Citations

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Abstract Introduction: MYC+BCL2+ double expression (DE) is a biomarker for poor prognosis in diffuse large B-cell lymphoma (DLBCL), likely due to the cooperation between MYC and BCL2 oncoproteins in tumor cells. However, as generally MYC and BCL2 are separately assessed on two different slides by immunohistochemistry (IHC), MYC+ and BCL2+ results are from different cells. With the WHO-recommended cutoffs, ≥40% for MYC and ≥50% for BCL2 (sum < 100%), there is chance that the so-called DE comes from non-overlapping regions of the tumor (not single-cell DE). Moreover, tumor expression scores based on morphology assessment often vary among pathologists. In this study, we performed fluorescent multiplex IHC (fmIHC) using a MultiOmyxTM immunofluorescence platform (NeoGenomics Laboratories, Inc.) to determine single-cell MYC and BCL2 co-expression for prognostic analysis in DLBCL. Patients and Methods: Co-expression of MYC, BCL2, and 11 immunophenotypic markers by fmIHC was digitally quantified for 547 patients with DLBCL. Percentage of cells with MYC/BCL2 double or single expression was calculated for various cell types. Prognostic analysis was performed for de novo DLBCL cases, including 108 patients treated CHOP chemotherapy, and 356 patients treated with rituximab (R)-CHOP. Results: First, although MYC and BCL2 were expressed in multiple cell types, the vast majority (>90%) of MYC+BCL2+ DE cells were lymphoma cells. Frequencies of MYC and BCL2 co-expression were consistent with random distribution of independent MYC/BCL2 expression in positive cases. The activated B-cell-like subtype compared with the germinal center B-cell-like subtype had a significantly higher mean percentage of MYC+BCL2+ DE, but not single BCL2 or MYC expression, in PAX5+ cells. Second, in both the R-CHOP and CHOP cohorts, high percentages of DE in PAX5+ cells and in all DAPI+ cells were associated with significantly poorer survival of DLBCL patients. Very high percentage of single BCL2 expression in PAX5+ cells was also associated with poorer survival, however, only in a small number of patients in both cohorts. Only in the R-CHOP cohort, high single MYC expression in PAX5+ cells (in a significant proportion of the cohort) was associated with significantly poorer overall survival. In the R-CHOP cohort, eight cases had MYC/BCL2 double hit by FISH, including 3 cases with MYC/IGH fusions (DE) and 5 cases with MYC/non-IGH rearrangements (only one DE). The exclusion of these double hit cases did not impact the significance of DE and single MYC+ expression. Summary: True MYC+BCL2+ double protein expression at the single cell level is predominantly in lymphoma cells, and associated with significantly poor survival of DLBCL patients. Our results suggest high cutoffs for common MYC/BCL2 IHC to identify true double expressor lymphoma. Citation Format: Zijun Yidan Xu-Monette, Yong Li, Qingyan Au, Harry Nunns, Wenyu Shi, Alexandar Tzankov, Carlo Visco, Govind Bhagat, Eric Hsi, Xiaoxian X. Zhao, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Fredrick B. Hagemeister, Andrew Song, Michele Pellegrino, Heounjeong Go, Maurilio Ponzoni, Andrés Ferreri, Michael B. Møller, Benjamin Parsons, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Mingzhi Zhang, Bing Xu, Ken H. Young. Single-cell double expression of MYC and BCL2 proteins by fluorescent multiplex IHC is mainly in lymphoma cells with significant prognostic impact in large B-cell lymphoma while suggesting high cutoffs for routine IHC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6418.

AbstractAxicabtagene ciloleucel (axi‐cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real‐world effectiveness of axi‐cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi‐cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR‐1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow‐up of 24 months for patients receiving axi‐cel and 60 months for patients receiving CIT, 12‐month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24–0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi‐cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi‐cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi‐cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi‐cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

OBJECTIVE Dural arteriovenous fistulas (dAVFs) of the superior sagittal sinus (SSS) are uncommon and represent 5%–12% of all intracranial dAVFs. SSS dAVFs can be divided into two main subtypes. The first type involves direct arterialization of the SSS, whereas the second type consists of a parasagittal arteriovenous shunt draining into a cortical vein directly lateral to the SSS and has retrograde cortical venous drainage with only secondary involvement of the SSS. Descriptions of the latter type of SSS dAVF are limited. As such, the authors present a consecutive case series of parasagittal SSS dAVFs from their institution. They detail clinical presentation, treatment strategies, and clinical and radiographic outcomes. METHODS The authors retrospectively reviewed a prospectively collected database of dAVFs that were treated between 2017 and 2023. All dAVFs characterized by an arterialized parasagittal vein directly lateral to the SSS were included in this study. Baseline demographic, clinical, radiological, treatment, and outcome-specific variables of interest were abstracted. RESULTS One hundred fifty-four dAVFs were seen at the authors’ institution over the 6-year period of interest. Eight (5.2%) were parasagittal dAVFs. At initial diagnostic imaging, 7 were Cognard grade III and 1 was grade IV. All patients initially underwent embolization of their dAVF. Three patients did not have complete obliteration of their dAVF after the first embolization. One patient underwent further treatment with repeat embolization, and 1 underwent microsurgical disconnection—both resulted in complete occlusion of the dAVF. Seven dAVFs were obliterated at final follow-up and 1 remained patent as the patient refused further treatment despite angiographic progression of dAVF. All symptomatic patients had resolution of their symptoms, and the average length of follow-up was 16.8 months. CONCLUSIONS Treatment of parasagittal dAVFs consists of occluding the proximal portion of the parasagittal arterialized draining vein. Endovascular therapy with liquid embolic agents is usually the first line of treatment. Surgical ligation is a valid option if the fistula cannot be successfully obliterated with embolization. Symptoms related to the SSS dAVF resolve after their obliteration.

Objectives To investigate the impact of the COVID-19 pandemic as well as concomitant COVID-19 itself on stroke care, focusing on middle cerebral artery (MCA) territory infarctions. Design Registry-based study. Setting We used the National Inpatient Sample (NIS) database, which covers a wide range of hospitals within the USA. Participants The NIS was queried for patients with MCA strokes between 2016 and 2020. In total, 35 231 patients were included. Outcome measures Outcome measures were postprocedural complications, length of stays (LOSs), in-hospital mortality and non-routine discharge. Propensity score matching using all available baseline variables was performed to reduce confounders when comparing patients with and without concomitant COVID-19. Results Mechanical thrombectomy (MT) was performed in 48.4%, intravenous thrombolysis (IVT) in 38.2%, and both MT and IVT (MT+IVT) in 13.4% of patients. A gradual increase in the use of MT and an opposite decrease in the use of IVT (p<0.001) was detected during the study period. Overall, 25.0% of all patients were admitted for MCA strokes during the pandemic period (2020), of these 209 (2.4%) were concomitantly diagnosed with COVID-19. Patients with MCA strokes and concomitant COVID-19 were significantly younger (64.9 vs 70.0; p<0.001), had significantly worse NIH Stroke Severity scores, and worse outcomes in terms of LOS (12.3 vs 8.2; p<0.001), in-hospital mortality (26.3% vs 9.8%; p<0.001) and non-routine discharge (84.2% vs 76.9%; p=0.013), as compared with those without COVID-19. After matching, only in-hospital mortality rates remained significantly higher in patients with COVID-19 (26.7% vs 8.5%; p<0.001). Additionally, patients with COVID-19 had higher rates of thromboembolic (12.3% vs 7.6%; p=0.035) and respiratory (11.3% vs 6.6%; p=0.029) complications. Conclusions Among patients with MCA stroke, those with concomitant COVID-19 were significantly younger and had higher stroke severity scores. They were more likely to experience thromboembolic and respiratory complications and in-hospital mortality compared with matched controls.

BACKGROUND AND OBJECTIVES: Carotid endarterectomy (CEA) is a well-established treatment option for carotid stenosis. The choice between general anesthesia (GA) and nongeneral anesthesia (non-GA) during CEA remains a subject of debate, with concerns regarding perioperative complications, particularly myocardial infarctions. This study aimed to evaluate the outcomes associated with GA vs non-GA CEA using a large, nationwide database. METHODS: The National Surgical Quality Improvement Project database was queried for patients undergoing CEA between 2013 and 2020. Primary outcome measures including surgical outcomes and 30-day postoperative complications were compared between the 2 anesthesia methods, after 2:1 propensity score matching. RESULTS: After propensity score matching, a total of 25 356 patients (16 904 in the GA and 8452 in the non-GA group) were included. Non-GA compared with GA CEA was associated with significantly shorter operative times (101.9, 95% CI: 100.5-103.3 vs 115.8 95% CI: 114.4-117.2 minutes, P < .001), reduced length of hospital stays (2.3, 95% CI: 2.15-2.4 vs 2.5, 95% CI: 2.4-2.6 days, P < .001), and lower rates of 30-day postoperative complications, including myocardial infarctions (0.8% vs 1.2%, P = .003), unplanned intubations (0.8% vs 1.1%, P = .016), pneumonia (0.5% vs 1%, P < .001), and urinary tract infections (0.4% vs 0.7%, P = .003). These outcomes were notably more pronounced in the younger (≤70 years) and high morbidity (American Society of Anesthesiologists 3-5) cohorts. CONCLUSION: In this nationwide registry-based study, non-GA CEA was associated with better short-term outcomes in terms of perioperative complications, compared with GA CEA. The findings suggest that non-GA CEA may be a safer alternative, especially in younger patients and those with more comorbidities.

AbstractBackgroundAnimal models and human data have suggested macrophage‐driven immune dysregulation in diabetic gastroparesis (DG). Translocator protein (TSPO) upregulation has been suggested to indicate activated state of macrophages and ER176 is a high affinity third generation TSPO‐specific radioligand. The aim of this study was to determine feasibility of dynamic 11C‐ER 176 PET to identify macrophage activation in DG.MethodsTwelve patients, all females, were recruited (4 DG, 4 diabetics, and 4 healthy volunteers) for 11C‐ER 176 PET/CT scanning. The standardized uptake value (SUVmax) in the gastric fundus, body, pylorus, and descending part of the duodenum were compared between three groups using Kruskal‐Wallis test to perform the comparisons, and a p‐value of 0.05 was considered statistically significant.Key ResultsAge was comparable among the three groups with a median of 53 years. The uptake was higher in pylorus in diabetics compared to DG and healthy (SUVmax healthy 4.6 ± 0.2, diabetics 8.4 ± 4.1, DG 5.5 ± 1.0, p = 0.04). The uptake was similar in gastric fundus (9.0 ± 1.6, 13.1 ± 8.3, 7.8 ± 1.9 respectively, p = 0.3), body (7.7 ± 1.9, 13 ± 9.2, 7.8 ± 1.9 respectively, p = 0.8), and duodenum (6.2 ± 2.1, 9.5 ± 6.8, 7.0 ± 1.8 respectively, p = 0.6). No correlation was observed between SUVmax uptake and either HbA1C or fasting blood glucose.Conclusions and InferencesFemale diabetic gastroparesis patients did not demonstrate increased TSPO ligand 11C‐ER 176 uptake in the stomach. Possible explanations include lack of specificity of ligand for specific macrophage phenotypes in DG, sex effect, or small sample size. Further studies investigating non‐invasive ways of analyzing immune dysregulation in neurogastrointestinal disorders are warranted.

Abstract Background Although typically benign, 5% of spinal meningiomas (SMs) present with higher-grade features (World Health Organization grades 2 and 3). High-grade SMs are poorly studied and the role of adjuvant radiotherapy in their management remains controversial. We hence aimed to study the demographic characteristics of this rare tumor and investigate the outcomes associated with the use of surgery with adjuvant therapy in contrast to surgery alone. Methods The National Cancer Database was queried for patients with SMs from 2004 to 2017. Basic statistics were used to identify differences between low- and high-grade tumors in terms of baseline characteristics. Surgery with and without adjuvant radiotherapy were compared after (1:1) propensity-score matching. Kaplan–Meier survival analysis was conducted to study overall survival. All analyses were performed on R. Results A total of 13 184 patients diagnosed with SMs were included, of whom only 5% (n = 669) had high-grade SMs. Patients with high-grade SMs presented at a younger median age (57 years [IQR: 44–68] versus 65 years [54–75]; P &lt; .001) and were more commonly males (33% vs 20%; P &lt; .001). After propensity-score matching, survival analysis revealed similar overall survival outcomes in patients with high-grade SM undergoing both surgery and radiotherapy as compared to those only receiving surgery (P = .19). Conclusions This study reveals major demographic differences between high- and low-grade SMs. There were no benefits associated with the use of adjuvant radiotherapy. However, due to confounding, overall survival outcomes between patients receiving surgery alone and those receiving surgery with adjuvant radiotherapy are not causally interpretable.

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×106 and 600×106 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×106 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .