Citations

Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6. The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.

AbstractObjectiveWe describe neurologic phenotype, clinical associations, and outcomes in autoimmune brainstem encephalitis.MethodsMedical records of neural‐IgG positive autoimmune brainstem encephalitis patients diagnosed at Mayo Clinic (January 1, 2006–December 31, 2022) were reviewed.ResultsNinety‐eight patients (57 male) were included. Median age of symptom onset was 51 years (range, 8 months‐85 years). Frequent presenting features were ≥1: diplopia (80%), ataxia (78%), dysarthria (68%), vestibulocochlear symptoms (67%), dysphagia (61%), nausea/vomiting (42%), and facial weakness (32%). Altered mental status (11%) was uncommon. Neural antibodies detected were as follows: KLHL‐11 (26 patients), GAD65 (high titer, 12), ANNA‐1 (anti‐Hu, 8), ANNA‐2 (anti‐Ri, 8), Ma2 (7), IgLON‐5 (6), AQP4 (6), MOG (4), glycine receptor (4), GQ1B (4), PCA‐1 (anti‐Yo, 4), DPPX (2), neurochondrin (2), neurofilament (2), NMDA‐R (2), AGNA‐1 (SOX‐1, 1), ANNA‐3 (DACH1, 1), amphiphysin (1), CRMP‐5 (1), ITPR‐1 (1), PCA‐Tr (DNER, 1), and PDE10A (1). Cancer was identified in 55 patients: germ cell (23 patients; 3 extra‐testicular), ductal breast adenocarcinoma (8), small cell carcinoma (6, lung 4), adenocarcinomas (6), neuroendocrine carcinoma (3), hematologic (2), squamous cell (2), and other (7). Median modified Ranking score (mRS) at last follow‐up was 3 (range, 0–6). Factors associated with poor outcome included abnormal brain MRI, bulbar symptoms, and elevated CSF IgG index. Kaplan–Meier analysis revealed faster progression to wheelchair in patients who were immunotherapy refractory and with elevated CSF IgG index. Diagnostic criteria for autoimmune brainstem encephalitis (definite and probable) are proposed.InterpretationAutoimmune brainstem encephalitis is a distinct clinical subphenotype of autoimmune encephalitis. Abnormal brain MRI, bulbar symptoms, and elevated CSF‐IgG index associate with poor outcome.

Abstract Vasculitic neuropathy is caused by inflammatory destruction of nerve blood vessels resulting in nerve ischaemia. Nerve vasculitis can be divided into two categories based on vessel size: large-arteriole vasculitis (≥75 µm) and microvasculitis (<75 µm). Herein, we characterize the clinical features of nerve large-arteriole vasculitis in comparison to nerve microvasculitis. This is a retrospective cohort study of patients evaluated and biopsied at Mayo sites between 2001 and 2020. We collected clinical and histopathological data from patients whose nerve biopsies were either diagnostic or highly suggestive of nerve vasculitis. Two hundred and seventy-eight cases were identified: 125 cases of large-arteriole vasculitis and 153 cases of microvasculitis. Nerve large-arteriole vasculitis presented with a more acute (50.4% versus 26.8%) versus chronic onset (33.6% versus 57.5%) than nerve microvasculitis (P = 0.0001). Nerve microvasculitis had longer mean time to diagnosis (10.5 versus 4.3 months; P < 0.0001) and longer time to plateau (8.9 versus 3.5 months; P < 0.0001). Nerve large-arteriole vasculitis typically presented as distal asymmetric polyneuropathy (48.0%), whereas nerve microvasculitis typically presented as radiculoplexus neuropathy/polyradiculoneuropathy (more proximal involvement of shoulder and thigh) (43.8%) (P < 0.0001). Systemic autoimmune disease was more common in nerve large-arteriole vasculitis (70.4% versus 22.9%, odds ratio, 8.0; 95% confidence interval, 4.7–13.7; P < 0.0001). Nerve microvasculitis was significantly related to non-systemic vasculitis (71% versus 23%, odds ratio, 7.9; 95% confidence interval, 4.6–13.6; P < 0.0001). Nerve microvasculitis had more autonomic involvement (24.2% versus 7.2%, odds ratio, 4.1; 95% confidence interval, 1.9–8.9; P = 0.0002). Nerve large-arteriole vasculitis and nerve microvasculitis have different but overlapping clinical features. Nerve large-arteriole vasculitis usually presents with acute onset, distal asymmetric polyneuropathy, associated with other autoimmune diseases and systemic involvement. In contrast, nerve microvasculitis usually presents with a subacute/chronic onset, as radiculoplexus neuropathy/polyradiculopathy (distal and proximal pattern) with autonomic involvement, and is more often a form of non-systemic vasculitis.

Objectives To reassess the role of primary retroperitoneal lymph node dissection (RPLND) in patients with marker‐negative non‐seminomatous germ cell tumour (NSGCT) clinical stage (CS) 2a, to explore results in patients with CS 2b and to evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Materials and Methods Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for CS 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and disease‐free survival (DFS). Results A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.07; P = 0.03), but no association was observed with DFS. The 5‐year DFS rates in marker negative CS 2a and 2b were 79% and 76%. In men with non‐teratomatous viable cancer in the RPLND specimen, the 5‐year DFS rates for CS 2a and 2b were 95% and 87% with adjuvant chemotherapy, and 67% and 74% without adjuvant chemotherapy. We did not identify an association between the number of adjuvant chemotherapy cycles and DFS. Conclusions Our study suggests considering primary RPLND not only in marker‐negative CS 2a but also in CS 2b. Further research should determine the efficacy of primary RPLND in men with CS 2c and marker‐positive CS 2, as well as which patients may benefit from adjuvant chemotherapy and the optimal cycle number.

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.