ALL 7 cases, the median onset age of 9.5 (range 5-14) years old, male: Female =8:5, in the R/R-ALL group, there was 1 case of sustained no remission (NR), 1 case of very early recurrence(<18 months) and 1 case of late recurrence(≥36 months), and 3 cases of early recurrence, ALL of which were isolated bone marrow recurrence for the first time. 3 cases were treated with reinduction chemotherapy before blinatumomab. The mean proportion of blast cells in bone marrow (BM) prior therapy was 34.3 (range 0-96) %. The mean flow cytometry MRD was 30.26 (range 0.11-78.3) %. 3 patients were with no dose uphill due to low tumor load. 3 patients were given uphill 5ug/m2 qd d1-7, 15ug/m2 d8-28, of which 1 was treated for 14 days and 2 for 21 days. The investigator evaluated the efficacy of the treatment and stopped the drug. After treatment, bone marrow morphology was complete response (CR) in 3 cases, of which 2 cases had MRD negative (MRD-), the Cytokine release syndrome (CRS) incidence was 83.3%, 2 cases had CRS grade 2, 3 cases CRS grade 1, and the main manifestations were fever and hypotension. The levels of cytokines were significantly increased in patients with CRS, especially in IL-6, IL-8 and IL-10. The median level of IL-6 in CRS was 3081.8 (range 12.6-10405.0). IL-8 214.5 (range 23-408.0) and IL-10 377.7 (range 6.7-1398.0) (normal value ≤ 4.91) were significantly higher than those before blinatumomab and after CRS disappeared. In the MRD+ ALL group, there were 2 cases of chemotherapy drug intolerance, 1 case of inadequate treatment, and 4 cases of continuous MRD+ after standard chemotherapy. In MRD+ALL group, the BM of All cases were CR before treatment, the mean flow MRD value was 0.63 (range 0.01-4.00) %, the blinatumomab was 15ug/m2 (weight < 45kg) or 28ug (weight ≥45kg) for 7-28 days. After treatment, the MRD of 7 cases were all turned negative and the incidence of CRS was 71%. All of which were CRS grade I. When CRS occurs, the median IL-6 level is 76.4 (range 4.4-271.0) (normal value ≤ 5.3), IL-8 18.7 (range 8.0-35.5) (normal value ≤ 20.6), IL-10 447.3 (range 8.9-2570.0) (normal value ≤ 4.91) Conclusion: The CR rate of R/R pediatric B-ALL was 50%, the MRD- rate was 67%. The rate of MRD turned negative was 100% in MRD+ B-ALL group. In this study, the tolerance of blinatumomab in children with B-ALL was good, and the incidence of CRS was about grade 1/2, and no neurological complications occurred. The occurrence of CRS was mainly caused by the increase of cytokines, especially IL-6, IL-8 and IL-10. The IL-6 of CRS in R/R ALL group was significantly higher than that in MRD+ ALL (Fig.12.798, P=0.007).

Cytokine Release Syndrome during Antithymocyte Globulin/Anti-T Lymphocyte Globulin Serotherapy for Graft-versus-Host Disease Prophylaxis before Allogeneic Hematopoietic Stem Cell Transplantation: Incidence and Early Clinical Impact According to American Society of Transplantation and Cellular Therapy Grading Criteria

Antithymocyte globulin (ATG)/anti-T lymphocyte globulin (ATLG) aids graft-versus-host disease (GVHD) prophylaxis in HLA-matched related and unrelated donor hematopoietic stem cell transplantation (HSCT). Its use is frequently accompanied by systemic infusion reactions attributable to cytokine release syndrome (CRS). However, detailed data on ATG/ATLG-induced CRS and its correlation with clinical outcome parameters are lacking. This study aimed to analyze the incidence, characteristics, risk factors, and early clinical impact of CRS during ATG/ATLG administration before allogeneic HSCT according to the American Society of Transplantation and Cellular Therapy (ASTCT) CRS grading criteria. This retrospective single-center analysis included consecutive recipients of allogeneic HSCT treated with ATG/ATLG as GVHD prophylaxis at the Medical University of Vienna between January 1, 2014, and August 15, 2021. Multivariate regression models were used to explore risk factors for CRS and its association with clinical outcomes (acute GVHD grade II-IV, clinically significant cytomegalovirus infection, nonrelapse mortality, and overall survival) at 6 months after HSCT. A total of 284 patients (median age, 54 years; interquartile range [IQR], 45 to 61 years; 120 females, 164 males) were included in the study. ATLG was used in 222 patients (78%); ATG, in 62 (22%). One hundred sixty-six patients (58%) developed CRS grade ≥1 during ATG/ATLG administration. CRS was mostly mild, with 92% of the cases CRS grade 1-2. Thirteen patients (5%) developed CRS grade 3, and 1 patient had CRS grade 4. No CRS-related death (grade 5) occurred. Patients with CRS showed a pronounced systemic inflammatory response as measured by inflammatory markers C-reactive protein, IL-6, and procalcitonin. In multivariate analysis, lymphoma as the underlying disease, high ATLG dose of 60 mg/kg, and body weight were significantly associated with CRS. Patients with CRS grade ≥1 had a higher 6-month incidence of acute GVHD II-IV compared with patients without CRS (24% versus 14%; P=.04). This effect remained statistically significant only for CRS grade 3-4 (subdistribution hazard ratio, 3.70; 95% confidence interval, 1.58 to 8.68; P < .01) after adjusting for relevant confounders. Other clinical outcome parameters were not affected by the occurrence of CRS. In our cohort, CRS defined by ASTCT grading was a frequent but mostly mild complication following ATG/ATLG administration for GVHD prophylaxis. Our data suggest a possible interaction of (higher-grade) CRS with an increased risk for developing acute GVHD. Further studies to corroborate this finding are warranted, as it could inform the investigation of additional prophylactic interventions, such as IL-6 blockade, in this setting.

Cytokine Release Syndrome After Modified CAR-NK Therapy in an Advanced Non-small Cell Lung Cancer Patient: A Case Report

Use of chimeric antigen receptors (CARs), as an immune cell therapy, has generated excellent clinical outcomes against hematologic tumors in recent years. Among them, the CAR-NK (natural killer) therapy has shown better efficacy, and less toxicity, than chimeric antigen receptor T-cell (CAR-T) therapy. In our phase II clinical trials, administering chimeric costimulatory converting receptor (CCCR)-NK92 cells on advanced non-small cell lung cancer patients proved efficacious in cell and animal experiments. However, we observed occurrence of cytokine release syndrome (CRS), a rare and unexpected side effect, never reported before during CAR-NK therapy. Here, we provide a detailed report of the patient’s case, emphasize on the need to pay attention to CRS in NK cell therapy, and suggest improvements that will minimize potential toxicity.

Viability of Chimeric Antigen Receptor T Cell Therapy in Latin America

Introduction: Treatment of diffuse large B cell lymphoma (DLBCL) may be a challenge for Latin American countries. Thus, novel strategies to reduce the economic burden of oncological care are necessary. In Brazil, the DLBCL annual incidence is approximately 6.000 cases, among which 30% will relapse or become refractory (R/R). In this scenario, the limited access to the new therapies reinforce the need to develop new local technologies and improve research initiatives. Here we report the development and clinical application of a Brazilian platform to manufacture genetically modified T-cells to treat patients with R/R leukemia and lymphomas, which may also help reverse the poor prognosis of these patients in low and middle-income countries. Patients and Methods: All patients were referred to our center to consider compassionate use of anti-CD19 CAR-T cell therapy. The treatment was authorized by the local medical ethical committee. Once patients were deemed to be eligible for CAR-T, they were scheduled for lymphopheresis and the cells were processed and cryopreserved. During the manufacturing process and after completion of lymphophersis, all three patients received bridging therapy. Prior to infusion of CAR-T, patients were given lymphodepletion chemotherapy with cyclophosphamide and fludarabine for 3 days. Patients were monitored daily for the occurrence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), which were graduated according to the criteria of the American Society for Transplantation and Cellular Therapy. These treatments were only available because we developed a Brazilian platform to manufacture genetically modified T-cells. Firstly, we developed and validated in vitro and in vivo anti-CD19 CAR T cell expression, expansion, and cytotoxicity. Secondly, in-house lentiviral good-manufacturing practice (GMP) protocols were established for clinical purposes. Thirdly, we upscaled the manufacturing process into the GMP facility originally developed for MSCs and adapted it to genetically modified T-cells. Finally, in-house procedures to deliver anti-CD19 CAR T cells for clinical use were established according to the Brazilian Health Regulatory Agency (ANVISA) policies. Once these steps were implemented, we were able to treat the first three patients of a patient with CAR-T cells produced in Latin America. Results: Two patients presented CAR-T cell expansion after the procedure (Figure 1). Within thirty days after the infusion one patient achieved complete response, one had partial response and one was not evaluated (Table 1). All patients had CRS and only one had ICANS. Two patients died, one from infection and other from intracranial hemorrhage due to domestic accident, — and — days after CAR-T cell infusion, respectively. Discussion: At least two of the reported patients presented improvement of their disease. The other one died before the expected response could have been evaluated. None of the patients died from complications related to manufacturing or infusion procedures, highlighting an acceptable safety profile of the platform. Although these are preliminary results, the CAR-T cell expansion profile, presence of systemic inflammatory response and lack of early disease progression suggest the treatment effectiveness. Conclusion: Apart from all the scientific challenges, this experience highlights the feasibility to implement a viable and efficient CAR-T platform in middle-income countries. Besides, implementation of advanced cellular therapy can also contribute to enhancing the quality of other cellular therapies. [Display omitted] DisclosuresGuerino-Cunha: Novartis: Other: Speaker; BMS: Other: Speaker; Janssen: Other: Speaker. Calado: Instituto Butantan: Consultancy; Alexion Brasil: Consultancy; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding.