Vandenberghe, Peter

Introduction CD19 CAR T cell therapies are highly effective for several aggressive B-cell malignancies. Emerging data suggest that these therapies may lead to durable, treatment-free responses in multiple autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIMs), systemic sclerosis (SSc), and multiple sclerosis (MS). BMS-986353 (CC-97540) is an investigational CAR T cell therapy expressing the CD19-targeting CAR used in FDA-approved lisocabtagene maraleucel (liso-cel). BMS-986353 is manufactured using the NEX-TTM process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Here, we report updated data on BMS-986353 in severe, refractory autoimmune diseases. Methods Two phase 1, multicenter, open-label studies are investigating BMS-986353 in patients (pts) with severe, refractory SLE, IIM, and SSc (CA061-1001; NCT05869955), and relapsing or progressive forms of MS (CA061-1006; NCT06220201). CAR T cells were manufactured using the NEX-T process and autoimmune-directed therapies were tapered before BMS-986353 infusion. Two to 9 d after lymphodepletion (3 d of fludarabine [30 mg/m2/d], cyclophosphamide [300 mg/m2/d]), a single infusion of BMS-986353 was administered. Pts were treated with 5 × 106 (MS only), 10 × 106, or 25 × 106 CAR+ T cells according to dose level. Pharmacokinetics were evaluated using droplet digital PCR to detect transgene copy numbers, and pharmacodynamics were measured using flow cytometry. Results As of Jul 12, 2024, 7 pts were treated with BMS-986353 (SLE, n=5; SSc, n=1; relapsing-remitting MS [RRMS], n=1). Seven pts were evaluable for safety; 4 pts were evaluable for efficacy (median follow-up of 167.5 d [range, 68-240]). All 5 pts with SLE had history of renal organ system involvement (BILAG category A) and disease refractory to multiple prior therapies (range 5-8); at screening, scores were (median [range]): SLE Disease Activity Index 2000 (SLEDAI-2K), 12.0 (7.0-22.0); Physician's Global Assessment (PGA), 2.3 (1.5-2.5). The pt with SSc was aged 43 y, and had history of progression of diffuse cutaneous SSc after 2 therapies and a modified Rodnan skin score of 18; the pt with RRMS was aged 33 y, and had history of active clinical disease despite 3 prior anti-CD20 therapies and an Expanded Disability Status Scale score of 3.0. Cytokine release syndrome was reported in 1 pt with SLE (grade [gr] 1) and 1 pt with SSc (gr 2), both resolved within 1 d. ICANS was reported in 1 pt with SSc (gr 1) and resolved in 1 d. Gr 3/4 transient lymphodepletion-related cytopenia occurred in 4 pts with SLE and 1 pt with MS. There were no prolonged gr ≥3 cytopenias or dose-limiting toxicities reported. In all efficacy evaluable pts, significant improvements in SLEDAI-2K (median, 4.0) and PGA (median, 0.55) were observed. dsDNA seroconverted and complements normalized for all pts who had abnormal values at screening. All pts remain off autoimmune-directed therapies without evidence of disease flare. Pts with SLE treated with 10 x 106 CAR+ T cell dose of BMS-986353 showed complete B-cell depletion and similar robust cellular expansion compared with pts with diffuse large B-cell lymphoma treated with liso-cel (TRANSFORM; NCT03575351) at the recommended phase 2 dose (RP2D; 100 x 106 CAR+ T cells). At the time of B-cell reconstitution following BMS-986353, re-emerging B cells were predominantly naive. Conclusions BMS-986353, a NEX-T investigational CD19-targeted CAR T cell therapy, has a more rapid manufacturing time and optimized phenotypic attributes. In pts with severe, refractory autoimmune diseases, BMS-986353 demonstrates a low rate of low gr CRS and ICANS events. Preliminary data suggest promising efficacy in pts with SLE despite discontinuation of all lupus therapies. Robust CAR T cell expansion comparable to the RP2D of liso-cel and complete B-cell depletion were observed after BMS-986353 at a dose of 10 x 106 CAR+ T cells despite being 1/10 of the RP2D of liso-cel. The studies continue to enroll pts in all autoimmune indications. Updated safety, efficacy, and translational data will be presented.

Introduction: Historically, older patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL) were often deemed ineligible for curative-intent autologous stem cell transplant (ASCT) due to age and concern for increased toxicity related to comorbidities. We previously demonstrated in the pivotal ZUMA-7 study that older pts with R/R LBCL can safely receive axicabtagene ciloleucel (axi-cel) as second-line (2L) therapy with improved event-free survival (EFS), response rate, and quality of life compared with standard of care (SOC) based on results from the primary EFS analysis (Westin, et al. Clin Cancer Res. 2023). At a median follow-up of 47.2 months (mo), results from the ZUMA-7 primary overall survival (OS) analysis demonstrated superior OS in the intention-to-treat (ITT) analysis (hazard ratio [HR], 0.73; 95% CI, 0.54-0.98; stratified two-sided log-rank P=0.03; Westin, et al. N Engl J Med. 2023; NCT03391466). We now report updated efficacy and safety results from the primary OS analysis among ZUMA-7 pts aged ≥65 years (y) and ≥70 y. Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based chemoimmunotherapy; responding pts proceeded to high-dose chemotherapy with ASCT). The primary OS analysis occurred 5 y after the first pt was randomized (01/25/2018) per protocol. Other endpoints included progression-free survival (PFS) per investigator assessment and safety. A planned subgroup analysis of pts aged ≥65 y was conducted in addition to an analysis for those ≥70 y. Multivariate analyses were performed to examine treatment efficacy with axi-cel compared with SOC after adjusting for multiple covariates, including sex, disease type, molecular subgroup, lactate dehydrogenase (LDH), tumor burden, and age; strata for these analyses included second-line age-adjusted International Prognostic Index (aaIPI), and relapsed vs refractory disease. Exploratory analyses were conducted to determine the association between OS and axi-cel product characteristics for pts aged ≥65 y. Results: A total of 109 pts were included in the analysis (axi-cel: 51 were ≥65 y, 26 of whom were ≥70 y, maximum age was 80 y; SOC: 58 were ≥65 y, 27 of whom were ≥70 y, maximum age was 81 y). Compared with SOC pts at baseline, more axi-cel pts had high-risk features, including aaIPI 2-3, elevated LDH, and high-grade B-cell lymphoma. At a median follow-up of 46.6 mo, OS was prolonged in the axicel vs SOC arm in pts aged ≥65 y (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). Similar results were observed using the piecewise Cox regression model. The median OS for axi-cel and SOC pts was 43.5 mo (95% CI, 20.9-not estimable [NE]) and 19.6 mo (95% CI, 12.3-NE), respectively, among those aged ≥65 y, and 24.7 mo (95% CI, 12.8-NE) and 11.2 mo (95% CI, 6.1-NE), respectively, among those aged ≥70 y. In the SOC arm, 57% and 52% of pts received subsequent cellular immunotherapy off protocol in pts aged ≥65 y and ≥70 y, respectively. Multivariate analyses demonstrated an even greater OS benefit with axi-cel over SOC when adjusting for differences in baseline characteristics in pts aged ≥65 y (HR, 0.526; 95% CI, 0.266-1.041) and in pts aged ≥70 y (HR, 0.184; 95% CI, 0.045-0.755). PFS assessed by investigator confirmed benefit of axi-cel over SOC in pts aged ≥65 y (HR, 0.406; 95% CI, 0.230-0.715) and in pts aged ≥70 y (HR, 0.206; 95% CI, 0.078-0.547). The median PFS for axi-cel and SOC pts was 28.7 mo (95% CI, 5.1-NE) and 5.0 mo (95% CI, 2.8-7.2), respectively, for those aged ≥65 y, and 11.4 mo (95% CI, 4.1-NE) and 2.7 mo (95% CI, 1.7-5.0), respectively, for those aged ≥70 y. No new treatment-related deaths occurred since the primary EFS analysis. There were no manufacturing failures for any pt who underwent leukapheresis. Similar associations between product characteristics and outcomes were observed among the elderly and overall populations, including improved OS associated with a greater (>median) proportion of juvenile or stem memory T-cell phenotype cells (CCR7+CD45RA+ T cells) in the axi-cel product among pts aged ≥65 y (HR, 0.369; 95% CI, 0.138-0.984). Conclusion: Axi-cel as 2L therapy prolonged survival over SOC in pts aged ≥65 y, including in pts aged ≥70 y. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy, supporting the use of axi-cel as a curative-intent 2L therapeutic option for older pts with R/R LBCL.

Abstract Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE‐induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be “non‐clonal” cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.