Prior CAR Research Articles

Analysis of polyfunctionality for enhanced BAFF-R CAR T-cell therapy for hematologic malignancies

AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic strategy for eradicating human cancers. Their therapeutic success and durability of clinical responses hinges, in large part, on their functional capacity, including the ability of these engineered cells to simultaneously expand and persist after infusion into patients. CD19 CAR T-cell polyfunctionality, assessing the simultaneous functions of cytokine production, proliferation, and cytotoxicity has been reported to correlate with clinical outcomes. Assay optimization is potentially limited by the heterogeneous nature of CAR T-cell infusion products and target specificity. We optimized a single-cell platform for polyfunctionality using CAR T-cell products manufactured from healthy donors, engineered against a novel target, B-cell–activating factor receptor (BAFF-R) and validated the protocol using CD19 CAR T cells. We observed distinct qualitative differences between BAFF-R and CD19 CAR T cells relative to the proportions of stimulatory vs effector cytokines, based on target antigen density, and, generally, CD19 CAR T cells exhibited lower indices of polyfunctionality. Finally, we applied our assay to the autologous BAFF-R CAR T-cell product generated from the first patient with non-Hodgkin lymphoma treated in an ongoing clinical trial who had progressed after prior CD19 CAR T-cell therapy. We observed robust indicators of polyfunctionality, which correlated with successful CAR T-cell expansion after infusion and achievement of durable complete remission ongoing after 18 months. The precise identification of factors determining the role of BAFF-R CAR T-cell fitness in toxicity and clinical outcome will require the application of this robust assay in the analysis of additional treated patients. This trial was registered at www.ClinicalTrials.gov as #NCT05370430.

PMB-CT01 (BAFFR-CAR T cell) therapy to examine preliminary safety and clinical responses in patients with B-cell malignancies who are ineligible for or failed CD19-directed therapy, including CD19-negative disease.

6534 Background: CD19-targeted therapies have shown remarkable efficacy in patients with B-cell malignancies. However, relapse with CD19 loss as a mechanism of tumor escape is common and represents a serious challenge. Patients who are ineligible for or have failed prior CD19-directed therapy have limited salvage options and a very poor prognosis. The B-cell activating factor receptor (BAFF-R) is functionally expressed in B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphomas (NHL), including in patients with CD19-negative relapse (Qin et al., Sci Transl Med. 2019). As a critical regulator of B-cell function and survival, BAFF-R may be less prone to downregulation by tumors as a mechanism of antigen escape. Methods: We are conducting two phase 1 clinical trials of BAFFR-CAR T cells in patients with relapsed/refractory (r/r) B-ALL (NCT04690595) and NHL (NCT05370430). Primary endpoints are dose limiting toxicities (DLTs) and all other toxicities. Secondary endpoints include response rate, minimal residual disease (MRD) negative rate, PFS and OS. Response is evaluated using European LeukemiaNet criteria for B-ALL and Lugano 2014 for NHL. Results: As of Feb. 1st, 2024, 1 B-ALL and 3 NHL patients have completed treatment and post-treatment evaluations. Each received 50M BAFFR CAR T cells (starting dose level in both trials). The B-ALL patient had CD19/CD20/CD22-negative disease, and had received prior blinatumomab. NHL patients #1 and #2 both had CD19-expressing mantle cell lymphoma (MCL) and had received prior CD19 CAR T cells. Patient #2 had also received a CD3/CD20 bispecific antibody. NHL patient #3 had CD19/CD20-negative T cell/histiocyte-rich large B-cell lymphoma (THRBCL) and had not received prior CD19 CAR T cells. There were no DLTs, all patients had Gr. 1 cytokine release syndrome, and 2/3 NHL patients had Gr. 1 immune effector cell-associated neurotoxicity syndrome. Robust CAR T cell expansion was seen in all patients with a peak on days 12-14 post-infusion. The B-ALL and the 2 MCL patients reached MRD-negative complete response (CR) at 1 month post-treatment. The THRBCL patient had partial response (PR) at 1 month that converted to CR at 3 months. The B-ALL patient successfully transitioned to allogeneic HCT while in CR at 3 months post-infusion. Responses are ongoing in all NHL patients at 14, 10, and 8 months for patients #1, #2 and #3, respectively. Additional patients have been enrolled at the next dose level (200M CAR T cells). Results for these patients will be presented at the meeting. Conclusions: With a 100% CR rate at 3 months in the first 4 patients and durable responses at dose level 1, BAFFR-CAR T cells are a promising therapeutic option for patients with r/r B-cell malignancies who are ineligible or failed prior CD19-targeted therapy, including with CD19 antigen loss. Clinical trial information: NCT04690595 , NCT05370430 .

Epcoritamab + R-DHAX/C in transplant-eligible patients (pts) with high-risk relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7032 Background: While high-dose therapy (HDT)–autologous stem cell transplant (ASCT) is potentially curative for pts with R/R DLBCL, many do not receive this treatment (tx) due to insufficient response to salvage chemoimmunotherapy; better options are needed. Epcoritamab is a CD3xCD20 bispecific antibody with efficacy and safety in R/R DLBCL as a single agent and in combination. We report updated data from epcoritamab in combination with rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) in pts with R/R DLBCL eligible for HDT-ASCT, including high-risk pts (progressed within 12 mo of initial tx or primary refractory), from EPCORE™ NHL-2 (phase 1/2; NCT04663347). Methods: Adults with R/R CD20+ DLBCL eligible for HDT-ASCT received R-DHAX/C and epcoritamab (2 step-up doses, then 24- or 48-mg full doses) in 21-d cycles (Cs): QW, C1–3. If HDT-ASCT was deferred, pts could continue epcoritamab (21-d C: QW, C4; 28-d Cs: Q2W, C5–9; Q4W, C≥10) until disease progression. Primary endpoint was overall response rate (ORR; Lugano criteria). Results: As of Dec 15, 2023, 29 pts (median age, 58 y) received epcoritamab (24 mg, n=3; 48 mg, n=26) + R-DHAX/C. At baseline, 24 pts (83%) had progressed within 12 mo of initial tx, 19 (66%) had primary refractory disease (no response or relapse within 6 mo of initial tx), and 3 (10%) had prior CAR T. At 27.5 mo median follow-up, 16 (55%) pts had proceeded to HDT-ASCT and 2 (7%) remained on tx. ORR was 76% and complete response (CR) rate was 69% (Table). Median time to response was 1.4 mo (CR, 1.5 mo). At 24 mo, per Kaplan–Meier estimates, 60% of pts remained progression free, while 90% of pts who proceeded to ASCT (n=16) and 60% of pts who continued epcoritamab without ASCT (n=5) remained progression free; additionally, 90% of pts with CR who received ASCT (n=15) and 100% of high-risk pts with CR who received ASCT (n=12) remained in response. An estimated 86% of pts remained alive at 24 mo. The most common tx-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia (76%), anemia (59%), nausea (48%), and neutropenia (48%; febrile neutropenia, 17%). CRS was low grade (38% G1, 7% G2), resolved, and did not lead to tx discontinuation. ICANS (G2) occurred in 1 pt and led to tx discontinuation. There were no fatal TEAEs. Conclusions: Longer follow-up reaffirms the efficacy and feasibility of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Response rates were high and most pts proceeded to ASCT. Safety was manageable and consistent with prior data. These results, including new high-risk subgroup analyses, support future evaluation of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

Subcutaneous epcoritamab + GemOx in patients with relapsed or refractory DLBCL: Updated results from EPCORE NHL-2.

7037 Background: Gemcitabine + oxaliplatin (GemOx) is commonly used with rituximab to treat relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL); however, outcomes are suboptimal: 33% complete response (CR) rate; 5 mo median progression-free survival (PFS); 10 mo median overall survival (OS; Cazelles et al, Leuk Lymphoma 2021). We report additional efficacy and safety results of epcoritamab + GemOx in difficult-to-treat R/R DLBCL (EPCORE™ NHL-2 phase 1/2 trial, NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for autologous stem cell transplant (ASCT) enrolled to receive subcutaneous (SC) epcoritamab (2 step-up doses followed by 48-mg full doses) in 28-d cycles (C): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until unacceptable toxicity or disease progression. GemOx was given Q2W in C1–4. The primary endpoint was overall response rate (ORR) per Lugano criteria. Subgroup analyses by prior treatment (tx) and response were performed. Results: As of Sept 1, 2023, 97 pts with ≥6 mo of follow-up had received epcoritamab 48 mg + GemOx (median follow-up, 9.7 mo). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 55% had primary refractory disease, 38% had bulky disease (>6 cm), 30% had prior CAR T, and 9% had prior ASCT. Median age was 72 y, with 34% of pts ≥75 y. A median of 7 cycles of epcoritamab and 4 cycles of GemOx were initiated. At data cutoff, tx was ongoing in 46% of pts. ORR was 78% and CR rate was 55%. Median time to CR was 1.7 mo; median duration of CR was 13.3 mo. Additional efficacy outcomes are shown in the Table. Safety was consistent with previous reports. The most common tx-emergent AEs (TEAEs) of any grade (G) were hematologic AEs (68% thrombocytopenia; 59% neutropenia [6% febrile neutropenia]; 51% anemia) and CRS (51%). CRS was primarily low grade (27% G1, 23% G2), with only 1 pt experiencing G3 CRS; all events resolved and none led to tx discontinuation. ICANS was reported in 3 pts (G1, n=2; G3, n=1); all events resolved, but 1 pt discontinued tx. There were 13 fatal TEAEs; in 3 cases, the contribution of epcoritamab + GemOx could not be ruled out: COVID-19, multiple organ dysfunction syndrome, and small intestinal perforation. Conclusions: These long-term results continue to demonstrate that SC epcoritamab in combination with GemOx leads to deep, durable responses, which translate to high rates of PFS and OS in challenging-to-treat, high-risk pts with R/R DLBCL. CR rates were consistently high across prespecified subgroups. Higher CR rates in pts with 1 vs ≥2 pLOT indicate that earlier use may further improve outcomes. No new safety signals were identified. The benefit-risk profile of this combination supports the combinability of epcoritamab in R/R DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

Subcutaneous epcoritamab (SC epcor) administered outpatient (outpt) for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL): Results from phase 2 EPCORE NHL-6.

7029 Background: Epcor is the only SC CD3xCD20 bispecific antibody approved for R/R DLBCL. In initial protocols, hospitalization after the 1st full dose of epcor was required to monitor patients (pts) for and characterize CRS. The EPCORE NHL-6 trial assessed whether R/R DLBCL/FL pts treated with SC epcor across US community and academic sites could be safely monitored in the outpt setting. Methods: Eligible pts had R/R DLBCL or FL and at least 2 prior lines of therapy. Epcor was given in 28-d cycles [C]; C1 SUD: 0.16 mg then 0.8 mg, followed by 48 mg; C1–3: QW; C4–9: Q2W; C≥10: Q4W. Pts received safety education, including early identification and reporting of symptoms of CRS and ICANS, and were required to stay ≤30 min of the site of care for 24 h after the 1st full dose. Based on C1 optimization (OPT) findings from EPCORE NHL-1 (Vose ASH 2023, Abs 1729), the trial was amended to implement C1 OPT with hydration and dexamethasone after enrollment of 34 pts. Results: At data cutoff, 36 pts (23 DLBCL, 13 FL) received ≥1 dose of epcor (median cycles, 3). 13 and 23 pts were from US academic and community sites, respectively. Median age was 65 y, 67% of pts had extranodal disease, and 39% had prior CAR T. Any grade CRS occurred in 47% of pts and were mostly low grade (G1, n=9; G2, n=7; G3, n=1). Median time to onset of CRS after 1st full dose was 23 h. No CRS events led to discontinuation; 11 pts (31%) were treated with tocilizumab, 8 (22%) with corticosteroids, and 5 (14%) with both. ICANS occurred in 8% (all G1-2) with a median time to onset of 20 days from C1D1, and all resolved. Of 31 pts receiving the 1st full dose, 3 pts (10%) received epcor in the inpatient (inpt) setting while admitted for AEs other than CRS (pain management, leg injury, UTI, n=1 each). The remaining 28 pts (90%) received epcor and were monitored in the outpt setting. 12 total pts had 13 CRS events after the 1st full dose with CRS starting in the outpt setting in 10 pts (G1, n=6; G2, n=4). 7/28 (25%) pts initially monitored as outpts were subsequently managed as inpt for CRS. All 12 pts had resolution of CRS with a median time to resolution of 45 h. Conclusions: Pts with R/R DLBCL and FL were successfully treated with SC epcor and monitored in the outpt setting across different types of sites. CRS events occurring in the outpt setting were appropriately managed, and the observed CRS incidence and severity was comparable to that of the pivotal EPCORE NHL-1 trial. These data suggest that SC epcor can be safely administered and pts monitored outpt, and then managed inpt as needed for CRS. Enrollment is ongoing, and a larger dataset with C1 OPT including hydration and dexamethasone, which are anticipated to further lower CRS incidence and severity, will be presented later. Clinical trial information: NCT05451810 . [Table: see text]

Safety and efficacy of chimeric antigen receptor T-cell therapy for acute myeloid leukemia: A subgroup based meta-analysis

IntroductionAcute myeloid leukemia (AML) is a significant hematological malignancy in the United States, with a high mortality rate and limited treatment options. CAR T-cell therapy, a new and promising treatment, is being investigated for its efficacy and safety in AML. This meta-analysis aims to assess the safety and efficacy of CAR T-cell therapy in AML, considering various subgroups such as study location, study design, prior transplantation status, conditioning regimen, and CAR T-cell source. MethodsWe conducted a comprehensive literature review across multiple databases, adhering to PRISMA guidelines and focusing on studies concerning CAR T-cell therapy in AML. We included original articles in English and excluded non-original reviews, abstracts, and non-English studies. The risk of bias was assessed using the Cochrane ROBINS-I tool. Statistical analysis involved meta-analysis with Cochrane’s Q-test and I² statistic, using both fixed-effect and random-effects models, and assessed for publication bias. ResultsOur search yielded studies encompassing 57 AML patients treated with CAR T-cell therapy. The meta-analysis revealed a 48% incidence of complete remission with CAR T-cell therapy, varying significantly across subgroups based on study design, location, prior transplantation, conditioning regimen, and CAR T-cell source. The highest complete remission rates were observed in patients from China, those who had undergone prior hematopoietic cell transplantation, and those treated with fludarabine and cyclophosphamide conditioning regimen. Adverse events included graft-versus-host disease (7%) and cytokine release syndrome (53%). ConclusionsThis meta-analysis highlights the potential of CAR T-cell therapy in AML treatment, especially when integrated with certain prior treatments and conditioning regimens. The findings suggest a higher efficacy in patients with previous hematopoietic cell transplantation and specific conditioning regimens. Further large-scale, randomized trials are essential to confirm these findings and establish CAR T-cell therapy as a standard treatment for AML.

Treatment Outcomes with Standard of Care in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Real-World Data Analysis.

Despite new therapies for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), treatments with chemotherapy, single-agent rituximab/obinutuzumab, single-agent lenalidomide, or combinations of these agents continue to be commonly used. This retrospective study utilized longitudinal data from 4226 real-world electronic health records to characterize outcomes in patients with R/R DLBCL. Eligible patients were diagnosed with DLBCL between January 2010 and March 2022 and had R/R disease treated with ≥ 1 prior systemic line of therapy (LOT), including ≥ 1 anti-CD20-containing regimen. A total of 573 patients treated with ≥ 1 prior LOT were included (31.2% and 13.4% with ≥ 2 and ≥ 3 prior LOTs, respectively). Median duration of follow-up was 7.7months. Most patients (57.1%) were male; mean standard deviation (SD) age was 63 (14.7) years. Overall and complete response rates (95% confidence interval (CI) were 52% (48-56) and 23% (19-27). Median duration of response and duration of complete response were 3.5 and 18.4months. Median progression-free and overall survival (95% CI) was 3.0 (2.8-3.3) and 12.9 (10.1-16.9) months, respectively. Patients with a higher number of prior LOTs, primary refractoriness, refractoriness to last LOT, refractoriness to last anti-CD20-containing regimen, and prior CAR T exposure had worse outcomes (i.e., challenging-to-treat R/R DLBCL) compared with those without these characteristics. Outcomes in patients with R/R DLBCL treated with chemotherapy, single-agent rituximab/obinutuzumab, single-agent lenalidomide, or combinations of these agents remain poor, especially for those with challenging-to-treat R/R DLBCL. These findings underscore the unmet need for new, safe, and effective therapies, especially for challenging-to-treat R/R DLBCL populations.

Outcomes of Sequential CD19-Directed Therapies in Relapsed and Refractory Large B Cell Lymphoma

Multiple CD19-directed therapies are available for the treatment of relapsed and refractory (R/R) DLBCL, including CAR T cells, tafasitamab/lenalidomide (TL), and loncastuximab tesirine (lonca-T) (Sermer D., Blood Rev 2023). However, there are few data available on the efficacy of sequential CD19-directed therapies. We performed a retrospective study evaluating all patients with R/R LBCL treated consecutively with TL at 11 institutions from 8/2020 to 8/2022, identifying 178 patients. In this study, we specifically evaluate outcomes in patients who received anti-CD19 therapy prior to or after TL. The primary outcome of interest was progression-free survival (PFS) in TL recipients who previously received CD19-directed CAR T therapy, with overall response rate (ORR), complete response rate (CRR), and overall survival (OS) also evaluated. Outcomes of lonca-T and CAR T after TL therapy were evaluated. Data on CD19 expression was assessed on biopsies after TL; this was determined locally using flow cytometry or immunohistochemistry per institutional protocols. In subgroup analyses, ORR and CRR were compared using Fisher's exact test. PFS and OS were estimated using the Kaplan-Meier method, with differences tested using the log-rank test. Of 178 patients who received TL, 52 had received prior anti-CD19 CAR T therapy, at a median of 7.4 months before TL (Table 1). Median PFS was lower in prior CAR T recipients (1.6 mo, 95% CI 1.1-2.5) vs no prior CAR T (2.1 mo, 95% CI 1.8-3.2), with hazard ratio 1.46 (p = 0.04; Figure 1). Best ORR was lower in patients with prior CAR T exposure (15% vs 33%, p = 0.02) though CRR was not significantly different (15% vs 18%, p = 1.0). We specifically evaluated TL outcomes based on prior response to CAR T, given the previously identified association of refractory disease with poor TL outcomes (Qualls D et al., presented at ASH 2022). Of 19 patients who had progressive disease more than 6 months after CAR T, ORR and CRR to TL therapy were 31.6% (all responses were CRs); in 33 patients with refractory disease (less than CR or relapse within 6 months) after CAR T, ORR and CRR to TL were significantly lower, at 6.1% (p = 0.04). Median PFS after TL was shorter in CAR-refractory than CAR-relapsed disease, at 1.4 vs 3.5 months (HR 2.2, p = 0.02). Of 88 patients who received therapy after TL, 20 (23%) received lonca-T and 14 (16%) received CAR T. Data on survival and initiation of new treatment after CAR T or lonca-T was available, but response and progression data after CAR T or lonca-T therapy is pending. These data allowed an estimate of OS and event-free survival (EFS), defined as survival without initiation of a new treatment after CAR T or lonca-T. With a median 3.9 months' follow-up, median EFS after CAR T administration was 3.7 months (95% CI, 0.9 - 6.5), and median OS was 8.1 months (95% CI, 0.6 - 15.7). In patients who received lonca-T, with median 2.7 months' follow-up from initiation, median EFS was 2.8 months (95% CI, 0.9 - 4.7), and median OS was 3.5 months (95% CI, 1.2 - 5.7). When comparing CAR T and lonca-T to polatuzumab vedotin- or chemotherapy-based therapies after TL, there were no significant differences in OS or EFS. In patients who discontinued TL, 24 had a biopsy a median of 18 days after the last dose of tafasitamab. Of these, 13 (54%) were CD19-positive and 11 (46%) were CD19-negative. All samples obtained more than 21 days after tafasitamab (6/6) were CD19-positive, while 46% obtained within 21 days were CD19-positive. These time-dependent findings may reflect “epitope masking” by tafasitamab rather than CD19 loss, reflecting other recent reports (Fitzgerald K., Leuk Lym 2022; Duell J., Leuk Lym 2022). In patients receiving TL after CAR T, responses and PFS were lower than in patients without prior CAR T therapy; however, with disease that was not refractory to prior CAR T, results were similar to patients who had not had prior CAR T. This may reflect that refractory disease, regardless of prior therapy, is associated with shorter PFS, though the possibility of CD19-mediated mechanisms of resistance remains. Modest EFS and OS were seen in patients receiving CAR T therapy or lonca-T after already receiving TL, though this may also reflect the high-risk disease characteristics of this cohort. Overall, in a high-risk, real-world cohort of TL-treated patients, these data suggest that some patients may benefit from subsequent CD19-directed therapies, but better therapeutic options are needed.

Prior Immune Effector Cell Therapy, Is Not Associated with an Increased Infectious Risk of Subsequent Bispecific Antibody Therapy for Multiple Myeloma

Introduction: Bispecific antibodies (BisAb) are effective therapies for relapsed myeloma yet associated with high risk of potentially severe infections. A prior study from our center did not associate any baseline characteristics with 90-day risk of infection. In clinical practice patients are already receiving sequential immune effector cell therapy (IET; BisAb or CAR T) it remains unclear whether this compounds the infectious risk. Herein, we examined whether a prior T-cell redirecting therapy predisposes to increased risk of infection during subsequent BisAb. Methods: This is a single-center, retrospective analysis of patients receiving BisAb therapy targeting B-cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor-homolog 5 (FCRH5) between January 2017 and February 2023. BisAb treatment was considered a treatment event (TE) such that if a patient received two different BisAbs, this would be considered two separate TEs. We obtained clinical data from before BisAb therapy start date: prior CAR T therapy, prior BisAb therapy, and infections 90 days before TE). Infection data during the full duration of BisAb therapy was also collected from the time of the first priming dose until 30 days after the last BisAb dose. For follow up for infections, we included any TE with at least one target dose of BisAb. We utilized two-sample proportion tests to analyze the differences in rates of infections between the BCMA and non-BCMA groups. Results: 91 patients and 123 TE episodes were identified. The TE episodes consisted of 40 with BCMA-directed therapy, 48 with GPRC5D-directed therapy, and 35 with FcRH5-directed therapy. Of these 123 treatment episodes, 26 TEs had 1 prior CAR T and 2 TEs had 2 prior CAR T and 28 TEs had received 1 prior BisAb and 6 TEs had received 2 prior BisAb. The most common infections were viral (46.1%) followed by bacterial (30.4%) and fungal (5.2%). We evaluated the relationship between prior IET (either CAR T or BisAb therapy) and incidence of infections during and up to 30 days BisAb (Table 1). In TEs with at least 1 prior CAR T the incidence of infections was: 62.5% (BCMA), 44% (GPRC5D) and 64% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 62.5% vs 55% (p=1.0). In TEs with at least 1 prior BisAb, the incidence of infections following subsequent BisAB was 50% (BCMA), 100% (GPRC5D) and 50% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 50% vs 65% (p=0.6). In TEs without prior IET, the incidence of infections was 50% (BCMA), 42.8% (GPRC5D), 75% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 50% VS 52.9% (p=1.0). On comparing these cohorts, we found no significant differences between the BCMA and non-BCMA BisAb therapy for following groups: prior BiSAb, prior CAR T, and the group without prior IET. We evaluated TEs with infections in the 90 days prior to BisAb and their relationship to infections during the first 90 days following BisAb therapy. The infection rate in the 90 days following BisAb therapy increased in TEs with earlier infection in the 90 days before BisAb priming dose from 30% to 43% for BCMA and 34.9% to 45.9% for non-BCMA BisAb. Conclusions: In this retrospective study we found similar rates of infection between groups with and without prior IET exposure. In patients who had infections during the 90 days before BisAb therapy, there was an increase in infection rate from baseline of 13% for BCMA BisAb and 11% from non-BCMA BisAb in the first 90 days after BisAb therapy. This is the largest cohort to report real-world data on infections following BisAb therapy after prior IET.

Timing of Vaccination Impacts Serological Response to COVID-19 Myeloma Patients after BCMA-Targeted CAR T

Whereas COVID-19 mRNA vaccines have shown remarkable efficacy in the prevention of severe disease and mortality in healthy individuals, the effectiveness in cancer patients has been more variable. Patients with multiple myeloma (MM) are at a high risk for severe infection due to disease- or treatment-related immune suppression. Our prior work demonstrated that the immune response to SARS-CoV-2 immunization in MM patients with 2 doses of mRNA vaccine was suboptimal and that a 3rd dose significantly improved neutralization of viral variants. MM patients undergoing treatment targeting BCMA were among those at a higher risk of ineffective immune responses. As BCMA-targeted (CAR T) treatment becomes more widely available, guidance on initiation of vaccination after treatment is needed. To assess the impact of BCMA-targeted CAR T (BCMA CAR T) on the serological immune response to COVID-19, we studied 45 MM patients who received ≥1 dose of a COVID-19 mRNA vaccine after prior BCMA CAR T. We collected demographics, disease/treatment characteristics, and COVID-19 infection/vaccination data via retrospective chart review. We analyzed SARS-CoV-2 spike-binding (anti-spike) IgG level using a validated assay (FDA/EUA approved Kantaro). Cumulative incidence of COVID-19 was analyzed using Kaplan-Meier statistics. All subjects were enrolled to studies approved by the Institutional Review Board at a single US academic hospital. Our cohort consisted of 16 women and 29 men with a median age of 61 years. The patients had received a median 6 lines of treatment and 33/45 (73%) had an ongoing response to BCMA CAR T. Patients received dose 1 at median 567 days after CAR T infusion (range 73-1,374 days). 36 patients (80%) received ≥3 doses and 17 (38%) received ≥4 doses. Across the cohort, anti-spike IgG levels increased from median 8 AU/mL after a single dose to 91, 474 and 612 AU/mL after 2, 3 or 4 mRNA vaccine doses respectively. After 2 doses, 6 patients (of 28 for which the timepoint was available, 21%) had no detectable anti-spike IgG levels, whereas all patients in the cohort had a detectable serological response after ≥3 vaccine doses. We compared the 13 patients (29%) that initiated mRNA vaccination at <12 months (mo) after CAR T infusion (i.e. “early vaccination”) with those who received the first dose after >12 mo. In the early vaccination group, anti-spike IgG levels were significantly lower when measured 0-3 months after 2 vaccine doses (p<0.01). Serological responses were not different when measured after 3 or 4 doses respectively (Fig A). Nevertheless, after 3 vaccine doses, 30% of patients (3/10) in the early vaccination group had anti-spike IgG <100 AU/mL, a level previously shown to be associated with less effective viral neutralization, versus only 5% (1/20) of patients in the group that started vaccination > 12 mo after CAR T. Twenty-four patients (52%) developed a documented COVID-19 infection after vaccination. Of these, 21 (88%) were characterized as mild (i.e. not requiring hospital admission); two patients required hospitalization and recovered, and 1 patient in the early vaccination group passed away from COVID-19. Of note, in the early vaccination group, there was a non-significant trend towards earlier breakthrough infections (Fig B, p=0.16), consistent with the finding of a delayed serological response with suboptimal antibody levels after 2 doses. In this study, all MM patients who initiated mRNA vaccination after prior BCMA CAR T therapy had detectable anti-spike IgG after ≥3 vaccine doses. However, starting vaccination against COVID-19 early (i.e. within 1 year) after CAR T therapy does not result in protective levels of antibody as quickly and to the same extent as when vaccinated >1 year post CAR T infusion. Patients starting vaccination within 12 months need ≥3 doses to achieve comparable serological efficacy to later initiation. A trend towards earlier breakthrough infections suggests that study of neutralizing titers against variants and comprehensive immune phenotyping may be needed to confirm effective immunity in these vulnerable patients. For the first year after CAR T cell therapy, adherence to preventive measures and passive immunization with IVIG with higher titers of anti-spike IgG may be warranted. Analyses comparing this cohort with MM patients receiving other modalities of BCMA-targeted therapy incl. bispecific antibodies are ongoing and will be presented at the meeting.

Cost-Effectiveness of Epcoritamab in Relapsed or Refractory Diffuse Large B-Cell Lymphoma after at Least Two Lines of Therapy in the United States

Introduction: Epcoritamab (SC) is a CD3xCD20 bispecific antibody developed using the DuoBody ® platform for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy in the US. In the single-arm, phase I/II, EPCORE-NHL-1trial (NCT03625037), epcoritamab (SC) demonstrated deep and durable responses and manageable safety in patients withr/r DLBCL. This study evaluated the cost-effectiveness of epcoritamab versus gemcitabine-oxaliplatin plus rituximab (R-GemOx) and the chimeric antigen receptor T-cell (CAR T) therapy axicabtagene ciloleucel (axi-cel) for adult patients with r/r DLBCL and no prior CAR T therapy from a US health system perspective. Methods: A partitioned survival model with three health states (progression-free [PF], progressive disease [PD], and death) based on overall survival (OS) and progression-free survival (PFS) was developed. OS, PFS, time to treatment discontinuation (TTD), health utilities, and adverse events of epcoritamab were informed by the corresponding patient level data from EPCORE-NHL-1 (data cut-off: June 2022). In the model base case, parametric survival models were chosen to extrapolating OS and PFS as well as TTD for epcoritamab based on statistical fit and plausibility on long-term clinical estimates. Two separate unanchored matching-adjusted indirect comparison (MAIC) analyses were conducted to assess the relative effectiveness of epcoritamab versus R-GemOx or axi-cel. In the first analysis, epcoritamab patients were matched with SCHOLAR-1 patients for comparison with R-GemOx (OS hazard ratio [HR] 0.288, 95% confidence interval [CI] 0.162-0.511). SCHOLAR-1 was chosen because it was the largest patient-level pooled retrospective analysis for r/r DLBCL, pooling outcomes from 2 large RCTs and 2 academic databases. In the second analysis, epcoritamab patients were matched with ZUMA-1 for comparison with axi-cel (OS HR 0.695, 95% CI 0.351-1.376). ZUMA-1 was chosen because it had long-term efficacy data reported. Patients in PF health states were assumed cured beyond two years when the risk of mortality became comparable to the general population (standard mortality ratio of 1.41 to be more conservative and consistent with prior NICE technology assessment submissions) and no further drug costs of epcoritamab were incurred. Health utilities for PF (0.825) and PD (0.779) health states were estimated using linear mixed-effects models based on EQ-5D-3L data collected from EPCORE-NHL-1 and a published US value set. Drug acquisition and administration costs and other resource use and cost data were based on package inserts, US standard sources, and literature. The model reported costs, life years (LYs), quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB) at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per QALY. All outcomes and costs were discounted by 3% annually. Probabilistic and one-way sensitivity analyses were conducted to assess the robustness of the results. Results: Over a lifetime horizon, epcoritamab was estimated to result in a mean gain of 4.26 LYs and 2.70 QALYs with additional costs of $285,093 versus R-GemOx, leading to an ICER of $105,502 per QALY; epcoritamab was estimated to dominate axi-cel by gaining 2.12 LYs and 1.29 QALYs while saving $180,518 costs. When drug acquisition costs (e.g. axi-cel one-time treatment cost) are not included in the sensitivity analyses, model results were most sensitive to OS HR, age, and HR to adjust background mortality for the cured population for comparison with R-GemOx; and to OS HR, PFS HR, and age for comparison with axi-cel. Epcoritamab was highly cost-effective compared to R-GemOx and aix-cel when WTP threshold was $150,000 per QALY or higher. This study had several limitations including unanchored MAIC approach used and the relatively short follow-up time and small (effective) sample size of the survival data of epcoritamab. Conclusion: Epcoritamab provides substantial LYs and QALYs gains versus R-GemOx and axi-cel and can be considered cost-effective compared to R-GemOx and axi-cel for the treatment of r/r DLBCL in the US.

Phase 1 Dose Escalation Study of Pembrolizumab in Combination with Rituximab and Lenalidomide for Relapsed/Refractory Large B-Cell or Follicular Lymphoma Following Progression after Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Introduction: While autologous CD19-targeting chimeric antigen receptor T-cells (CAR T) can induce high complete response (CR) rates in relapsed and refractory (r/r) large B-cell lymphoma (LBCL) and follicular lymphoma (FL), over 50% of patients experience progressive disease. Survival following CAR T failure is dismal, with only 1 in 5 patients living >2 years. Multiple studies indicated that resistance to CAR T therapy may be driven by CAR T cell intrinsic and/or tumor intrinsic mechanisms. Here, we evaluated the combination of PD-1 blockade with rituximab (R) and lenalidomide (len) with the rationale that it would restore the function of exhausted T cells, enhance CAR T function with len and target the tumor and its immunosuppressive microenvironment. Methods: In this single center, phase I dose-escalation study, eligible patients included adults with r/r LBCL or FL who progressed following CD19 CAR T. Treatment consisted of R (375 mg/m2/day) on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2. Pembrolizumab (200 mg/day) was administered on day 1 of each 21-day cycle with the cycles repeated for up to 2 years (those who attain an investigator-determined CR could stop pembrolizumab after 24 weeks). A standard 3+3 dose escalation of len was pursued to determine the recommended phase 2 dose (RP2D), starting at 2.5 mg and escalated up to 10 mg on days 1-14 of each cycle for up to 12 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included safety, CR rate, progression-free survival (PFS), and overall survival (OS). Exploratory objectives sought to determine the effect of combination therapy on peripheral blood T cells and evaluate baseline tumor characteristics that associated with clinical outcomes. Results: Fourteen patients initiated study treatment, 13 had LBCL (high grade B-cell lymphoma n=4; non-GCB DLBCL n=4; GCB DLBCL n=3; transformed FL n=2), 1 had FL. 12 progressed following axicabtagene ciloleucel, 1 progressed after lisocabtagene maraleucel, and 1 following an investigational allogeneic CAR T. The median time from CAR (day 0) to enrollment was 171 days (range 60-1134). The median time to progression following prior CAR T was 104 days (range 22-280). Median age was 57.5 years (range 41-73), 64% were male, all had advanced stage disease (stage III n=1, stage IV n=13), 79% had high-risk IPI, and 79% had an ECOG performance status of 1. Patients had a median of 3 prior lines of therapy (range 2-5), 86% were refractory to their last therapy. Four were treated at dose level 1 (2.5 mg len), 7 at dose level 2 (5 mg len), and 3 at dose level 3 (10 mg len). Five DLTs were observed, 3 at dose level 2 (3 gr 4 neutropenia > 7 days) and 2 at dose level 3 (1 gr 4 neutropenia > 7 days and 1 gr 3 febrile neutropenia). The RP2D was determined to be 2.5 mg of len. The most common all grade treatment-emergent non-hematologic adverse events (TEAEs) included rash (n=6, 43%), hyperglycemia (n=6, 43%), arthralgia/myalgia (n=5, 36%), diarrhea (n=4, 29%), and AST/ALT elevation (n=3, 21%). Grade 3 or higher TEAEs included 79% neutropenia (gr3 n=2; gr4 n=9), 29% lung infection (gr3 n=3; gr5 n=1), 21% febrile neutropenia (gr3 n=3), 21% lymphopenia (gr3 n=3), 21% anemia (gr3 n=3), and 14% thrombocytopenia (gr3 n=1; gr 4 n=1). With a median follow up of 37.5 months, the most common reason for discontinuation was progressive disease (n=7). Four patients (all LBCL) responded with all achieving a CR (ORR and CR rates were 29%) and all 4 patients remain in CR beyond 2 years, Figure 1. Median time to CR was 39.5 days. Median PFS was 2.3 months (95% CI: 1.6 mos-NR). Six patients died due to progressive lymphoma. Two patients died as a result of treatment-related AEs, 1 due to COVID19 infection, and 1 due to pneumonia/respiratory failure. Median OS was 21.3 months (95% CI:4.7 mos-NR). Conclusion: In these heavily pre-treated patients who progressed following CAR T-cell therapy, neutropenia was the dose limiting toxicity that prevented escalation of lenalidomide beyond 2.5 mg when combined with pembrolizumab and R. Four durable CRs were observed, none were observed at the RP2D. Risk mitigating strategies to reduce the incidence of febrile or grade 4 neutropenia and biomarker exploration to identify those likely to achieve a durable response are needed to explore this combination further.

CD22 CAR T Cell-Related IEC-HS Is Associated with an IFN-γ Cytokine Signature

Introduction Chimeric antigen receptor T-cell therapy targeting CD22 (CAR22) shows promise for patients with relapsed / refractory B-cell acute lymphoblastic leukemia (ALL) and large B cell lymphoma (LBCL) (Fry et al. Nat Med 2018; Baird et al. Blood 2020). The overall response rate for CAR22 in adults who received prior CD19 CAR therapy is 100% and 68% in ALL and LBCL respectively (Tandem 2023) (NCT04088890). However, 33% of pediatric ALL patients who received CAR22 developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) (Shah et al. JCO 2020). IEC-HS is characterized by hyperferritinemia, cytopenias, coagulopathy and end organ damage. Pediatric ALL data suggest many cytokines including IFN-γ, IL-1β, IL-18 and TNF-α are upregulated in IEC-HS (Ishii et al. JCI 2020, Lichtenstein et al. Blood 2021). Here, we report the clinical features and cytokines associated with IEC-HS after CAR22 infusion in predominantly adult subjects with ALL and LBCL. Methods Plasma was collected weekly from Day 0 to 28 for 54 patients (ALL: n = 16, LBCL: n = 38; adult: n = 51, pediatrics: n = 3) who were treated with CAR22 manufactured using an automated, closed-system Miltenyi CliniMACS Prodigy device. Three dose levels were tested (ALL: 3 x 10 5 cells/kg, LBCL dose level 1 (DL1): 1 x 10 6 cells/kg, LBCL dose level 2 (DL2): 3 x 10 6 cells/kg). Clinical characteristics associated with IEC-HS were retrospectively collected and graded according to consensus criteria (Hines et al. TCT 2023). Eighty cytokines were quantified in batch via multiplexed fluorescence immunoassay (Luminex) to generate mean fluorescent indices (MFIs). Unsupervised hierarchical clustering using Euclidean distance and ward.D2 linkage were employed to analyze cytokine dynamics. Statistical analyses were performed using R (v 4.2.2). Results 8 of 54 (15%) patients developed IEC-HS, all were ≥18 years old. 5 patients had LBCL, 3 had ALL. 5 cases were grade 2, 3 were grade 4. Median onset was D+12 (range 8 - 21). All patients had prior CRS with median onset at D+1 (range 0 - 9). The 3 ALL patients had ongoing CRS and spectral overlap with IEC-HS at time of diagnosis whereas LBCL patients' CRS resolved prior to IEC-HS onset. IEC-HS patients had significant increases in inflammatory markers (ferritin, CRP, LDH, triglycerides), coagulation markers (INR, PTT), cytopenias (hemoglobin, platelets) and transaminases (Table 1). Patients most commonly received high-dose glucocorticoids, tocilizumab and anakinra. Additional agents for grade 4 IEC-HS included anti-thymoglobulin, dasatanib and emapalumab. 5 of 8 patients developed serious infections requiring IV antimicrobials including bacteremia, invasive fungal infections and viral reactivation. 5 patients with IEC-HS died after achieving complete response: 3 due to IEC-HS and concomitant infection, 1 from t-AML and 1 lost to follow up. IEC-HS occurred more frequently at higher doses in LBCL where multiple doses were tested (DL2: 33% vs DL1: 7%, p = 0.08). Peak serum CAR22 concentration was markedly elevated in patients who developed IEC-HS compared to those who did not (median 648 vs 42 cells/µL, p<0.001). Unsupervised hierarchical clustering performed on serial cytokine measurements identified a signature of IFN-γ-related cytokines including CXCL9, CXCL10, TNFα, FasL, IL6 and IL18 as being closely related in IEC-HS (Figure 1). Most cytokines in the signature peaked at D+14, consistent with onset of clinical IEC-HS. Peak levels of nearly all cytokines in the interferon-γ cluster were significantly elevated in IEC-HS patients compared to patients who did not develop IEC-HS, and this cluster contained most cytokines with significant increases in peak levels (Figure 1). Conclusions IEC-HS is a potentially life-threatening toxicity associated with CAR22 across age and underlying malignancy. The high rates of non-relapse mortality and severe infections in this study highlight the importance of understanding the immune dysregulation underlying IEC-HS. Higher CAR22 dose and expansion were associated with IEC-HS, indicating optimal dosing as a potential preventive strategy. The observed IFN-γ cytokine signature is consistent with myeloid cell activation and Th1 T-cell skewing that likely contributes to IEC-HS pathogenesis. These cytokines may be amenable to therapeutic intervention and further study of approaches targeting JAK/STAT and IFN-γ are warranted.

Nivolumab and Ibrutinib for Treatment of Patients with Refractory or Relapsed Central Nervous System Lymphoma

Background: Central Nervous System (CNS) lymphoma is a distinct entity of large B-cell lymphoma (LBCL) with a unique genomic profile with similarities to the activated B-cell (ABC) subtype, which may offer potential targets for therapy. These aberrancies commonly include MYD88 mutations, which enhances sensitivity to Bruton's tyrosine kinase (BTK) inhibitors, and translocation or copy number alterations of 9p24, which may associate with sensitivity with programmed death (PD)-targeted therapies. Expression of PD-L1 is common in CNS lymphoma and tumor infiltrating lymphocytes, and the majority of CNS lymphomas have a copy gain of 9p24.1. This suggests an attenuated immune response against CNS lymphoma. Ibrutinib in combination with nivolumab has shown safety and clinical activity in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia in a phase 1/2 trial, and therefore we hypothesized that this combination may be active in CNS lymphoma. Methods: We conducted an investigator-initiated, open label, single center, phase 2 clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Adult patients were eligible if they had CNS lymphoma (primary or secondary) refractory to or relapsed after at least 1 prior CNS directed therapy, with adequate organ and bone marrow function, without prior ibrutinib or PD1 inhibitor therapy, and did not require persistent high dose steroids. The trial had two sequentially enrolled cohorts: Cohort A included ibrutinib 560mg oral daily for one cycle (28-days per cycle), followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B included ibrutinib and nivolumab during the first cycle. Patients with a partial response or greater after 6 cycles of combined ibrutinib and nivolumab could continue therapy for up to 2 years or until progression of disease or unacceptable toxicity occurs. The primary objective was to determine the best overall response rate (ORR) of ibrutinib and nivolumab. Secondary objectives included the ORR of ibrutinib as a lead in prior to the combination, best complete response (CR) rate, landmark survival outcomes, and the safety of the combination. The trial planned to enroll 20 patients in both cohort A and B, but closed early due to slow accrual, due in part to the COVID19 pandemic. Results: The trial accrued 18 patients from February 2019 to June 2022, with all patients evaluable for response. The median age was 63 years (range 43-88), 33% were >70 years, and 78% were female. 89% had primary CNS lymphoma, 50% had non-GCB, 22% had GCB, and 28% were unable to be classified due to missing components of the Hans algorithm. The median number of prior lines of therapy was 2 (range, 1-4), 55% had refractory disease, 17% had prior stem cell transplant, and 11% had prior CAR T-cell therapy. 10 patients were enrolled to Cohort A (ibrutinib lead in), and 8 patients were enrolled to Cohort B (initial combination therapy). Adverse events included 50% with fatigue, 33% with nausea, and 28% with mucositis. For both cohorts, the best ORR was 77.8% (95% CI: 52~94%) and the best CR rate was 50% (95% CI: 26-74%). In cohort A, the ORR of ibrutinib as a lead in after 1 cycle was 90% (95% CI: 55.5-99.7%), and the CR rate was 60%. In GCB patients (n = 4), the ORR and CR rates were 25%. In non-GCB patients (n =9), the ORR and CR rates were 100% and 56%, respectively. With a median follow up time of 34.6 months, the median overall survival (OS) was 25.4 months (95% CI 12.5-NR), and the OS rate at 12 months was 70%. The median progression free survival (PFS) was 6.6 months (95% CI: 2.9 - NR), and the PFS rate at 18 months was 47%. 4 patients withdrew from protocol therapy in CR, including 2 who proceeded to stem cell transplant consolidation, and 2 who stopped due to fatigue. 3 patients withdrew from protocol therapy in PR, 2 due to mucositis and 1 due to arthralgias. 1 patient died of COVID19 infection with a CR after 4 cycles of therapy. Conclusion: Ibrutinib and Nivolumab resulted in significant clinical activity in patients with refractory/relapsed CNS lymphoma. Our trial is limited by small patient numbers but suggests the potential for targeted therapy combinations in future larger clinical studies.

Efficacy and Safety of Golcadomide, a Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, Combined with Rituximab in a Phase 1/2 Open-Label Study of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: Golcadomide is a novel, oral, small-molecule CELMoD ® agent that co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, which are crucial to B-cell malignancy development. We previously reported promising efficacy with a predictable and manageable safety profile of golcadomide in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (Michot et al. ICML 2023, presentation #90). Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part, multicenter, first-in-human study with dose escalation (Part A) of golcadomide monotherapy and expansion (Part B) ± combination partners. Patients with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients with R/R DLBCL after ≥ 1 line of therapy were included. Following dose exploration in Part A, golcadomide was administered at 0.2 or 0.4 mg alone or with rituximab on 2 intermittent schedules in Part B. Total duration of treatment is up to 2 years. Here, we report efficacy and safety results for golcadomide + rituximab in patients with DLBCL treated in Part B expansion on a 14 days on/14 days off schedule. The efficacy-evaluable population consisted of patients completing ≥ 1 cycle of golcadomide (taking ≥ 75% of assigned doses) and having baseline and ≥ 1 post-baseline tumor assessment. Results: As of May 10, 2023, 35 patients with DLBCL were enrolled and 34 received ≥ 1 dose of golcadomide or rituximab (safety population); 17 (49%) patients were ongoing and 17 (49%) had discontinued treatment, mostly due to progressive disease (n = 10, 29%). The median age was 60 years (range, 35-80). The median number of prior anticancer therapies was 4.5 (range, 1-11); 68% (n/N = 23/34) of patients had prior CAR T-cell therapy and 49% (n/N = 17/35) were refractory to their last regimen. Golcadomide median treatment duration was 8 weeks (range, 4-48) and median follow up was 15 weeks (range, 2-55). In the efficacy-evaluable population (n = 16), overall response rate (complete response [CR] + partial response) was 50% (n = 8), with CR occurring in 13% (n = 2) of patients. Median duration of response was 17.4 weeks (range, 7.4-45.9). Response data in the 0.2-mg and 0.4-mg golcadomide-treated groups are shown in the table. In the safety population (n = 34), neutropenia was the most common any-grade treatment-emergent adverse event (TEAE), occurring in 15 (44%) patients, all of which were grade 3/4. No febrile neutropenia occurred. The most common treatment-related adverse event (TRAE) for golcadomide was neutropenia (all grade 3/4), occurring in 14 (41%) patients, comprising 5/19 (26%) patients treated at the 0.2-mg and 9/15 (60%) patients treated at the 0.4-mg dose level. Granulocyte colony-stimulating factors were used in 14 (41%) patients. Six serious TRAEs related to golcadomide were reported (n = 1 each), all in the 0.4-mg group. One grade 5 TEAE occurred (tubulo-interstitial nephritis in the 0.2-mg group), which was reported to be due to progressive disease and considered unrelated to study treatment. TEAEs led to golcadomide discontinuation in 2 (6%) patients (1 at each dose level) and rituximab discontinuation in 5 (15%) patients. Similar pharmacokinetic (PK) exposures of golcadomide were observed when golcadomide was dosed alone and in combination with rituximab, indicating no apparent impact of rituximab on golcadomide PK. Analysis of circulating tumor DNA data is underway and will be presented. Conclusions: Golcadomide oral therapy combined with rituximab showed promising efficacy in heavily pretreated patients with R/R DLBCL, including 1 durable response over 300 days. Golcadomide can be safely combined with rituximab, and the combination showed a safety profile similar to that previously reported for golcadomide monotherapy. This study is ongoing, with continued enrolment in the monotherapy and golcadomide + rituximab combination expansion cohorts.

726. Risk factor analysis for cefepime and piperacillin/tazobactam resistant organisms

Abstract Background Carbapenems (CAR) are first line therapy for patients with infections caused by multidrug resistant organisms. As the prevalence of antibiotic resistance is increasing, CAR use has become a common choice for empiric therapy. This increase in use is concerning as prior CAR exposure is a risk factor for CAR resistance. Identification of risk factors associated with resistance for other beta-lactam antibiotics could aid in the appropriate use of CAR therapy while minimizing overuse. The objective of this study was to identify risk factors for cefepime (FEP) and piperacillin/tazobactam (PTZ) resistance and which population required CAR as an empiric therapy. Methods This is a retrospective cohort conducted at HonorHealth John C Lincoln Medical Center, Phoenix AZ between January 2020 to July 2021. The case patients will be those who had an infection which is resistant to FEP or PTZ, while control patients have infection which is susceptible to FEP or PTZ. Recurrence of infection after receiving appropriate antimicrobial therapy considered as a separate case. Patients who do not have antimicrobial susceptibilities were excluded. Variables were compared between groups. Multivariate analysis using logistic regression was used to control for confounding variables. Results Overall, 230 patients met inclusion criteria and were evenly distributed between cohorts. The mean age of the population at baseline was 64 ± 17.4, 111 (48.3%) patients were in an ICU and 103 (44.8%) patients required mechanical ventilation. Clinical variables which were significant in univariate analysis were included in multivariate analyses. Multivariate analyses revealed prior resistance to FEP or PTZ in the past 12 months (OR 8.35, 95% CI [2.28-30.50], p=0.001), transferred from outside facility (OR 3.40, 95% CI [1.80-6.42], p< 0.001), prior ICU admission in the past 90 days (OR 4.40, 95% CI [1.72-11.27], p=0.002), and prior antibiotic use in the past 30 days (OR 2.60, 95% CI [1.33-5.09], p=0.005) were associated with increased risk of FEP- or PTZ-resistant infections. Conclusion Patients with prior resistance to FEP and PTZ within the last 12 months can benefit by initiating empiric therapy with CAR due to the increased risk for subsequent FEP- or PTZ-resistant organisms. Further investigation is warranted. Disclosures All Authors: No reported disclosures

Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy

BACKGROUND T cells engineered with a CD19-targeted chimeric antigen receptor (CD19 CAR T cells) have revolutionized the treatment of high-risk, relapsed, or refractory large B-cell lymphoma (LBCL), but durable responses are only achieved in 30-40% of patients (pts). Outcomes are dismal in case of disease recurrence after CD19 CAR T-therapy; in this situation we have previously reported low efficacy and limited duration of response after a second infusion of the same CD19 CAR T-cell product (Gauthier, Blood, 2022). We observed that repeat CD19 CAR T-cell infusions were impaired by CD8+ T-cell responses against murine amino acid sequences located in the single chain variable fragment (scFv) of the CAR, which led to rapid immune rejection of CAR T cells. We hypothesized that CAR T cells engineered with a fully human scFv could circumvent anti-murine scFv immune responses in pts previously exposed to murine scFv-bearing CAR T cells. We report our phase 2 clinical trial results investigating treatment with fully human scFv-bearing CD19 CAR T cells (JCAR021) in R/R LBCL pts with relapsed or progressive disease after murine scFv-bearing CD19 CAR T-cell therapy. METHODS Pts with R/R LBCL were enrolled at the Fred Hutchinson Cancer Center on a phase II study (NCT03103971). Key eligibility criteria included: i) relapsed disease after complete response (CR) to prior CD19-targeted non-JCAR021 CAR T-cell therapy or persistent disease after partial response to prior CD19-targeted non-JCAR021 CAR T-cell therapy; ii) CD19-positive disease since completing the prior CD19-targeted CAR T-cell therapy. Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded according to the Lee 2014 criteria and CTCAE v4.03 criteria, respectively. Disease response was evaluated at day +28 after JCAR021 infusion per PET-CT Lugano criteria. The planned sample size and CAR T-cell dose were n=27 and 7x10 6 CAR T cells/kg, respectively. RESULTS Pt characteristics, and outcomes are shown in the Table. All eight screened pts were enrolled, received LD, and JCAR021 infusion. Median age at enrollment was 63 (range: 41-77). Prior to lymphodepletion, 4 pts (50%) had bulky disease (largest lesion ≥5cm). All pts had extranodal disease. We observed elevated LDH prior to lymphodepletion in 6 pts (75%). Median prior lines of therapy was 5 (range: 3-7). Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1. Response to the prior CD19 CAR T-cell therapy was CR in 5 pts (62%) and PR in 3 pts (38%). Median time from the first CAR T-cell infusion to relapse or progression was 165 days (range 49-434). Median time from the first CAR T-cell infusion to JCAR021 infusion was 304 days (range: 202-603). JCAR021 was administered at the dose of 7x10 6 (n=6, 75%) or 2x10 6 CAR T-cells/kg (n=2, 25%; dose reduction due to grade 5 NT in subject #6). We observed all-grade CRS in 4 pts (50%; grade 1, n=2; grade 2, n=2 not requiring vasopressors) and NT in 1 patient (dose limiting toxicity, grade 5 NT from intracerebral hemorrhage with concurrent acute kidney injury and toxic encephalopathy). At day+28 responses were seen in 3 of 8 pts (37%; CR, n=2; PR, n=1), all of whom received 7x10 6 CAR T-cells/kg. Two pts in CR after JCAR021 had bulky disease and elevated LDH prior to LD. In both pts, the prior CD19 CAR T-cell therapy had induced CR lasting ≥ 6 months. In the two evaluable responders (death in CR, n=1), we observed disease relapse or progression within 3 months. Median overall survival was 105 days (95%CI, 92-NA). We measured expansion of JCAR021 CAR T-cells in all pts. Exploratory analyses showed lower in vitro CAR T-cell expansion during manufacturing (fold expansion of CD8+ CAR T-cells, p<0.001) and lower in vivo CAR T-cell expansion (peak CD8+ CAR-T, p=0.002; AUC day0-28, p=0.01; JCAR021 dose, 7x10 6/kg) compared to pts receiving JCAR021 as their first CD19 CAR-T product (CAR-naïve cohort). CONCLUSION In LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

Epcoritamab SC + GemOx Leads to High Complete Metabolic Response Rates in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail or are ineligible for autologous stem cell transplant (ASCT) have poor outcomes with standard chemotherapy, and novel, effective therapeutic options are needed. A retrospective analysis showed that treatment with rituximab and gemcitabine + oxaliplatin (GemOx) in a transplant-ineligible population resulted in a complete response rate of 33% in the overall population; among patients refractory to previous therapy, 10% achieved complete response (Cazelles et al, Leuk Lymphoma 2021). Epcoritamab, a subcutaneously administered (SC) CD3xCD20 bispecific antibody, has demonstrated deep, durable responses with a manageable safety profile as a single agent in patients with R/R DLBCL. Based on these data, epcoritamab SC was approved by the US FDA for the treatment of adults with R/R DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma, after ≥2 lines of systemic therapy. In the EPCORE ™ NHL-2 phase 1/2 trial (NCT04663347), epcoritamab + GemOx treatment showed encouraging preliminary efficacy with overall expected and manageable safety in patients with R/R DLBCL who failed or were ineligible for ASCT. Here, we present updated results with longer follow-up. Methods: Adults with R/R CD20 + DLBCL who had failed or were ineligible for ASCT were enrolled. Patients received epcoritamab SC in 28-d cycles (Cs) as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received GemOx every 2 weeks in C1-4. Step-up epcoritamab dosing (step-up doses 1 and 2 followed by 48-mg full doses) and corticosteroid prophylaxis were required in C1 to mitigate CRS. The primary endpoint was overall response rate (ORR) as assessed by PET-CT per Lugano criteria. Results: A total of 34 patients (median age, 71 y; range, 47-87) with a median follow-up of 20.3 mo (range, 1.0+ to 26.8) received epcoritamab SC 48 mg + GemOx on or prior to August 24, 2022. At the data cutoff date (April 24, 2023), treatment was ongoing in 35% of patients. A majority of patients (68%) had stage III or IV disease, 53% had primary refractory disease, 38% were refractory to ≥2 consecutive lines of prior therapy, and 79% were refractory to the last line of therapy. The median number of prior lines of treatment was 2 (range, 1-6); 11 patients (32%) had 3 or more prior lines of treatment. A total of 7 patients (21%) had prior CAR T, and 5 patients (15%) had previously received ASCT. The most common treatment-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia/decreased platelet count (68%), diarrhea (59%), anemia (56%), CRS (56%), and neutropenia/decreased neutrophil count (56%). This trial was conducted amid the COVID-19 pandemic and 32% of patients experienced COVID-19. Most CRS events were low grade (53% G1-2; 3% G3) and primarily occurred following the first full dose (C1D15); no incidence of CRS resulted in epcoritamab discontinuation, and all events resolved. ICANS (G1) was reported in 1 patient; this event resolved in 2 d. No clinical tumor lysis syndrome was reported. There were 10 G5 TEAEs; in 2 cases, the contribution of epcoritamab could not be ruled out by the investigator (small intestinal perforation and multiple organ dysfunction syndrome; both patients had multiple confounding factors). The ORR was 91% (31/34), with 59% (20/34) of patients achieving complete metabolic response (CMR). Median times to response and CMR were 1.5 mo and 2.6 mo, respectively. The ORR and CMR rates were 94% and 39% among patients with primary refractory disease, 89% and 78% among patients ≥75 y of age, and 90% and 50% among patients with IPI ≥3 ( Table). Response rates were comparable for patients with and without prior CAR T treatment: ORR of 86% and CMR rate of 57% among patients with prior CAR T; ORR of 93% and CMR rate of 59% among CAR T-naive patients. Conclusions: Epcoritamab SC + GemOx led to high CMR rates in this difficult-to-treat R/R DLBCL population ineligible for transplant with high unmet medical need. No new safety signals were identified, and the safety profile was consistent with those of the individual drugs. These data are encouraging and underline the versatility of epcoritamab SC for the treatment of R/R DLBCL. Additional data and subgroup analyses will be presented.

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.

Subcutaneous Epcoritamab Plus Lenalidomide in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma from EPCORE NHL-5

Background: The prognosis for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor, even if treated with salvage chemotherapy and autologous stem cell transplantation. CAR T cell therapy provides long-term remission in only 40% of patients. Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody developed using the DuoBody ® platform, received accelerated FDA approval for adults with R/R DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. Single-agent epcoritamab has demonstrated deep and durable responses (overall response rate, 63%; complete responses, 40%) and a manageable safety profile in patients with R/R large B-cell lymphoma in the EPCORE NHL-1 trial (Karimi et al, ASCO 2023, abstract 7525). Combining epcoritamab with antineoplastic agents that have different mechanisms of action may offer enhanced clinical benefit to patients. Therefore, EPCORE NHL-5 (NCT05283720) evaluated the safety, tolerability, and preliminary efficacy of epcoritamab, as well as defining its recommended dose when coadministered with other antineoplastic agents in patients with non-Hodgkin lymphoma. Here, we present results from arm 1 that evaluated epcoritamab combined with lenalidomide in patients with R/R DLBCL. Methods: EPCORE NHL-5 is a phase 1b/2, nonrandomized, open-label, multicenter study. In arm 1, adults with CD20 + R/R DLBCL (ECOG 0-2) received subcutaneous epcoritamab (weekly during cycle 1-3, every 4 weeks during cycle 4-12) and oral lenalidomide (once daily on days 1-21) for 12 cycles of 28 days. Patients had received at least 1 prior combined systemic therapy that contained an anti-CD20 monoclonal antibody. The primary endpoint was the identification of dose-limiting toxicities (DLTs). Key secondary endpoints included investigator-assessed best overall response by Lugano 2014 criteria and time to response. Safety endpoints included severity and incidence of adverse events (AEs) including AEs of special interest to epcoritamab (cytokine release syndrome [CRS], immune cell-associated neurotoxicity syndrome [ICANS], and clinical tumor lysis syndrome). Results: As of May 22, 2023, 26 patients (median age, 71 years; DLBCL, n=24 [92%]; follicular lymphoma grade [G] 3b, n=2 [8%]) had received epcoritamab plus lenalidomide. Median duration of epcoritamab exposure was 3.8 months (range, 0-7.5) and median duration of lenalidomide exposure was 4.0 months (range, 0.1-8.2); 15 patients (58%) remain on epcoritamab and lenalidomide. Median number of prior lines of therapy was 1 (range, 1-4), with 15 (58%) receiving 1 prior line of anticancer therapy. Six patients (23%) had received prior CAR T and 2 patients had undergone hematopoietic stem cell transplantation. One DLT (neutropenia) was observed. The most common G3-4 treatment-emergent AEs (TEAEs) were neutropenia (n=15; 58%), anemia (n=4; 15%), thrombocytopenia (n=4; 15%), and febrile neutropenia (n=3; 12%). Primary granulocyte colony-stimulating factor prophylaxis was not mandatory. TEAEs led to epcoritamab discontinuation in 1 patient (3.8%; thrombocytopenia). No patients experienced a TEAE leading to death that was considered related to epcoritamab. CRS was predominantly low grade (73% [19/26] any grade; 65% G1-2; 8% G3) and occurred mostly after the first full dose (C1D15). Preliminary biomarker analysis showed pharmacodynamic profiles consistent with the mechanism of action of epcoritamab. These include predictable cytokine peaks immediately after the first full dose (IFN-gamma, IL-2, and IL-6) with a rapid and sustained depletion of peripheral B cells. One patient experienced ICANS (G3), which resolved after 2 days. Among response-evaluable patients (n=24), the overall response rate was 75% (95% CI, 53.3, 90.2). Complete metabolic responses were seen in 14 patients (58%) and partial responses in 4 patients (17%), of which 3 were ongoing at time of data cutoff ( Table). Median time to first response was 1.8 months (range, 1.0-2.8). Follow-up is ongoing. Conclusions: Epcoritamab combined with lenalidomide showed promising antitumor activity with a tolerable safety profile in patients with R/R DLBCL.