Citations

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.

Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. Results: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)–methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. Conclusions: The combination of three key features—PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule—supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217

AbstractCancer and its treatment produce deleterious symptoms across the phases of care. Poorly controlled symptoms negatively affect quality of life and result in increased health-care needs and hospitalization. The Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium was created to develop 3 large-scale, systematic symptom management systems, deployed through electronic health record platforms, and to test them in pragmatic, randomized, hybrid effectiveness and implementation trials. Here, we describe the IMPACT Consortium’s conceptual framework, its organizational components, and plans for evaluation. The study designs and lessons learned are highlighted in the context of disruptions related to the COVID-19 pandemic.

Abstract Percutaneous core-needle biopsy (PCNB) plays a growing and essential role in many medical specialties. Proper and effective use of various PCNB devices requires basic understanding of how they function. Current literature lacks a detailed overview and illustration of needle function and design differences, a potentially valuable reference for users ranging from early trainees to experts who are less familiar with certain devices. This pictorial aims to provide such an overview, using diagrams and magnified photographs to illustrate the intricate components of these devices. Following a brief historical review of biopsy needle technology for context, we emphasize distinctions in design between 2 major classes of PCNB devices (side- and end-cutting devices), focusing on practical implications for how each device is most effectively used. We believe a nuanced understanding of biopsy device function sheds light on certain lingering ambiguities in biopsy practice, such as the optimal needle gauge in organ biopsy, the benefits and risks associated with coaxial technique, the impact of needle selection and technique on bleeding, and the risk of unsuccessful sampling. In a subsequent pictorial, we will draw on the concepts presented here to illustrate examples of biopsy needle failure and how unrecognized needle failure can be an important and often preventable cause of increased biopsy risk and lower tissue yield.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701 .

Abstract Background Warfarin monitoring may be done at the point-of-care (POC) at home, in a clinic environment, or be performed using plasma specimens in a central laboratory. With a goal of standardizing International Normalization Ratio (INR) measurements and improving data integrity by enabling electronic transmission of results from any location, we evaluated two POC INR devices against an internal plasma INR reference method. Methods We conducted a multicenter study to test the accuracy of two commercially available point of care devices: Coag-Sense PT2 Meter (Coagusense, Inc., Fremont, CA) and CoaguChek XS Pro or XS Plus (Roche Diagnostics, Indianapolis, IN) compared with plasma INR values among warfarin treated patients. Bias and linear regression analysis were assessed for device-plasma INR comparisons. Warfarin dosing decisions were assessed for each device compared to an internal plasma INR reference method (Instrumentation Laboratories ACLTOP 500, 550, 750 analyzers (Werfen Diagnostics, Bedford MA) in one of three CLIA-certified laboratories. The thromboplastin used at our institution for INR measures is HemosIL RecombiPlasTin 2G (R2G) reagent (Werfen Diagnostics, Bedford MA) which has an International Sensitivity Index (ISI) of 1.0. Results Two hundred ninety-nine warfarin patients treated across three Mayo Clinic sites agreed to participate in the study. Common anticoagulant indications were atrial fibrillation (63.9%), venous thromboembolism (21.7%) and heart valve prosthesis (15.4%) with a 2.0–3.0 INR target range for 93.6% of patients. For the CoaguChek devices, 81.3% of values fell within 0.2 INR units of plasma INR referent and 95.3% within 0.4 units. The correlation between CoaguChek whole blood and plasma INR was excellent (R2 = 0.93). For the Coag-Sense device, 34.1% of values fell within 0.2 INR units and 60.2% within 0.4 INR units of plasma INR values, with a slightly weaker correlation between Coag-Sense whole blood and plasma INR (R2 = 0.83; P < 0.0001). Mean (± standard deviation) deviation from plasma INR was 0.04 ± 0.2 for CoaguChek compared to 0.4 ± 0.3 for Coag-Sense (P < 0.0001). The difference between POC devices was largely attributed to systematic negative bias between Coag-Sense and ACL TOP plasma INR values. Using the plasma INR as the reference method for dosing decision making, appropriate dosing recommendations would have occurred for 97.7% of CoaguChek and 81.6% of Coag-Sense results. Conclusion Compared to our institution's plasma reference method, INR values obtained from the CoaguChek devices (XS Pro and XS Plus) exhibited less systematic bias compared to the Coag-Sense values. This translates to greater percentage of concordant management decisions between POC and laboratory plasma INR methods when the CoaguChek device is used.

See the Reply by Semla and Steinman in this issue.

Purpose: The purpose of this article was to appraise the various methods of reconstruction for meningomyelocele (MMC) defects. Methods: A systematic review of the literature was performed to evaluate all reconstructions for MMC. The method of reconstruction was categorized by: primary closure with and without fascial flaps, random pattern flaps, VY advancement flaps (VY), perforator flaps, and myocutaneous flaps. Perforator flaps were subsequently subcategorized based on the type of flap. Results: Upon systematic review, 567 articles were screened with 104 articles assessed for eligibility. Twenty-nine articles were further reviewed and included for qualitative synthesis. Two hundred seventy patients underwent MMC repair. The lowest rates of major wound complications (MWC) were associated with myocutaneous and random pattern flaps. A majority of MWC was in the lumbrosacral/sacral region (87.5% of MWC). In this region, random patterns and perforator flaps demonstrated the lowest rate of MWC (4.5, 8.1%). Conclusions: Plastic surgery consultation should be strongly considered for MMC with defects in the lumbosacral/sacral region. Perforator flaps are excellent options for the reconstruction of these defects.