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Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR-T) cell therapy that recently received U.S. FDA approval as the first CAR-T cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Social determinants of health (SDoH) are shown to significantly influence outcomes in B-ALL. However, how SDoH relate to and affect outcomes in patients with B-ALL receiving CAR-T therapy has not been well established. We studied the impact of SDoH on outcomes of adults with B-ALL receiving brexu-cel as part of the Real-world Outcomes Collaborative of CAR-T in Adult ALL (ROCCA). Methods This retrospective multicenter analysis spanning 25 U.S centers included adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel between 2021-2023. Progression-free survival (PFS) and overall survival (OS) were calculated from the day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. Univariate and multivariate Cox proportional hazards models were used to evaluate the association of age, sex, pre-apheresis disease burden, and SDoH (referral source, insurance, distance from home to CAR-T site, marital status, and the social deprivation index) with progression-free survival (PFS) and overall survival (OS). The social deprivation index (SDI), a composite measure (including income, education, employment, housing, household characteristics, and transportation) used to quantify socio-economic variation in health outcomes, with higher SDI indicating greater social disadvantage, was estimated at the zip code level. (Butler et al., 2013) Results Of the 152 patients who received brexu-cel (Table 1), 57% were male. 51% identified as non-Hispanic White, with the remainder identifying as Hispanic (34%), Asian/Pacific Islander (7%), Black (6%), American Indian/Alaskan Native (1%), or mixed race (1%). A majority (46%) were referred for brexu-cel from private/community-based practices and 62% lived within 50 miles of the CAR-T center (36% lived >50 miles and 2% were unknown). Health insurance coverage included primarily public (49%) and private (42%); no patients were uninsured. High SDI (76-100% percentile) was present in 26%, while 14% had a low SDI (0-25 th percentile). In unadjusted analyses, there was no difference in PFS or OS between patients with high versus low SDI; closer distance to the CAR-T site (<50 miles versus >50 miles)) was associated with worse OS (HR 1.96; 95% CI 1.00, 3.84; p=0.05). Multivariate analysis (Table 2) revealed that male sex was associated with inferior PFS (HR 1.98; 95% CI 1.02, 3.85; p=0.04) and OS (HR 2.52; 95% CI 1.09, 5.84; p=0.03). There was no difference in PFS (HR 0.95, 95% CI 0.48-1.88, p=0.88) or OS (HR 0.80; 95% CI 0.33,1.92; p=0.62) when comparing Hispanic and non-Hispanic White patients. Additionally, there was no difference in PFS or OS based on any SDoH, including insurance type, marital status, referral source, caregiver type, and distance to transplant center. Conclusions In patients receiving brexu-cel, survival outcomes appear independent of SDoH. Contrary to previous reports suggesting inferior outcomes for Hispanic patients with B-ALL after receiving traditional systemic therapies, we observed comparable outcomes to non-Hispanic patients treated with brexu-cel. Distance from the CAR-T site and referrals from the community did not affect outcomes. Additionally, those with higher SDI had similar outcomes to those with a lower SDI, although this analysis was limited by sample size and the selection bias that exists in being referred for brexu-cel in the first place. The relatively lower logistical burden of CAR-T compared to allogeneic stem cell transplant or non-fixed duration systemic therapies may have mitigated the impact of SDoH on outcomes. These real-world data suggest that continuing to improve access to and treatment with brexu-cel may improve overall outcomes for disadvantaged populations with r/r B-ALL.

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL. Methods: Retrospective data were collected from 25 centers across the U.S. as part of the real-world outcomes collaborative study of CAR-T in B-ALL (ROCCA). Consecutive patients treated with brexu-cel from 2021 to 2023 were categorized by blinatumomab exposure status. Those exposed were separated into “blinatumomab responders” (B-R), defined as patients achieving a CR/CRi in response to any number of cycles of blinatumomab, and “non-responders” (B-NR). Each cohort was compared for outcomes of interest. The primary outcome was CR/CRi rate at day 28 following brexu-cel administration. Secondary outcomes were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated from day of brexu-cel infusion and were not censored for allogeneic hematopoietic cell transplantation or maintenance therapy. All living patients were censored at data cutoff on June 30, 2023. Survival comparisons were made by log rank test. Results: Among 152 patients who received brexu-cel, the median follow-up time was 8.4 months. Eighty-eight (57%) of 152 r/r B-ALL brexu-cel recipients had received blinatumomab prior to apheresis. The median number of pre-apheresis blinatumomab cycles was 2 (range 1-12). The baseline characteristics of B-R, B-NR, and blinatumomab-naïve (B-NV) patients were similar, including pre-apheresis disease burden and receipt of maintenance therapy following brexu-cel infusion (Table 1). Seventy percent (N= 62) of the blinatumomab-exposed patients were B-R, while 30% (N=26) were B-NR. Rates of CR/CRi at day 28 following brexu-cel infusion were similar between B-R, B-NR, and B-NV patients (79% vs 84% vs 78%, respectively). Most of these remissions were negative for measurable residual disease (MRD), with similar MRD negativity rates in the three groups (table 2). 1-year DOR and PFS were significantly higher in the B-NV group compared to B-R or B-NR (77% vs 49% vs 50%, p<.0001; 60% vs 37% vs 30%, p<.0001). B-NV and B-R had better 1-year survival compared to B-NR (71% vs 65% vs 32%, p<.0001). There were more CD19-negative relapses following brexu-cel in B-NR (29%) and B-R (18%) compared to B-NV patients (8%), although this was not statistically significant. Conclusions: Brexu-cel induced deep responses in a majority of adults with r/r B-ALL, irrespective of prior exposure or response to blinatumomab. Similar to data published by the pediatric CAR-T cell groups, our data draw speculation that adult patients who did not respond to blinatumomab experience shorter overall survival following brexu-cel compared to those who responded to or did not receive blinatumomab. This should be confirmed in a larger, prospective clinical trial. Because this analysis could not account for patients who achieved durable remission after blinatumomab, these differences may not reflect superiority of sequencing brexu-cel before blinatumomab. The higher number of CD19-negative relapses in the blinatumomab-exposed cohort add to the interest in pursuing strategies to address antigen escape following CAR-T cell therapy directed against a previously targeted antigen.

Introduction: In recent years, increasing evidence suggests an important role of tumor-infiltrating B lymphocytes (TIL-Bs) in cancer immunity. In various types of solid tumors, high density of TIL-Bs and presence of mature tertiary lymphoid structures consistently correlate with better prognosis and response to immune checkpoint blockade therapies. Diffuse large B-cell lymphoma (DLBCL) is a type of aggressive lymphoma arising from mature B cells. TIL-Bs have been identified in DLBCL based on single-cell gene-expression data in several previous studies, but their prognostic significance in DLBCL is unknown. In this study, we determined the clinical significance of TIL-B abundance and investigated the potential underlying mechanisms. Patients and Methods: This abstract includes a discovery study in which we distinguished TIL-Bs from malignant B-cells by immunoglobulin gene (IG) clonotype analysis and a validation study using flow cytometry. In the discovery study, a molecularly well-characterized DLBCL cohort assembled by the International DLBCL R-CHOP Consortium Program was analyzed. DNA samples from DLBCL patients were sequenced by high-throughput ultra-deep sequencing assays using multiplexed forward and reverse primers. Based on the IG heavy chain (IGH) sequencing results, malignant B-cell and TIL-B VDJ clonotypes were identified for 138 patients, and the frequencies and numbers of TIL-B clonotypes in individual sequence repertoires were calculated. In 79 DLBCL cases, a DJ-only sequence was predominant and no productive VDJ sequences met the criteria for diagnostic sequences. Total frequencies of productive VDJ sequences in the sequence repertoires were then used to access high and low TIL-B frequencies. TIL-B frequencies were also evaluated by IG light chain clonotypes for these 217 patients and additional 52 patients. The TIL-B frequencies were correlated with patient survival, gene-expression profiling (GEP) data GSE31312, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex immunohistochemistry (mIHC). To validate the prognostic significance of TIL-B frequencies, we assembled a validation cohort of 94 DLBCL patients treated at Duke University Medical Center. TIL-Bs in tissues were quantified by flow cytometry immunophenotyping. Ratios of TIL-Bs to abnormal B cells were assessed for prognostic effects. Results: First, we found thathigh frequencies of TIL-Bs and clonotypic diversity were associated with significantly favorable prognostic effects in 138 DLBCL patients with their malignant B-cell IGH-VDJ clonotypes identified (Figure A). The prognostic effects of TIL-Bs outweighed those of the germinal center B-cell-like/activated B-cell-like classification (Figure B). Second, patients with high frequencies of TIL-Bs compared with those without had significant upregulation of immune response genes by GEP (Figure C), higher CD4 T cell infiltration quantified by fluorescent mIHC (Figure D), and enrichment of EcoTyper-defined specific cell states, including significantly increased frequencies of B cell state S2 (pre-memory), CD4 T cell state S3 (naïve), follicular helper T cell state S3, and endothelial cell state S3, whereas lower frequencies of B cell state S5 (plasmablast) and follicular helper T cell state S1. Third, high TIL-B abundance in 79 ‘DJ-only’ clonotype cases and additional 52 cases assessed by light chain clonotype analysis showed similar favorable prognostic effects and associations with upregulated immune gene expression and CD4 T cell infiltration. Fourth, the identified GEP signatures, prominent with genes involved in T-dependent B cell activation and T cell activation and differentiation, showed significant prognostic effects in two GEO datasets. Fifth, TIL-B abundance showed significant prognostic effects in DLBCL cases infiltrated with T-cells in both the discovery study (Figure E) and validation study (Figure F, flow cytometry cohort). Conclusions: TIL-B frequencies and clonotypic diversity have remarkable prognostic and biological effects in DLBCL, which has significant implications for developing novel therapeutic strategies. Our study identified a new prognostic biomarker in DLBCL and an important player in anti-lymphoma immune responses, providing a new point of view to analyze the tumor biology in aggressive B-cell lymphoma and precisely identify prognostic determinants.

Background: Obe-cel is an autologous chimeric antigen receptor (CAR) T cell product with a novel CD19 binding domain CAT conferring a fast antigen off-rate designed to mitigate safety concerns and improve persistence over approved CD19 CAR T therapies. Early results from the pivotal FELIX study Phase IIA cohort (N=94) were recently presented (Roddie C et al. J Clin Oncol 2023;41[16 Suppl]:7000). We report findings from a pooled analysis of all patients (pts) treated to date with obe-cel in the FELIX Phase Ib/II study (NCT04404660), with a focus on pts with low leukemia burden prior to obe-cel infusion. Methods: The FELIX study enrolled adults with R/R B-ALL at screening with either morphological disease ≥5% bone marrow (BM) blasts (Cohort A), or in ≥2 nd complete remission (CR)/CR with incomplete hematologic recovery (CRi) with measurable residual disease (MRD) (Cohort B), or with isolated extramedullary disease (EMD) (Cohort C). The Phase Ib part of the study enrolled Cohorts A and B; the Phase II part enrolled Cohorts A, B, and C. CAR T products were generated from leukapheresis material using an automated process. Pts received bridging therapy as needed and lymphodepletion with fludarabine (4 × 30mg/m 2) and cyclophosphamide (2 × 500mg/m 2). A target dose of 410 × 10 6 CAR T cells was infused as a split dose on Days 1 and 10 based on pre-lymphodepletion BM blast burden. The primary endpoint was overall remission rate (best response of CR/CRi by independent review). Secondary endpoints included duration of remission (DoR), MRD negative remission rate, safety, and CAR T expansion/persistence. This pooled analysis included data from pts treated with obe-cel across all cohorts in the Phase Ib/II parts of the study. Low leukemia burden was defined as morphological remission per investigator assessment (<5% BM blasts without EMD) as measured at screening or at the start of lymphodepletion. Results: Between September 2020 and December 2022, 152 pts were enrolled and underwent leukapheresis. As of 16 March 2023, obe-cel was successfully administered to 126/152 (83%) pts (Phase Ib: Cohort A n=13, B n=3; Phase II: Cohort A n=94, B n=9, C n=7). Baseline characteristics at screening (n=126): median age 46.5 (range 20-81) yrs; Philadelphia positive B-ALL 27%; median 2 (range 1-6) prior lines of therapy; prior blinatumomab/inotuzumab 42%/32%; median BM blast burden 37% (range 0-100) including 23% pts with EMD; prior allogeneic stem cell transplant 44%. At a median follow up of 11.0 (range 0.9-30.6) months, the CR/CRi rate was 77% (95/124 response evaluable pts) with CR rate 57% (71/124). Among MRD evaluable responders, 96% achieved MRD negative status by central flow cytometry analysis. Median DoR was not reached at the current follow up. Low rates of Grade (Gr) ≥3 cytokine release syndrome (CRS; 2.4%) and/or Gr ≥3 immune effector cell associated neurotoxicity syndrome (ICANS; 7.1%) were observed. CAR T expansion was similar across the Phase Ib/II cohorts and CAR T persistence was ongoing in the majority of responders at the current follow up. Preliminary data indicate favorable efficacy and safety in pts with low leukemia burden prior to obe-cel infusion. Among 12 pts with MRD at screening (Cohort B), two pts were not evaluable and 9/10 evaluable pts achieved CR/CRi, with 100% achieving MRD negative status by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no Gr ≥3 CRS was observed; one pt had Gr ≥3 ICANS. In a subset of 28 pts (across all cohorts) in morphological remission at the time of lymphodepletion, 24/27 (89%) response evaluable pts achieved CR/CRi and 100% of MRD evaluable responders achieved MRD negative CR/CRi by central flow cytometry analysis post obe-cel. Median DoR was not reached at the current follow up. In this subset, no pts experienced Gr ≥3 CRS/ICANS. Conclusions:This pooled analysis of data from all pts treated to date in the FELIX study demonstrates high rates of CR/CRi after obe-cel treatment, durable responses (median DoR not reached), and a favorable safety profile. Preliminary data suggest better outcomes in pts with low leukemia burden at screening/lymphodepletion, with higher rates of deep MRD negative complete remission, median DoR not reached at the current follow up, no Gr ≥3 CRS and one Gr ≥3 ICANS. These data support further exploration of CAR T therapy earlier in the treatment algorithm for adults with ALL.

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Bridging therapy, defined as anti-leukemia therapy given between apheresis and lymphodepleting chemotherapy, was permitted on the pivotal ZUMA-3 trial. The optimal bridging therapy is unknown in this setting. Here we report patient and disease characteristics in those receiving bridging therapies prior to brexu-cel and the impact of bridging on clinical outcomes in a large multicenter cohort. Methods and Results: ROCCA includes 25 US institutions contributing retrospective data from 152 B-ALL patients treated with standard of care brexu-cel between 2021-2023. Ninety-nine patients (65%) received bridging therapy, while 53 patients (35%) received no bridging therapy. Bridging therapy consisted of cytotoxic chemotherapy ( n=65, 66%), immunotherapy ( n=26, 26%; 23 inotuzumab, 3 blinatumomab), tyrosine kinase inhibitors (TKI) ( n=20, 20%; 16 ponatinib), steroids only ( n=10, 10%), and intrathecal chemotherapy ( n=22, 22%). The median age of the cohort was 46 (IQR 32-61). Patients were heavily pre-treated with a median of 4 prior lines of therapy. The median days from apheresis to infusion was 33 (IQR 26-42). 119 patients had known pre-apheresis blast counts; the bridging group had higher pre-apheresis blast burden, with 21 of 76 patients (28%) having ≥ 50% blasts compared to only 5 of 43 patients (12%) in the no bridging group ( p=0.02). In addition, more patients who received bridging had pre-apheresis extramedullary disease (32% vs. 15%, p=0.02). All other baseline characteristics were similar between the two groups (Table 1). Fifty-four (54%) patients had response assessment after bridging therapy and prior to brexu-cel infusion. In patients who received inotuzumab for pre-apheresis active disease, defined as ≥ 5% blasts, 6 of 13 (46%) who had post-bridging assessment achieved a complete response (CR; 5 measurable residual disease (MRD)+, 1 MRD-), with a mean proportional reduction in blast burden of 46% from baseline. In contrast, after chemotherapy bridging, only 2 of 16 patients (13%) with pre-apheresis active disease had a CR. Patients receiving chemotherapy bridging had a mean proportional increase in blast burden of 4.4%. In recipients of TKI bridging, 2 of 4 patients (50%) with pre-apheresis active disease had a CR. Compared to no bridging, patients in the bridging group had similar rates of grade 3 or 4 CRS (9% bridging vs. 8% no bridging, p=0.73) and grade 3 or 4 ICANS (34% vs. 26%, p=0.32). In univariate analysis, there was no statistically significant difference in day 28 response with 63 patients (72%) achieving MRD- complete response in the bridging group as compared to 36 patients (78%) in the no bridging group ( p=0.60). Non-relapse mortality was similar between the two groups (17% bridging vs. 9% no bridging, p=0.20). Overall survival (OS) and progression-free survival (PFS) were superior in the no bridging group: 1-year OS 74.7% vs 56.8% (log-rank p=0.04), and 1-year PFS 57.3% vs 41.7% (log-rank p=0.04). In a multivariate analysis stratified by bridging and pre-apheresis disease burden, patients with pre-apheresis blasts ≥ 5% and bridging had worse survival than ≥ 5% blasts and no bridging: 1-year OS 45.3% vs. 87.5% and 1-year PFS 27.7% vs. 64.3% (Figure 1). However, patients with < 5% blasts had similar survival regardless of bridging. Conclusions: In our real-world analysis, adults with R/R B-ALL receiving bridging therapy had a higher disease burden at baseline. Despite greater baseline disease, there were no significant differences in toxicity and day 28 response in those receiving bridging therapy vs. not. While survival was inferior in patients with pre-apheresis active disease who received bridging, this may be confounded by the degree of tumor burden. In patients with < 5% blasts pre-apheresis, bridging did not impact survival. Furthermore, inotuzumab bridging demonstrated the most significant disease debulking. However, the comparisons in this study are limited by the variability in practice for post-bridging disease reassessment and the small proportion of patients with active disease who did not receive bridging. A more uniform approach to peri-CAR disease assessment would enable more robust study of optimal bridging strategies.

In this paper we report on the inaugural meetings of the Musical Care International Network held online in 2022. The term “musical care” is defined by Spiro and Sanfilippo (2022) as “the role of music—music listening as well as music-making—in supporting any aspect of people's developmental or health needs” (pp. 2–3). Musical care takes varied forms in different cultural contexts and involves people from different disciplines and areas of expertise. Therefore, the Musical Care International Network takes an interdisciplinary and international approach and aims to better reflect the disciplinary, geographic, and cultural diversity relevant to musical care. Forty-two delegates participated in 5 inaugural meetings over 2 days, representing 24 countries and numerous disciplines and areas of practice. Based on the meetings, the aims of this paper are to (1) better understand the diverse practices, applications, contexts, and impacts of musical care around the globe and (2) introduce the Musical Care International Network. Transcriptions of the recordings, alongside notes taken by the hosts, were used to summarise the conversations. The discussions developed ideas in three areas: (a) musical care as context-dependent and social, (b) musical care's position within the broader research and practice context, and (c) debates about the impact of and evidence for musical care. We can conclude that musical care refers to context-dependent and social phenomena. The term musical care was seen as useful in talking across boundaries while not minimizing individual disciplinary and professional expertise. The use of the term was seen to help balance the importance and place of multiple disciplines, with a role to play in the development of a collective identity. This collective identity was seen as important in advocacy and in helping to shape policy. The paper closes with proposed future directions for the network and its emerging mission statement.

Abstract Purpose: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. Experimental Design: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. Results: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased pre-memory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell–like/activated B-cell–like classification and TIL-T frequency. The identified TIL-B–high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. Conclusions: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.

Surgical treatment for Legg–Calve–Perthes disease (LCPD) is recommended for older children with moderate to severe disease. We sought to determine whether double osteotomies lead to improved radiologic outcomes compared to reported non-operative outcomes. Patients older than 6 years of age diagnosed with LCPD lateral pillar B or C who were treated with pelvic and femoral osteotomies were included. Radiologic outcomes and leg-length discrepancies were assessed using the Stulberg classification and were compared with the current literature. Fifteen hips in fourteen patients were treated with double osteotomy for LCPD, and seven had lateral pillar C disease (47%). The mean age at surgery was 8.6 years (range, 7.2–10.4) and the mean age at follow-up was 20.2 years (range, 14.2–35.6). At a mean 11.6-year follow-up (range: 6.3–25.2), double osteotomy resulted in 40% of patients having Stulberg I/II scores, 27% having Stulberg III scores, and 33% having Stulberg IV/V scores. The mean leg-length discrepancy was 1.4 cm in lateral pillar C patients compared to 0.8 cm in lateral pillar B patients. Four patients underwent additional surgeries, including two who required total hip arthroplasty. Double osteotomy as an alternative surgical procedure for the treatment of LCPD did not show improved outcomes when compared to historic non-operative cohorts.