Higher Cytokine Release Syndrome Research Articles

Inaticabtagene Autoleucel (CNCT19) in adult relapsed or refractory B-cell acute lymphoblastic leukemia.

Prior to November 2023, CD19 CAR-T therapies had not been approved in China for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), leaving a significant unmet need. In response, Inaticabtagene Autoleucel (Inati-cel), a novel CD19 CAR-T therapy with a distinct scFv (HI19α), was developed and showed promising efficacy in preliminary clinical research. We conducted a phase 2, single-arm, multicenter study of Inati-cel in adult CD19+ r/r B-ALL in China. The primary endpoint was the overall remission rate (ORR) at the end of Month 3. Forty-eight patients who underwent Inati-cel infusion were evaluated for both efficacy and safety. Among them, thirty-four patients achieved and maintained remission beyond 3 months, with 3-month ORR of 70.8% (95%CI, 55.9-83.1). The best ORR was 85.4% with all responders reaching minimal residual disease (MRD) negativity. With median follow-up of 23.7 months, the median DOR was 20.7 months (95%CI, 6.4-not reached), and the median OS was not reached (95%CI, 13.0 months-not reached). Additionally, grade 3 or higher cytokine release syndrome and neurologic events occurred in 12.5% and 6.2% of patients respectively. The 2-year follow-up data suggest that Inati-cel demonstrated an encouraging and durable responses with manageable safety profiles in r/r B-ALL. Based on the data from this pivotal trial, Inati-cel was approved as the first CAR-T therapy for adult r/r B-ALL in China and underscores its potential therapeutic benefits for this patient population. NCT04684147.

Acute kidney injury following CAR-T cell therapy: a nephrologist's perspective.

Chimeric antigen receptor T (CAR-T) cell therapy, an emerging personalized immunotherapy for various haematologic malignancies, autoimmune diseases and other conditions, involves the modification of patients' T cells to express a chimeric antigen receptor that recognizes tumour or autoimmune cell antigens, allowing CAR-T cells to destroy cancerous and other target cells selectively. Despite remarkable clinical improvements in patients, multiple adverse effects have been associated with CAR-T cell therapy. Among the most recognized adverse effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and tumour lysis syndrome. Even though less recognized, the incidence of acute kidney injury (AKI) ranges from 5 to 33%. The wide range of reported AKI incidence rates might depend on patient population characteristics and comorbidities and specific CAR-T cell therapy features. Even though the exact pathophysiology remains unknown, several key mechanisms, including cytokine release syndrome, tumour lysis syndrome and other factors such as direct renal toxicity of CAR-T cell therapy, conditioning regimens or other medications (e.g. antibiotics), and infectious complications (e.g. sepsis) have been proposed. Risk factors for CAR-T-related AKI include lower baseline glomerular filtration rate, higher rates of allopurinol or rasburicase use, intravenous contrast material exposure, elevated baseline lactate dehydrogenase and grade 3 or higher cytokine release syndrome. Future prospective studies with larger patient populations are needed to gain insights into the pathophysiology of CAR-T-related AKI and, more importantly, to be able to prevent as well as to develop novel and more efficient treatment modalities. In this narrative review, we discuss the underlying pathophysiology, risk factors, potential interventions and future directions related to AKI following CAR-T cell therapy.

CD27-Armored BCMA CAR T-cell Therapy (CBG-002) for Relapsed and Refractory Multiple Myeloma: A Phase I Clinical Trial.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM); however, whether patients have long-term responses has yet to be established. We investigated the feasibility of CBG-002, a CD27-armored BCMA CAR T-cell therapy, to improve clinical efficacy in patients with RRMM. We present preclinical data showing the activity of CBG-002 against myeloma and results from a phase I clinical trial (NCT04706936) evaluating its safety and efficacy in patients with RRMM. The primary endpoint was safety, as assessed by grade 3 or 4 adverse events (AE). Key secondary endpoints were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). A total of 11 patients were enrolled and received CBG-002 therapy. Nine patients developed grade 1 or 2 cytokine release syndrome (CRS), whereas no patients experienced grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome. Other grade 3 or higher AEs included neutropenia (72.7%), thrombocytopenia (45.5%), and anemia (36.4%). At a median follow-up of 16.7 months, the ORR was 81.8%, including a stringent complete response/complete response rate of 45.5%, very good partial response rate of 18.2%, and partial response rate of 18.2%, with a median DOR of 8.9 (range 1.8-21.9) months. The median OS was not reached, and the median PFS was 8.5 (2.7-22.9) months. In this phase I study, CBG-002, a CD27-armored BCMA CAR T-cell therapy, demonstrated safety and clinical efficacy in patients with RRMM.

CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study

Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

Prevalence of adverse events following bispecific antibody therapy in non-Hodgkin lymphoma: A meta-analysis.

e19008 Background: Bispecific antibodies (BsAb) have emerged as a new treatment modality for relapsed/refractory non-Hodgkin lymphomas (R/R NHL). They exert their effect by binding to CD3 on T-cells and CD19 or CD20 on lymphoma cells, activating the T-cell to exert cytotoxic effects against the tumor and normal B-cells. Treatment related adverse events (TRAE) include infections, cytokine release syndrome (CRS), neurotoxicity (ICANS). This meta-analysis was conducted to assess prevalence of TRAEs from prospective clinical trials that evaluated BsAb in R/R NHL. Methods: A systematic review was conducted through PubMed, Embase, Scopus, Web of Science, and Cochrane to identify BsAb clinical trials in NHL through October 2023. Eligible studies included phase I-III trials evaluating BsAb in any type of NHL, either as monotherapy or combination therapy irrespective of prior lines of treatment. Primary outcomes of interest include infection, neutropenia, CRS, and ICANS. All studies were weighted equally. Pooled prevalence estimates of TRAE were calculated using common and random effects models. Heterogeneity tests were performed using Cochran’s Q test. Subgroup analysis examined infection rates in monotherapy versus combination therapy cohorts. Results: After screening 1039 studies, 36 clinical trials with 2162 patients were included. The lymphoma subtypes were diffuse-large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. The BsAbs included mosunetuzumab (13 studies), epcoritamab (10 studies), blinatumomab (5 studies), glofitamab (5 studies), odronextamab (2 studies), and AFM11 (1 study). The median age of patients was 66 years, and patients had received a median of two prior lines of therapy. Median follow-up duration was 9.1 months. The prevalence of all-grade infections was 35% (95% CI: 0.33-0.38; I2 = 79%). For grade ≥3 infections, the prevalence was 16% (95% CI: 0.14-0.18, (I2 = 77%). There were higher rates of all-grade infections in the combination therapy cohort (41%, 95% CI: 0.36-0.47) compared with the monotherapy cohort (33%, 95% CI: 0.30-0.36). All-grade and grade ≥3 neutropenia occurred in 31% (95% CI: 0.29-0.34; I2 = 80%) and 22% (95% CI: 0.20-0.24, I2 = 61%) of patients. CRS was observed in 45% of patients (95% CI: 0.43-0.48, I2 = 85%). Grade ≥3 CRS occurred in only 2% of patients (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). ICANS occurred in 12% (95% CI: 0.10-0.14, I2 = 90%) while grade ≥3 ICANS was rare, at 3% (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). Conclusions: BsAb is associated with nontrivial rates of infections and neutropenia. The rates of high grade CRS and ICANS are low. The heterogeneity of the findings could be attributed by an underreporting of TRAE and small sample sizes from various studies. These results highlight the need for vigilant practices to diagnose and treat infections early and consideration for antibacterial prophylaxis in this immunocompromised population.

Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.

CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.

FDA Approval Summary: Ciltacabtagene Autoleucel for Relapsed or Refractory Multiple Myeloma.

In February 2022, the FDA approved ciltacabtagene autoleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen, for adult patients with relapsed/refractory multiple myeloma after ≥4 lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Approval was based on overall response rate (ORR), complete response (CR) rate, and duration of response (DoR) in 97 adult patients in a single-arm, open-label, multicenter phase 2 trial (CARTITUDE-1 [NCT03548207]). Patients received a single infusion of ciltacabtagene autoleucel, preceded by lymphodepleting chemotherapy. Of the 97 patients evaluable, ORR was 97.9% [95% confidence interval (CI), 92.7-99.7] with a stringent CR rate of 78.4% (95% CI, 68.8-86.1). After median follow-up of 18 months, the median DoR was 21.8 months (95% CI, 21.8-not estimable [NE]) in responders (PR or better) and NE (95% CI, 21.8 months-NE) in patients who achieved stringent CR. Serious adverse reactions occurred in 55% of the 97 patients evaluated for safety. Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities occurred in 5% and 11% of the patients, respectively, leading to a Risk Evaluation and Mitigation Strategy. Neurologic toxicities included immune effector cell-associated neurologic syndrome, typically seen with CAR-T products, parkinsonism, peripheral neuropathy, cranial nerve palsies, and Guillain-Barré syndrome. One fatal case of hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred. Prolonged and recurrent grade 3 or 4 cytopenias occurred; a single patient required hematopoietic stem-cell rescue.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas

AbstractDespite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.

EX103, a Novel CD20xCD3 Bispecific Antibody, Showed a Favorable Safety and Potent Single-Agent Antitumor Activity in Heavily Pretreated Relapsed/Refractory Patients with B-Cell Non-Hodgkin Lymphoma

Introduction Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States, and relapsed or refractory (R/R) B cell NHL had a poor prognosis. In recent years, T cell engaging bispecific antibody (TCB) emerged as a promising therapy. Nevertheless, severe cytokine release syndrome (CRS) remains to be a significant challenge in TCB treatment. To overcome this issue, we designed a new CD20xCD3 bispecific antibody (EX103) with a lower affinity to CD3. In the non-human primate tox study, EX103 induced much lower IL-6 release. Preliminary data from dose escalation part of Phase I clinical study demonstrates that EX103 has an encouraging safety and robust single-agent antitumor activity trend, even at low doses, in heavily pretreated R/R B-NHL patients. Method The dose-escalation part (8 dose cohorts, ranging from 1.2 to 36 mg) of this Phase I, multicenter, single-arm, open-label clinical trial has enrolled R/R CD20+ B-cell non-Hodgkin lymphoma subjects at 4 study sites in China. Objectives include safety, dose finding (RP2D), and antitumor activity. Eligible patients in each cohort received intravenous(iv) step-up doses of EX103 (with 1 priming dose and 2 intermediate doses followed by 1 target dose of EX103) administered in a 28-day dose limiting toxicity (DLT) observation period, and then received a target dose every 2 weeks for up to 12 cycles until disease progression or unacceptable toxicity. Response rates reported are based on the Lugano criteria (2014). Results As of June 2023, 5 cohorts (target dose from 1.2 to 18 mg) of the dose-escalation were completed. Among 13 evaluable patients , 9 of them are aggressive B-NHL (5 Diffuse large B-cell lymphoma (DLBCL), 3 Follicular lymphoma (FL) grade 3B, and 1 Mantle cell lymphoma (MCL)), 2 of them are indolent B-NHL (1 FL grade 1-3A, 1 Marginal zone lymphoma (MZL)), and 2 of them are Chronic lymphocytic leukemia (CLL). No DLT was observed, and the maximum tolerated dose (MTD) was not reached. The most common adverse events (AEs) were CRS, pyrexia, neutropenia, thrombocytopenia. All CRS were grade (Gr) 1-2, no Gr 3 or higher CRS. Most CRS events occurred in first or second treatment cycle, and all CRS related clinical symptoms were resolved within 48 hours. No Immune effector cell-associated neurotoxicity syndrome (ICANS) or other clinically significant neurologic AEs were reported. Among those patients, the median age was 51 years (range 43-66) and median number of prior lines of treatment was 5 (range 2-8). The preliminary Disease Control Rate (DCR) is 84.6% (11/13). Among 9 aggressive NHL patients, the overall response rate (ORR) was 67.7 % (6/9), including 3 DLBCL patients (1 each in 6 or 12 or 18 mg cohorts) and 1 MCL patient (in 3 mg cohort) achieving CR, and 2 grade 3B FL patients achieving PR (1 each in 6 or 18 mg cohorts). Both indolent NHL patients (1 FL (Grade 1-3A) and 1 MZL in 12 mg cohort) achieved PR and the preliminary ORR for indolent NHL was 100.0 % (2/2). Of 2 CLL patients, 1 achieved SD (3mg cohort). It is worth mentioning that two of the patients who failed prior CAR-T treatment had achieved PR after received 6-14 week treatment of EX103. Both patients are still under EX103 treatment. Conclusions Although this study has a limited number of subjects so far and the findings are preliminary, the available dose-escalation data demonstrate that single-agent EX103, even at low doses (3 or 6 mg), exhibits remarkable antitumor activity and favorable safety. Furthermore, EX103 demonstrates promising efficacy in heavily pretreated patients with R/R B-NHL, including some who have previously failed CAR-T treatment. The safety and efficacy of EX103 will be further evaluated in an ongoing clinical study.

Efficacy and Safety of Autologous Stem Cell Transplantation Combined with Chimeric Antigen Receptor T-Cell Therapy in the Treatment of Refractory/Relapsed B-Cell Lymphoma

Background Autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CART) are salvage therapies that are utilised for the treatment of relapsed or refractory (R/R) B-cell lymphoma. However, whether the combination therapy of ASCT and CART (ASCT-CART) can improve the survival of R/R B-cell lymphoma remains unknown. A im The objective is to explore the effectiveness and safety of ASCT-CART in the treatment of refractory/relapsed B-cell lymphoma and compare the effects of disease status before ASCT-CART on patient survival. Methods From October 2019 to October 2022, 49 patients with R/R B-cell lymphoma tract were enrolled. The male/female ratio was 1.2：1, with a median age of 40 years (range, 16-69 years).The diagnosis included diffuse large B-cell lymphoma (DLBCL) (n=31）, High-grade B-cell lymphoma(n=8), Primary mediastinal B-cell lymphoma (PMBCL) (n=7), Burkitt lymphoma (BL) (n=2) and Richer (n=1). Among them , stage III-IV accounted for 43/49 (87.8%) and GCB subtype 22/49 (44.9%)，and received a median of 7 cycles（3-14）of prior treatment, previous radiotherapy was 8/49 (16.3%), and previous other target CART patients were 20/49 (40.8%).The disease status of patients before ASCT-CART was 23 patients in complete remission, 17 patients in partial remission, 3 patients with stable disease, and 6 patients with progressive disease.Patients were treated with BEAM and fludarabine before ASCT. Autologous stem cells were transfused with D0, and the median number of CD34+ cells was 4.14*106/kg（range, 0.7-12.99*106/kg）. CART cells were transfused on D1, and the median infusion of CART cells was 2.06*106/kg（range, 0.07-9.5*106/kg）. Results In efficacy assessment at 3 months after treatment, the objective response rate (ORR) was 40/49(81.6%), and the complete response rate (CRR) was 38/49 (77.6%).After a median follow-up of 23.1 months, the median overall survival (OS) was not reached, with 1-year OS being 81.6%, 2-year OS being 76%, and 3-year OS being 72.3%（Figure 1A）. Median progression-free survival (PFS) was not reached, with 1-year PFS at 73.5%, 2-year FFS at 70.5%, and 3-year FFS at 66.6%（Figure 1B） . Neutrophil and platelet engraftment in all cases on median days 16 (range 10-62 days) and 16 (range 7-52), respectively.Grade 3 or higher cytokine release syndrome (≥grade 3 CRS) and immune efector cell-associated neurologic toxicity syndrome (≥grade 3 ICANS) events occurred in 22.4%（11/49） and 4.1%（2/49）of the patients, respectively.In the 3-month efficacy evaluation of CR group before ASCT-CART treatment, ORR was 21/23(91.3%) and CRR was 20/23(87.0%). ORR and CRR were 19/26(73.1%) and 18/26 (69.2%) in patients who did not reach CR before ASCT-CART treatment.The 3-year OS and 3-year PFS were 91.3% and 82.6% in CR group before ASCT-CART treatment（Figure 1C,D）. The 3-year OS and 3-year PFS in the non-CR group were 58.6% and 54.6% respectively（Figure 1C,D）. Patients in CR group before ASCT-CART treatment had significantly prolonged OS and PFS (P=0.0243) and OS (P= 0.0720). Summary/Conclusion The ASCT-CART therapy could enhance its the remission rate and long-term efficacy in the treatment of advanced relapsed/refractory B-cell lymphoma with controllable safety. Patients who were in remission before ASCT-CART therapy achieved a longer term remission after ASCT-CART cell therapy.

Panel Interview of Oncology Practices with Emergent Experience of Teclistamab in the Real World: The Tec-Pioneer Study

Background Teclistamab was recently approved as the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy with personalized weight-based dosing for relapsed or refractory multiple myeloma (MM). Given its novelty, there are immediate needs for data based on real-world (RW) practices to optimize operational processes and improve experiences while ensuring patient safety in the RW. The aims of this study were to describe how US clinicians with early RW experience with teclistamab (1) manage the step-up dosing (SUD) and transition of care (ToC) to and from referring sites; (2) monitor, manage, and prevent adverse events (AEs), i.e., cytokine release syndrome (CRS), infections, and immune effector cell-associated neurotoxicity syndrome (ICANS); and (3) perceive desired future care models for optimal patient care. Methods Between April and July 2023, 60-minute, 1-on-1 in-depth structured interviews were conducted virtually with hematologists and oncologists who had treated patients with teclistamab in a RW setting. Interviews elicited clinicians' current SUD and ToC processes in their practices, AE management, and perspectives on SUD model evolution. A subsequent 90-minute roundtable discussion was held in June 2023 to discuss interview findings. Results A total of 20 clinicians representing 19 practices across 14 states completed interviews: 84% (16/19 practices) treated >50 patients with MM monthly, 69% had treated >10 patients with teclistamab, and 90% were academic medical centers. Of these interviewees, 10 participated in the roundtable discussion, joined by 3 community clinicians without teclistamab experience. Among the 19 interviewed practices, 14 (74%) were administering SUD exclusively in inpatient settings. This was being done predominantly (86%; 12/14) in 1 continuous admission with a planned length of stay of 7 days, and with 71% (10/14) following a day 1-3-5 dosing schedule. Five practices reported using outpatient models (Figure 1). The sophistication of outpatient models varied and depended on multiple factors at the practice level, including prior outpatient cellular therapy experience, staffing/facility structure, patient volume, and outpatient monitoring capability. Most (95%) of the interviewed practices initiated teclistamab for patients referred from community practices; 53% transferred at least 1 patient back to a referring practice to continue teclistamab. The time to transfer ranged from 2 weeks to 2 months to (1) ensure that patients were responding to and tolerating treatment prior to transfer and (2) recover any financial loss from inpatient SUD. Community clinicians preferred to resume care of their patients once patients were deemed clinically stable. More than half (68%) of practices reported leveraging existing CAR-T protocols for AE monitoring and management. Patients were typically monitored for CRS every 4 hours for vital signs and daily for complete blood count, comprehensive metabolic panel, C-reactive protein, and ferritin. CRS prophylaxis with tocilizumab was reported by 11% of practices. 74% (14/19) of practices used tocilizumab for treatment of grade 2 or higher CRS. 94% (17/18) of reporting practices utilized intravenous immunoglobulin for primary infection prophylaxis, typically at a dose of 0.4 g/kg every 4-8 weeks to maintain an IgG level above 400 mg/dL. ICANS risk was considered low, and corticosteroids were the preferred treatment for ICANS. Payer reimbursement, treatment availability and lack of approved indications were noted as barriers for certain prophylactic treatments. Clinicians indicated a desire to administer SUD in an outpatient setting for patient convenience and to reduce healthcare resource use. Comorbidities, tumor burden, and caregiver support were key patient-level factors to be considered for outpatient SUD. Remote patient monitoring was a potential solution to enhance the outpatient SUD administration. Conclusions The results indicated diverse RW administration and patient management strategies in practices with early familiarity with teclistamab, and consolidated practice-based experiences to help inform clinicians employing this innovative therapy. As patient care models evolve, outpatient or community-based SUD may become more common in the future. Ongoing evidence generation on RW treatment outcomes of various SUD models and AE management strategies is warranted.

Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Introduction Axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) have been approved for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). In some cases, patients are identified as being in radiographic complete remission (CR) after CAR T cell manufacturing. However, there are limited studies with small sample sizes that have reported outcomes for this specific group, and prospective data are lacking. We hypothesize that patients with LBCL who are in CR prior to CAR T cell infusion have favorable progression-free survival (PFS) and overall survival (OS) with lower toxicity. Methods We analyzed CIBMTR registry data from adult patients with LBCL who received commercial axi-cel, liso-cel, or tisa-cel infusion between 2018 and 2021 while in radiographic CR. Kaplan-Meier estimators were used to assess PFS and OS. The cumulative incidence of relapse, non-relapse mortality (NRM), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) was reported according to the consensus ASTCT criteria. Univariable hazard ratios (HR) for PFS and OS were analyzed using a Cox regression model to evaluate the prognostic impact of each variable. A forest plot was generated to display relevant factors. Results A total of 134 LBCL patients in CR prior to CAR T cell infusion were identified across 53 centers. The median follow-up was 24.3 months (range 0.9-49.4). Baseline demographics are presented in Table 1. After CAR T infusion, 7/134 patients (5.2%) proceeded to subsequent transplant (6 allogeneic, 1 autologous). At two years post-infusion, the probability of PFS and OS was 43.5% (95% CI 34.4-52.8) and 63.8% (95% CI 54.4-72.6), respectively. The cumulative incidence of NRM at two years was 9% (95% CI 4.5-15.4), and the incidence of relapse/progression was 47.3% (95% CI 38.2-56.6). The rate of grade 3 or higher CRS was 3/134 (2.2%), with median time to onset of 3 days (range 1-16). Grade 3 or higher ICANS occurred in 11/134 (8.2%) with a median time to onset of 6 days (range 2-15). On univariate analyses, PFS was worse in patients with 5 or more lines of prior therapy before CAR T cell infusion (HR 2.39, 95% CI 1.18-484) (see Figure 1). The most common cause of death was relapse or disease progression, accounting for 26/46 (56.5%) deaths, followed by infection (8/46, 17.4%, including 4 (8.7%) from COVID-19), ICANS (2 out of 46, 4.3%), and other causes. Conclusions CAR T cell infusion in patients with LBCL who are in CR after receiving two or more lines of prior therapy is feasible, with a subset of patients remaining free of progression at two years. The high NRM rate of 9% at two years highlights the importance of continued follow-up in this at-risk population. The CIBMTR is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research.

Retrospective and Observational Study on CAR-T 19 Bridge Therapies in Pediatric, Adolescents and Young Adults

INTRODUCTION CAR-T therapy has revolutionized the treatment of B-ALL. The development of CAR-T therapy is a long and delicate process where once apheresis is done, a bridge period that least until CAR-T cells are infused starts. Meanwhile, the objective will be to maintain disease control, decrease tumor burden (TB) and prevent disease progression with no severe comorbidities by the administration of a bridge chemotherapy. That will decrease the risk of severe (grade 3-4 ASTCT) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) with an improvement of event free survival. Nevertheless, there is no consensus nor standard guidelines about bridge chemotherapy type, especially in pediatric patients. In this way, the main objective of this study is to identify CAR-T outcomes in pediatric, adolescents and young adults (AYA) diagnosed of BCP-ALL based on bridge chemotherapy. MATHERIAL AND METHODS An observational, retrospective and non-interventional study of Spanish pediatric and AYA under 24 years old diagnosed with BCP-ALL treated with tisagenlecleucel that have been registered by the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy (GETH-TC) CAR-T clinical database from years 2017 to 2022. Data have been collected from nine centers members of GETH-TC CAR-T workgroup: La Paz University Hospital, Sant Joan de Déu University Hospital, Virgen del Rocío University Hospital, Niño Jesús Pediatric University Hospital, Gregorio Marañón General University Hospital, Vall d'Hebron University Hospital, Salamanca Clinic University Hospital, Germans Trials i Pujol University Hospital and Valencia Clinic Hospital. General, pre-CAR-T, CAR-T-related and post-CAR-T variables have been analysed from GET-TC CAR-T database, highlighting those related to bridge therapy and related outcomes. Bridging chemotherapy was analyzed considering whether the patients had received high (myelosuppression ≥7 days) or low (myelosuppression ≤7 days) intensity schemes, or in contrast, immunotherapy. Fisher's Exact Test for count data and Log Rank test for Overall Survival (OS), Relapse Free Survival (RFS) and Duration of Response (DOR). Variables with p<0.05 value have been considered of statistical significance. RESULTS Baseline characteristics of the 103 patients are summarized in Table 1. CRS after infusion was presented in 86 (83.5%) patients. Grade 3-4 was developed in 4/29 (13.8%) with low pre infusion TB in contrast to 18/55 (32.7%) with high TB (p=0.001). Complete remission (CR) was achieved 87 (85.3%) patients. All patients (100%) with a low TB were in CR VS 78.2% in the high TB arm (p=0.015). Otherwise, 91.9% of those patients that received low intensity bridge chemotherapy or immunotherapy were in CR VS 71% of those where high intensity bridge was administered (p=0.027). With a median of 23.75 months, OS at 12 months was 62.23% (CI95% 51.71-74.89). No statistical significance was found between bridge chemotherapy groups, although it was higher in low intensity and immunotherapy group (68.33% CI95% 55.41-84.27) VS (57.89% CI95% 40.43-82.89) (p=0.11). With a median of 9.26 months, RFS at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, but was higher in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089). With a median of 8.28 months, DOR at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, with an increasing tendency in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089). In the multivariate analysis, grade 3-4 CRS HR 8.7 (CI95% 0.82-92) (p = 0.072) and high TB HR 4.7 (CI95% 1.1-20) (p = 0.038) were related with a decreased OS. CONCLUSIONS Receiving low intensity bridge or immunotherapy is related with high rates of CR. In the same way, in this group of patients there is tendency to achieve higher OS, RFS and DOR. This is the reason because its use should be prioritized avoiding those of high intensity bridge chemotherapy. High TB is an important risk factor related with a poor response and high grade CRS development, so it is essential to reduce TB previous CAR-T infusion in order to improve outcomes and reduce toxicities.

Myeloid Derived Suppressor Cell Kinetics in Peripheral Blood Correlate with Efficacy and Toxicity of CAR T Cell Therapy in Relapsed or Refractory B Cell Lymphoma

Introduction. CAR T-cell therapy is potentially curative for patients with relapsed or refractory B-cell lymphoma (BCL). However, about 60% of patients fail CAR T-cell therapy. Immune-related adverse events (irAE) like cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) occur in an inflammatory state. Myeloid-derived suppressor cells (MDSCs) expand during acute inflammation as steady-state hematopoiesis switches to emergency myelopoiesis. We hypothesized that the acute inflammatory conditions created by CAR T-cell therapy may alter MDSC kinetics and investigated MDSC expansion in the context of CAR T-cell efficacy and toxicity in BCL. Methods. Patients with BCL receiving standard-of-care CAR T-cell therapy were enrolled in a prospective sample collection study. Blood samples were collected before lymphodepletion (baseline), prior to and at early intervals after CAR T-cell infusion. Viable white blood cell (WBC) and MDSC counts were evaluated by multicolor flow cytometry. Phenotypically, MDSCs were defined as immature myeloid cells (CD11b + CD33 + HLA-DR -/low IL-4R +) and divided into monocytic (M-MDSC, CD14 +) and polymorphonuclear (PMN-MDSC, CD15 +) subsets. Clinical response was assessed by Lugano criteria at 1, 3 and 6 months. Incidence and severity of CRS and ICANS were recorded. Cell counts were analyzed by descriptive statistics and reported as mean ± standard error or fold-change from baseline. Kinetics of MDSCs in blood and correlation with clinical outcomes were evaluated by Wilcoxon matched pair signed rank t-test and Mann Whitney U-test. Results. Forty-three BCL patients (41 large BCL, 2 mantle cell lymphoma) were enrolled in the study. Median age was 64 (range 27-83), 32.6% were female. Racial and ethnic minority groups represented 14% of enrolled subjects. One patient developed grade 5 ICANS and was not evaluable for response. Thirty-seven (86%) developed leukopenia and all received granulocyte colony stimulating factor (G-CSF) starting on day 5 post-CAR T infusion. WBC count fell sharply from baseline following lymphodepletion (7.7E +05±8.6E +04 baseline vs 2.9E +05±9.2E +04/mL, p<0.0001) and continued to decline 2-3 days post-CAR T infusion (baseline vs 1.4E +05±2.1E +04/mL, p<0.0001) before returning to baseline within 1 week post-CAR T (i.e. within 3 days of G-CSF). MDSCs followed similar kinetics early on but significantly increased from baseline levels by 1-week post-CAR T (3.4E +03±5.8E +02 baseline vs 8.5E +03±1.7E +02 /mL, p<0.0001). This effect was mainly driven by an exuberant expansion of M-MDSC observed in 33/43 patients (median 6.1-fold increase from baseline at 1 week, range 0.5-4301). Seven patients (16.3%) had progressive disease (PD) at 1 month, 6 (13.9%) additional patients progressed at 3 months and 4 (9.3%) more progressed at 6 months after CAR T-cell infusion. M-MDSC expansion 1-week post-CAR T was only observed in 3/7 refractory patients compared with 28/35 responding patients (Fisher's exact test, p=0.0635). Patients who progressed at 3 months had poorer M-MDSC retention compared to patients with sustained response (1.7E +02±6.1E +01 PD vs 1.4E +03±2.4E +01/mL at 2-week post-infusion, p<0.1). Similarly, patients who progressed at 6 months had lower M-MDSC compared with sustained responders (2.0E +02±8.1E +01 PD vs 4.5E +02±1.4E +02 ml at 1-month post-infusion, p<0.05). Thirteen patients (30.2%) developed > grade 2 CRS and had lower PMN-MDSC retention rate 2-3 days post-CAR-T compared with those with no/low-grade CRS (4.4E +02±2.6E +02 vs 1.4E +03±3.9E +02/mL, p<0.05). Similarly, patients who had ICANS > grade 2 (n=14, 32.5%) had lower PMN-MDSC early retention compared to those with no or low-grade ICANS (5.0E +02±2.5E +02 vs 1.5E +03±4.1E +02/mL, p<0.05). Further analyses are currently underway to bridge these findings with the kinetics of CAR T-cells and T-cell repertoire post-CAR T. Conclusions. The proinflammatory milieu after CAR-T and the use of G-CSF can lead to significant expansion of M-MDSCs. Rather than an impediment to CAR T therapy, M-MDSC expansion and retention are associated with favorable clinical response and PMN-MDSC with a lower risk of developing high grades CRS or ICANS. Whether MDSCs play a mechanistic role remains to be elucidated, but they may have a role as a biomarker in predicting outcomes after CAR T-cell therapy in BCL.

A Real-World Comparison of Idecabtagene Vicleucel and Ciltacabtagene Autoleucel CAR-T Therapy: A Single Center Experience for Relapsed/ Refractory Multiple Myeloma

Background Chimeric antigen receptor modified T-cell therapy is a promising new treatment for patients with heavily pre-treated multiple myeloma (MM). BCMA (B-cell maturation antigen) directed therapies including idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-Cel) are currently approved for use in patients with four prior lines of therapy. Both therapies have shown efficacy producing a high overall response rates and durable responses. Both are second-generation designs with identical endodomain (CD3ζ - 4-1BB) to target BCMA on the target cells for patients with relapsed and refractory MM who have been triple-class exposed. The two distinct differences are ectodomain structure and recommended dose. In this single center retrospective study, we report our experience with the use of both CAR-T therapies in patients with heavily pre-treated MM. Methods Following institutional review board approval, we included all patients with MM who were treated with commercially approved BCMA directed CAR-T therapy. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Safety outcomes included the incidence and severity of adverse events (AEs). AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0). Cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) were graded as per the American Society for Transplantation and Cellular Therapy criteria. Efficacy outcomes included overall response rates (ORR), progression free survival (PFS), overall survival (OS), duration of response (DOR). Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). PFS was defined as time from initiation of treatment to progression of disease or death whichever occurred first. OS was defined as time from initiation of treatment to death. The IMW response criteria was utilized for response assessment. Results We identified 56 patients who were treated consecutively at Hackensack University Medical Center between 6/28/2021 and 7/3/2023. 53 patients had data available for evaluable responses and were included in our analysis. 35(66%) patients received Ide-cel, whereas 18(34%) patients received Cilta-Cel. For the entire cohort, 30(56.6%) were male, median age was 69.6 years median time from diagnosis to treatment was 8.1 years. Patients had received a median of 5 prior lines of therapy. 50(94.3%) patients were triple class refractory, all except one patient (98.1%) had a prior autologous stem cell transplant (ASCT). 27(60%) patients had high risk FISH defined as those with t(4;14), t(14;16), 17p(-) or 1q(+), 24(60%) patients were ISS-2 or 3 at diagnosis. Treatment was overall well tolerated, with only one therapy related mortality, 42(79.3%) patients experienced CRS, with only 1(1.9%) having grade 3 or higher CRS. 6(11.3%) patients experienced ICANS, with 2(3.8%) having grade 3 or higher ICANS. Baseline characteristics are summarized in table 1. Overall response rate for the entire cohort was 75.4%, with a median PFS of 11.9 months, median DOR of 13.2 months and mOS was not reached (NR). The median ORR for cilta-cel vs ide-cel was 94.4 % and 65.7% (p=0.01) respectively. The median PFS for cilta- cel vs ide-cel was NR vs 10.9 months (p=0.09) respectively (Figure 1), follow-up being very short for cilta- cel. Baseline characteristics, safety and efficacy data for the cohort and comparison between the two therapies are summarized in table 1. Conclusions In our single center experience, cilta-cel has shown superiority in terms of efficacy compared to ide-cel. Having said that, the authors do strongly recognize that longer manufacturing time for cilta-cel introduces a bias in favor of using ide-cel for patients with more aggressive/rapidly progressing disease, which may therefore result in inferior outcomes. The safety profile for both therapies is very similar and both offer promising results to patients with MM.

Dasatinib and CAR-T Cell Therapy for Newly Diagnosed Ph-Positive Acute Lymphoblastic Leukemia in Adults

Introduction The use of tyrosine kinase inhibitors has improved outcomes of Ph-positive Acute lymphoblastic leukemia (ALL), but combinations with other agents are needed to achieve molecular response. CAR-T cell therapy has made a breakthrough in refractory or relapsed ALL, but has not yet been applied in newly diagnosed patients. Methods We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL. Dasatinib in combination with a two-week vincristine and glucocorticoids regimen were administered, followed by sequential infusions of CD19 and CD22 CAR-T cells. All patients received single-agent dasatinib maintenance after CAR-T cell therapy. The primary endpoint was complete molecular response (defined as undetectable BCR/ABL1 transcript with a sensitivity of 0.001%) in the bone marrow after this treatment. Here we report initial results from this study. Results At the cut-off date of 31 May 2023, 18 patients have received CD19 CAR-T cell infusions, and 14 of these patients have received subsequent CD22 CAR-T cell infusions. At the end of induction therapy, the complete hematologic remission rate was 100%, and 27.8% (5/18) of the patients had a complete molecular response. The percentage of complete molecular response increased to 72.2% (13/18) after CD19 CAR-T cell therapy, and increased further to 76.9% (10/13) after CD22 CAR-T cell therapy (1 patient has not been evaluated). Notably, of the 5 patients who did not achieve complete molecular response after CD19 CAR-T cell therapy, 4 have received CD22 CAR-T cell therapy, of which 1 eventually achieved complete molecular response and 2 experienced relapses. One patient had a CD19+ CD22+ relapse accompanied by mutations in BCR/ABL1 (F317L and Y253H) and the other patient had a CD19dim CD22+ relapse. After a median follow-up of 13.5 months, 16 patients remained in complete hematologic remission, and 14 patients remained in sustained complete molecular response. No patient received allogeneic stem cell transplantation. No grade 3 or higher cytokine release syndrome or Immune effector cell-associated neurotoxicity syndrome was observed during CAR-T cell therapies. Conclusions Dasatinib in combination with CAR-T cell therapy has enabled chemotherapy-free treatment in newly diagnosed Ph-positive ALL. This treatment is characterized by high complete molecular response, high long-term survival, low toxicity and short treatment cycles.

Mitigating the Risk of Cytokine Release Syndrome (CRS): Preliminary Results from a DLBCL Cohort of Epcore NHL-1

Background: Epcoritamab SC, a CD3xCD20 T-cell-engaging bispecific antibody, has recently been approved by the US FDA for the treatment of adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. As a single agent, epcoritamab SC has demonstrated deep, durable responses with a manageable safety profile in patients with R/R large B-cell lymphoma in the expansion portion of the phase 1/2 EPCORE ™ NHL-1 trial (NCT03625037). Cytokine release syndrome (CRS) events in the dose expansion part of the trial were primarily low grade (49.7% overall; 31.8% grade [G] 1, 15.3% G2, 2.5% G3); timing was predictable, and the majority of events occurred following the first full dose at cycle 1 day 15 (C1D15). To mitigate CRS in dose expansion, subcutaneous administration, step-up dosing, and premedication, including prednisolone, were used. Here, we present preliminary results from a DLBCL optimization cohort of the EPCORE NHL-1 trial that further investigates mitigating the risk of CRS in patients treated with epcoritamab SC monotherapy. Methods: Adult patients with R/R CD20 + DLBCL (previously treated with ≥2 lines of systemic therapy) were enrolled to receive epcoritamab SC in 28-d cycles as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received 2 step-up doses (step-up dose 1, 0.16 mg, and step-up dose 2, 0.8 mg) followed by 48-mg full doses. To further mitigate CRS, C1 of the optimization cohort included mandatory administration of dexamethasone 15 mg as premedication on D1, D8, D15, and D22 and as prophylaxis on D2-4, D9-11, D16-18, and D23-25, and diphenhydramine and acetaminophen as premedication on D1, D8, D15, and D22 with each dose. In C1, it was strongly recommended that patients be well hydrated and that antihypertensive medications be held for 24 h prior to epcoritamab SC administration. Patients were also encouraged to monitor their temperatures following the first 4 doses. Hospitalization and inpatient observation were optional. The primary endpoint was rate of G2 or higher CRS and all CRS events. Secondary pharmacokinetic/pharmacodynamic (PK/PD) analyses were performed. Results: As of April 21, 2023, 24 patients (median age, 65 y) had been treated in this DLBCL optimization cohort. The median number of prior lines of treatment was 3 (range, 2-10), 75% of patients were primary refractory, 71% had stage IV disease, and 58% had prior CAR T. With a median follow-up of 1.3 mo, 18 patients (75%) remained on treatment. The most common treatment-emergent AEs (TEAEs) of any grade were infections (38%; COVID-19, 8%), fatigue (21%), CRS (17%), headache (17%), anemia (13%), constipation (13%), decreased platelet count (13%), dyspnea (13%), hyponatremia (13%), insomnia (13%), and neutropenia (13%; febrile neutropenia, 4%). All CRS events were G1; 1 patient was treated with anticytokine therapy (tocilizumab); there were no treatment discontinuations due to CRS. The most commonly observed CRS symptom was fever (100%). Most CRS events (3/5 events) occurred following the first full dose on C1D15. The median time to CRS resolution was 3.5 d (range, 1-25) and all events resolved. Compared with the DLBCL expansion cohort, circulating interleukin 6 (IL-6) levels were decreased 24 h after the first full dose (C1D15) of epcoritamab SC ( Figure). The median circulating IL-6 level at C1D16 was lower in the dose optimization cohort at 6.92 pg/mL (2.97 pg/mL at C1D1 predose), compared with 21.24 pg/mL (2.45 pg/mL at C1D1 predose) in the DLBCL expansion cohort. The addition of dexamethasone and fluids in optimization did not appear to interfere with T-cell margination or T-cell activation, given that the fold-change values of T-cell absolute counts and percentage of activated T cells were similar between DLBCL optimization and expansion cohorts at C1D16. No patients experienced ICANS, clinical tumor lysis syndrome, or fatal TEAEs. Conclusions: Encouraging preliminary data from this DLBCL CRS optimization cohort, which incorporates prophylactic dexamethasone and hydration of patients during cycle 1, indicate that this approach is effective in decreasing rates and severity of CRS. Data with additional patients and follow-up will be presented.

Deliriogenic Medication Use in Older Adults Receiving CAR-T Correlates with Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Background Chimeric Antigen Receptor T-Cell therapy (CAR-T) is increasingly used for older adults with hematologic malignancies. Real-world outcomes suggest chronological age alone does not have a strong impact on CAR-T outcomes or associated adverse effects, including cytokine release syndrome (CRS) and ICANS. A subset of CAR-T-eligible older adults have comorbidities managed with deliriogenic medications including opioids, benzodiazepines, and sedatives. Their effects may be exacerbated during prolonged hospitalizations for CAR-T therapy, precipitating delirium, which has clinical overlap with ICANS including inattention, altered sensorium, and reduced responsiveness. We hypothesized that exposure to high-risk deliriogenic medications may have an impact on observed ICANS incidence in older adults undergoing CAR-T therapy. Methods We performed a single-center retrospective analysis of all patients age 60 or older who received a FDA-approved CAR-T product for a hematologic malignancy at two UCLA Health hospitals from 8/2018 to 12/2022. We collected exposure to deliriogenic medications including opioids, benzodiazepines, sedatives/hypnotics, and anticholinergics prior to and during CAR-T hospitalization. Correlation with incidence of CRS and ICANS of any grade was modeled using logistic regression. If exposure to high-risk medication was found to be statistically significant, correlation with CRS and ICANS by each individual class of high-risk medications was analyzed. A multivariable logistic regression was performed including each predictor of CRS or ICANS that was statistically significant at the p<0.1 level in univariable regression. Results A total of 84 patients age 60 or older received an FDA-approved CAR-T product for a hematologic malignancy at our institution between 8/2018 to 12/2022. Patients ranged in age from 60 to 84 years (median 70). Baseline characteristics for all patients by cellular therapy target are shown inTable 1. The most common histology included was DLBCL (75%), followed by MCL (13%), MM (8%), ALL (2%), and FL (1%). With a median follow up of 9.6 months, CRS and ICANS of any grade were experienced by 76% and 45% of total patients with a median time to onset of 4 days and 5 days, and grade 3 or higher CRS and ICANS was experienced by 1% and 17% of patients, respectively. Most patients had exposure to a high-risk deliriogenic medication prior to and during their hospitalization for CAR-T infusions (57% and 74%, respectively). Age, performance status, and deliriogenic medication use prior to admission were not correlated with incidence of CRS or ICANS as shown in Table 2. However, exposure to high-risk medications during hospitalization was highly correlated with ICANS incidence (OR 2.64, p<0.001). In a multivariable model CAR-T product costimulatory domain (4-1BB vs. CD28, OR 6.21, p= 0.01), number of prior lines of therapy (OR 6.21, p=0.03), and exposure to opioids during admission (OR 10.5, p<0.001) were correlated with incidence of ICANS. Conclusion In our single-center real-world analysis of older adults receiving a FDA-approved CAR-T therapy, the CAR-T product infused, number of prior lines of therapy, and exposure to opioids during CAR-T hospitalization were correlated with incidence of ICANS. Increased incidence and severity of ICANS depending on CAR-T product has been well-described, but interestingly, our data suggest use of opioids in the immediate post-CAR-T infusion setting may also be a significant risk factor for ICANS. Limitations to our analysis include single-center practice patterns, unclear timing of exposure to deliriogenic medications to onset of ICANS, burden of comorbidities, and lack of baseline standardized cognitive and geriatric assessments in our elderly cohort. In addition to careful selection of CAR-T product in older adults, our findings support minimization of high-risk deliriogenic medications in the immediate post-CAR-T inpatient setting to mitigate risk of ICANS in this vulnerable patient population. Effects of ICANS and its treatments on outcomes and survival will be reported as this cohort matures.

Blinatumomab consolidation post–autologous stem cell transplantation in patients with diffuse large B-cell lymphoma

AbstractOutcomes in patients with relapsed diffuse large B-cell lymphoma (DLBCL) who undergo autologous stem cell transplant (auto-SCT) are poor. Blinatumomab is a CD3/CD19 bispecific T-cell engager that directs cytotoxic T cells to CD19+ cells. Here, we performed a pilot study of blinatumomab consolidation after auto-SCT for 14 patients with DLBCL or transformed follicular lymphoma. All patients underwent standard-of-care auto-SCT with carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning followed by 1 cycle (4 weeks continuous infusion) of blinatumomab consolidation starting at day 42 after auto-SCT. All 14 patients treated on study completed BEAM auto-SCT and 1 cycle of posttransplant blinatumomab. Five patients developed grade 1 cytokine release syndrome (CRS), with no grade 2 or higher CRS. Immune effector cell–associated neurotoxicity syndrome was not observed. Patients were followed up for 3 years after auto-SCT, with median follow-up of 37 (range, 12-65) months. One-hundred days after auto-SCT (1 month after blinatumomab consolidation), 12 patients (86%) had achieved complete remission. At 1 year after auto-SCT, 7 patients (50%) remained in CR, and 1 patient had died of progressive disease. Patients who relapsed had a lower CD8:CD4 T-cell ratio before starting blinatumomab than patients who remained in remission. This pilot study demonstrates blinatumomab consolidation after auto-SCT is safe and well tolerated. Strategies to increase the CD8:CD4 ratio and use additional cycles of consolidation in a larger randomized trial are needed to confirm the efficacy of consolidation with blinatumomab after auto-SCT. This trial was registered at www.clinicaltrials.gov as #NCT03072771.