Citations

Objectives The aim of this study is to introduce the infrapedicular approach to CT-guided spine interventions, a specialized technique that can safely expand the scope of spine lesions amenable to treatment, and to document the feasibility in a variety of procedural scenarios to the extent possible with a retrospective case series. Methods Data from 24 cases performed at a single institution over a 10-year period were retrospectively reviewed to assess the technical feasibility and safety profile of the technique. Results The infrapedicular approach enabled a technically satisfactory procedural result in 24 cases (mean age 63.9 years, range 35–83 years). Two peri-procedural complications occurred, including a small pneumothorax and a cerebrospinal fluid leak, both of which resolved with conservative treatment. No lasting injurious effects or additional complications were identified. The infrapedicular approach was found to be particularly useful in multiple technically challenging scenarios: it facilitates access to lesions in the inferior vertebral body, allows biopsy, cement augmentation, or ablation of high thoracic lesions difficult to treat due to limitations of steep angulation of fluoroscopy and CT scanners, and enables treatment of large lesions by using multiple overlapping probes.

Abstract Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. The single-arm, open-label, Phase 2 HORIZON study (NCT02963493), conducted in Europe and the USA, demonstrated in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM), including those with triple-class-refractory and extramedullary disease, that melflufen in combination with dexamethasone showed clinically meaningful efficacy and a manageable safety profile (Richardson PG, et al. J Clin Oncol. 2021;39:757-767). Comparative trials between all regimens/agents are not feasible, and hence, real-world datasets may be valuable to allow the comparison of patient outcomes in single-arm clinical trials with similar patient populations in the real world. The objective of the REAL-world Myeloma (REALM) study was to compare clinical outcomes between patients in the COTA database and those of patients in the HORIZON study in order to compare routine care with melflufen. Methods: REALM is a retrospective, observational study using real-world data from 605 patients with RRMM collected in the COTA database, a USA-based real-world evidence database comprising longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of patients with cancer. Patients in REALM met the main HORIZON eligibility criteria (aged ≥18 years; ≥2 lines of prior therapy [including an immunomodulatory drug and a proteasome inhibitor]; refractory to pomalidomide and/or daratumumab on or after January 1, 2015; and received a line of therapy after meeting the inclusion criteria). Propensity score (PS) matching is a commonly used approach for comparing the effectiveness of 2 treatment options across different studies where individual patient data are available for both treatments. This abstract presents adjusted clinical outcome results based on 1:1 PS matching of patients in the COTA and HORIZON datasets for 12 covariates (COTA PS and HORIZON PS, Table 1). These covariates were considered important because they reflect patient characteristics that impact clinical outcomes and were validated in a feasibility study, and by independent experts. The primary endpoint of the HORIZON study was overall response rate. The primary endpoints of the REALM study were time to treatment discontinuation (TTD) and time to next treatment (TTNT), to mitigate against missing treatment response data in the COTA database identified in the feasibility study. Results: Selected patient demographic and clinical characteristics were generally well matched (Table 1) between patients from COTA PS (n=110) and HORIZON PS (n=110), except for the Eastern Cooperative Oncology Group performance status, which was better in the COTA PS dataset than in the HORIZON PS dataset. Patients in both the COTA PS and the HORIZON PS datasets were predominantly male and White. Patients had a median age of 67 years in the COTA PS dataset and 64 years in the HORIZON PS dataset, with a median of 4 and 5 prior lines of therapy, respectively. The median time since first diagnosis to index data was 60.19 months in the COTA PS dataset and 72.56 months in the HORIZON PS dataset. The median TTNT (95% confidence interval [CI]) in the COTA PS dataset versus the HORIZON PS dataset was 4.6 (3.7-6.9) months and 5.9 (4.7-7.7) months, respectively (p=0.949). The median TTD (95% CI) in the COTA PS dataset versus the HORIZON PS dataset was 3.2 (2.6-3.9) months and 3.9 (3.0-4.6) months, respectively (p=0.642). Conclusions: Pharmacoepidemiologic methods using individual patient data play an important role in evaluating the effectiveness of treatments in the absence of randomized controlled trial data. Patients with RRMM receiving melflufen in combination with dexamethasone noted a trend toward improved TTNT and TTD compared with corresponding real-world treatment approaches. This benefit may be clinically meaningful especially in the triple-class-refractory patient population, which remains an unmet need in RRMM. Figure 1 Figure 1. Disclosures Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Wang: COTA, Inc.: Current Employment, Other: Equity ownership. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Jansson Blixt: Oncopeptides: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cripps: Oncopeptides: Other: Independent consultant. Zavisic: Oncopeptides: Current Employment, Current holder of stock options in a privately-held company. Ramasamy: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Celgene (BMS): Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: It has become increasingly apparent that chimeric antigen receptor T (CART) cell activation and differentiation level is an important determinant of CART cell fate and response to therapy. In this study, we aimed to 1) measure levels of activation-induced surface death receptors and ligands on CART cells; 2) investigate how CART cell activation could impact their fitness and clinical responses, and 3) identify cell-based targets to modulate CART cell activation, apoptosis, and cytotoxicity to improve anti-tumor activity. Methods: We performed flow cytometric studies on ex-vivo stimulated, clinically annotated CART products of patients with large B cell lymphoma from the pivotal ZUMA-1 clinical trial that led to FDA-approved Axicabtagene ciloleucel (Axi-Cel). We investigated possible correlations of a number of surface death receptors and ligands with T cell differentiation status and post-infusion CART cell expansion, utilizing samples from ZUMA-1 patients who achieved a complete response as a best outcome ('responders') vs patients who achieved stable or progressive disease('non-responders'). CART cell effector functions in vitro were measured, and CART apoptosis was assessed using Annexin V. For in vitro and in vivo functional studies, we used CART19 generated from healthy donors (HD CART19) as indicated in the specific experiment. CRISPR/Cas9 was employed during CART cell production to disrupt specific genes. A xenograft model of lymphoma was used to investigate the in vivo antitumor activity of CART19. Results: Following an ex vivo stimulation of Axi-Cel products with CD19 + target cells, we observed upregulation of death receptors and ligands in CART19 from non-responders, compared to responders. We also observed a possible association between such upregulated surface markers with CART cell differentiation as measured by CCR7 expression. In an extended in vitro co-culture assay, where HD CART19 cells were repeatedly stimulated through the CAR, we found that tumor necrosis factor α receptor 2 (TNFR2), unlike other death receptors and ligands, was persistently elevated, suggesting a possible role for TNFR2 in long-term antigen-dependent CART19 dysfunction (Figure 1A). We further found that HD CART19 upregulate TNFR2, but not TNFR1, upon CAR stimulation (Figure 1B). While non-specific TCR activation (CD3 stimulation) of HD CART19 cells protected them from activation-induced apoptosis, antigen-specific activation through the CAR resulted in significant initiation of apoptosis within 2 hours of stimulation (Figure 1C). Having identified a possible association between TNFR2 and CART19 dysfunction, we aimed to study the impact of TNFR2 knockout on HD CART19 functions. Using CRISPR/Cas9 during CART cell manufacturing, we generated TNFR2 k/o HD CART19 cells with a knockout efficiency of around 50%, where the expression levels of TNFR2 in activated CART19 cells were reduced, compared to control CART19 cells (with non-targeting gRNA CRISPR/Cas9, Figure 1D). TNFR2 k/o CART19 cells demonstrated reduced early activation surface markers compared to control CART19, as measured by CD25 and CD69 surface expression (Figure 1E), reduced apoptosis initiation as measured by the Annexin V assay (Figure 1F), and enhanced antigen-specific proliferation and cytotoxicity (Figure 1G). Finally, in an in vivo xenograft model of CD19 + lymphoma, TNFR2 k/o CART19 resulted in enhanced CART cell expansion and anti-tumor activity (Figure 1H). Conclusions: Our results indicate that TNFR2 plays a role in early activation and apoptosis initiation of CART19 following CAR stimulation with CD19 + target cells and present TNFR2 knockout as a strategy to enhance CART19 anti-tumor activity. Figure 1 Figure 1. Disclosures Cox: Humanigen: Patents & Royalties. Sakemura: Humanigen: Patents & Royalties. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Genentech: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Research Funding; Tolero Pharmaceuticals: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees. Scholler: Kite: Current Employment. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Mattie: Kite: Current Employment. Kim: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Filosto: Kite, a Gilead Company: Current Employment; Tusk Therapeutics: Patents & Royalties: or other intellecular property; Gilead Sciences: Other: stock or other ownership . Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding.

Osteochondritis dissecans (OCD) is a joint disease that is prevalent among youth athletes. Medical ultrasound is currently limited in its ability to detect and monitor OCD due to limitations of current Delay-and-Sum (DAS) reconstruction algorithms. In this work, we used a Delay-Multiply-and-Sum (DMAS) reconstruction algorithm to improve medical ultrasound’s ability to diagnose OCD. We artificially generated OCD lesions in unfixed cadaveric elbows and imaged them with a research ultrasound machine. We also imaged these cadaveric limbs with x-ray computed tomography (CT) with a high-resolution acquisition. These CT images were used as a gold standard for OCD geometry. We reconstructed the ultrasound images using both DAS and DMAS algorithms and compared them quantitatively by taking several profiles across the images of the artificial OCD lesions. The image metrics that we measured within these profiles were OCD lesion contrast, bone interface clarity, and lesion crack thickness accuracy. We found that the DMAS algorithm improved OCD lesion contrast by up to 26% when compared to DAS. We also found that the DMAS algorithm reduced the variability of bone interface clarity overall. Future work will involve an in vivo study, as well as optimization, of the DMAS algorithm for OCD lesion imaging.

Abstract PURPOSE Vertebral compression fracture (VCF) is a potential adverse effect following stereotactic body radiation therapy (SBRT) for spinal metastases. In this analysis, we developed and internally validated a risk stratification model for VCF. METHODS From an initial set of 680 treatments, we excluded those with proton therapy, prior surgical intervention, or missing data. The final dataset had 464 treatments in 313 patients. Delineations of VCF and all radiographic components of the spinal instability neoplastic score (SINS) were determined by a radiologist. Recursive partitioning analysis (RPA) was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was used as the criterion for node splitting. RESULTS With a median follow-up of 21 months, we identified 84 VCF (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median 9 months (IQR: 3 – 21) to VCF. From an initial set of 15 candidate variables, six were identified using the backwards selection method, feature importance testing, and a correlation heatmap. Four were then selected in the highest-fidelity RPA models: epidural tumor extension, lumbar location, gross tumor volume > 10 cc, and SINS > 6. One point was assigned to each variable, and the resulting multivariate Cox model had a concordance of 0.760. Each one point increase in score was associated with increasing rates of VCF. Low-risk lesions (score: 0-1, n=273) had 2-year freedom from VCF of 92%, compared to 80% for intermediate-risk (score: 2, n=99) and 56% (score: 3-4, n=92) for high-risk lesions (p < 0.0001). Cumulative incidence curves with death as a competing risk showed increased VCF with higher scores via Gray’s test (p < 0.001). CONCLUSIONS Our internally-validated model identifies a subgroup of patients with high risk for VCF who may benefit from prophylactic surgical stabilization or vertebroplasty.

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.