A Comprehensive Toxicity and Efficacy Analysis of Different Bridging Therapies Prior to Anti CD19-CAR-T Cell Therapy in Patients with DLBCL- a National Multi-Center Cohort Study

Introduction - Data regarding efficacy and toxicity of different bridging strategies prior to CAR-T therapy are scanty. Tisagenlecleucel (Kymriah TM, Novartis) and axictagene ciloleucel (Yescarta TM, Kite/Gilead) were commercially approved for relapsed/refractory (R/R) DLBCL since 2019. We analyzed real-life data of CAR-T therapy among all consecutive patients who were treated in 4 different CAR-T centers in Israel. Methods - From May 2019, 144 R/R DLBCL patients underwent apheresis and continued to receive bridging therapy that included chemo/immunotherapy (n=78, 54%), radiation (n=11, 7.6%), chemoradiation (n=22, 15%), steroids only (n=5, 3.5%) and none (n=28, 19.4%). All patients were evaluated after bridging therapy and prior to CAR-T infusion by PETCT (96%) or CT scan (4%). Results - Median age was 68 (20-88) years and Median follow-up was 13 (4-26) months. All 144 patients underwent successful apheresis. Reasoning for choosing specific bridging therapy was based on low tumor mass (n= 23, 16%), high tumor mass (n=73, 51%), frailty of the patient (n=27, 19%), ongoing significant prior regimen's toxicities (n=14, 10%) and local disease (n=7, 4%). In patients given radiation therapy median dose was 23 (range, 8-30) Gy. In patients given chemo/immunotherapy or chemoradiation, sepsis was the main complications (9% of all patients) during bridging therapy. However, none of the patients had a fatal event. 14 patients (9.7%) did not proceed to CAR-T infusion; 6 (4.2%) had disease progression and died; 8 (5.6%) had manufacture failure). Among the 130 patients that received CAR-T infusion, PET-CT prior to preparative regimen demonstrated CR/PR status in 38%, 50%, 40%, 17%, and 16% of patients given chemotherapy, radiation, chemoradiation, steroids only, or no bridging therapy, respectively (p=.15), Figure 1. Any bridging therapy was associated with a better disease control compared to either steroids only or no treatment (p=.012). There were no differences in the incidences of overall CRS (p=.692), grade 3-4 CRS (p=.196), overall ICANS (p=.941), grade 3-4 ICANS (p=.281), acute kidney disease (p=.244), and liver dysfunction (p=.45) between the 5 different bridging strategies. Cardiovascular complications were more common after chemoradiation (36%), chemotherapy (19%) and radiation (13%), compared with steroids (0%) or no bridging therapy (4%), p=.05. Non-relapse mortality was 0 in all subgroups. PETCT at 1-month post CAR-T infusion demonstrated an increase in CR status percentage across all subgroups with no statistically significant difference in the incidence between the subgroups (p=.27), Figure 1. There was no difference in both progression-free survival (Figure 2) and overall survival between the 5 subgroups (p=.7, and p=.23). Cox regression model identified preinfusion lower ECOG status (HR=0.8, p=.04), preinfusion CR/PR status (HR=.46, p=.037) and 1-month post infusion CR status as a time dependent co-variate (HR=.14, p<.01) to be associated with better progression-free survival, while age and type of bridging therapy did not predict survival. Conclusions - Bridging to CAR-T should be tailored based on patient's and disease's characteristics with the aim to achieve the best disease control prior to CAR-T. However the chosen strategy per-se does not impact long-term outcomes. Intensive bridging therapy is associated with more cardiovascular events after CAR-T infusion. A prospective-controlled-trial allocating patients to different bridging strategies is needed to verify these results. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Gurion: Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy; JC Health CARE; Roche: Honoraria. Levi: AbbVie: Consultancy, Research Funding.

SCOPE MISMATCH: EXPLAINING THE EXPANSION OF ANTI-MILITARY INFRASTRUCTURE-SITING CAMPAIGNS*

While scholars agree that frame bridging contributes to movement expansion, this article identifies the underinvestigated concept of frame-movement scope mismatch—the phenomenon where the scope of movement frames and the scope of the movements that employ such frames do not match, such as a movement that adopts internationalist rhetoric yet remains local. This study investigates this mismatch based on cases of anti-U.S. military siting campaigns where similar frame bridging strategies resulted in movements of different scales. Findings show that movement scope expansion depended on the politicization of siting disputes that provided siting opponents with political opportunities for coalition building and qualified the causal influence of frame bridging. Varying external political circumstances, in other words, interacted with the invariant feature of frame bridging to determine frame resonance and coalitional mobilization.

Do substrate roughness and gap distance impact gap-bridging strategies in arboreal chameleons?

Chameleons are well equipped for an arboreal lifestyle, having “zygodactylous” hands and feet as well as a fully prehensile tail. However, to what degree tail use is preferred over autopod prehension has been largely neglected. Using an indoor experimental set-up, where chameleons had to cross gaps of varying distances, we tested the effect of substrate diameter and roughness on tail use in Chamaeleo calyptratus. Our results show that when crossing greater distances, C. calyptratus is more likely to use its tail for additional stability. The animals were able to cross greater distances (up to 1.75 times the shoulder-hip length) on perches with a rougher surface. We saw that depending on the distance of the gap, chameleons would change how they use their prehensile tails when crossing. With shorter gaps the tails either do not touch, or only touch the perch without coiling around it. With larger distances the tails are fully coiled around the perch, and with the largest distances additionally they reposition the hind legs, shifting them towards the end of the perch. Males were able to cross relatively greater distances than females, likely due to their larger size and strength.

Do substrate roughness and gap distance impact gap-bridging strategies in arboreal chameleons

Chameleons are well-equipped for an arboreal lifestyle, having ‘zygodactylous’ hands and feet as well as a fully prehensile tail. However, to what degree tail use is preferred over autopod prehension has been largely neglected. Using an indoor experimental set-up, where chameleons had to cross gaps of varying distances, we tested the effect of substrate diameter and roughness on tail use in Chamaeleo calyptratus. Our results show that when crossing greater distances, C. calyptratus is more likely to use its tail for additional stability. The animals were able to cross greater distances (up to 1 75 times the shoulder-hip length) on perches with a rougher surface. We saw that depending on the distance of the gap, chameleons would change how they use their prehensile tails when crossing. With shorter gaps the tails either do not touch, or only touch the perch without coiling around it. With larger distances the tails are fully coiled around the perch, and with the largest distances additionally they reposition the hind legs, shifting them towards the end of the perch. Males were able to cross relatively greater distances than females, likely due to their larger size and strength.

Management strategies for supply risk dependencies: empirical evidence from the gulf region

PurposeThe purpose of this study is to propose a conceptual model for managing supply risk (SR) dependencies in regional supply networks (SNs). Grounded on resource dependency theory (RDT), the research conceptualises the management of SR as buffering and bridging strategies that enable organisations to redefine their SN to cope with SR and as a three-stage transformation mechanism.Design/methodology/approachFour supply failure case studies from the aluminium and the oil and gas industries in the Gulf Cooperation Council (GCC) region inductively provide empirical insights for a revised conceptual framing. Within and cross case analysis on transcribed semi-structured interviews with 11 SN managers focus on the SRs and dependencies associated with the supply failures and an abstraction of risk management (RM) strategies for coping with these failures.FindingsThe analysis finds that underpinning ‘second-order’ buffering and bridging strategies from RDT are four main ‘first-order’ RM strategies: unit independency, organisational adaptation, network reconfiguration and environmental acceptance. These RM strategies are due to controllability and predictability levels that influence investment in RM and reflect the locations for implementing RM practices, i.e. the business unit, the organisation, the SN and the environment.Originality/valueThe article contributes to research through the conceptual framework of SR dependencies and unique insights on SR management within the GCC region. Practically, the research is novel in offering strategic directions for RM evaluations and investments that reflect the controllability and predictability of risk incidents. Such evaluations are potentially valuable in orchestrating regional SNs, for managing GCC companies in global supply chains, and for strategic decisions to expand or outsource to the GCC region.