Final Data Research Articles

디지털 기술 역량이 기업의 양손잡이 역량에 미치는 영향

This study verified the impact of digital technology capability on ambidexterity strategies and the mediating role of digital leadership capability to promote company’s survival and competitive advantage in the context of rapid digital transformation. A survey was conducted on small and medium-sized enterprises in the korea’s manufacturing and ICT & telecommunications sectors, and 250 final effective data were obtained and the Jamovi 2.3.26 application was used for hierarchical regression analysis. As a result of the analysis of this study, digital technology capability has a positive effect on a company's ambidexterity strategy, and in this process, the complete mediating effect of digital leadership capability was confirmed. This study contributes to the theoretical expansion of the ambidexterity strategy literature due to the effects of technology and leadership in the context of digital transformation. It also presented practical implications that companies can achieve digital transformation more effectively by carrying out a ambidexterity strategy through leadership capability, although technical capability is important from a huge transformational perspective.

Organizational Factors and Knowledge Sharing Behavior: Mediating Model of Knowledge Sharing Intention

This research investigates the mechanism of how organizational factors (including organizational climate, formalization, and centralization) impact knowledge-sharing behavior by considering knowledge-sharing intention as a mediator. After conducting online surveys and offline interviews, we utilized a quantities method with the PLS-SEM tool to examine the potential findings. This study’s respondents were employees selected randomly from information technology enterprises in Vietnam; the final data set included 529 responses. The findings demonstrate that the organizational climate has a favorable link with knowledge-sharing behavior, whereas the remaining organizational factors, namely formalization and centralization, have a negative influence. Besides, this study found that knowledge-sharing intention plays a mediating role in these relationships. This research also provides some theoretical and practical implications, limitations as well as future research directions for further studies.

대학 태권도 학생선수의 능력믿음, 운동스트레스, 진로미결정 및 중도탈락의도의 관계

The purpose of this study is to verify the relationships among ability belief, exercise stress, career indecision, and dropout intention of the college taekwondo athletes. College taekwondo athletes were subjected to questionnaire and based on convenience sampling, total of 348 out of 407, excluding 57 samples that were not suitable for analysis were used for final data analysis. For statistical methods for data processing, frequency analysis, reliability analysis, exploratory factor analysis, correlation analysis, and structural equation model analysis were implemented utilizing SPSS 20.0 and AMOS 20.0 programs. The ability belief of college taekwondo athletes had significant impact upon dropout intention, and exercise stress, The exercise stress of college taekwondo athletes had significant impact upon career indecision, and dropout intention, The career indecision of college taekwondo athletes had significant impact upon dropout intention. Ultimately, in order to reduce the dropout of athletes, it suggests the importance of psychological management to increase athletes' ability belief, the creation of a light sports culture to reduce sports stress, and the need for career education considering individual aptitudes and interests.

Spinal Cord Injury Management Policies in High School Sports as Reported by Athletic Administrators

ABSTRACT Introduction/Purpose Athletic administrators (AA) in U.S. high schools are uniquely positioned to provide guidance and endorsement for the prevention and management of common sport-related catastrophic injuries, such as the development of a spinal cord injury management (SCIM) policy. The purpose of this project was to evaluate AA’s knowledge of comprehensive SCIM policies in U.S. high schools. Secondarily, we aimed to investigate the factors, facilitators, and barriers to the development and adoption of comprehensive policies. Methods An online questionnaire was distributed to 6423 AA working in U.S.-based high school athletics, with 366 included in the final data analysis. The questionnaire evaluated AA’s knowledge of comprehensive SCIM policies addressing components of adoption, documentation, and communication. The questionnaire was developed based on the 2002 “National Athletic Trainers’ Association Position Statement: Acute Management of the Cervical Spine-Injured Athlete.” The questionnaire also inquired about facilitators and barriers to developing and adopting comprehensive policies. Proportions were calculated for policy adoption, and independent-samples t-tests evaluated the influence of athletic training services on comprehensive SCIM policies. Results About half of AA (49.2%, n = 180/366) reported having all recommended components of a written SCIM policy. AA who had access to an athletic trainer (yes = 62.9%, no = 18.1%, unknown = 19%) were more likely to have a comprehensive SCIM policy compared with those without access (80.6% vs 19.4%, χ 2 1 = 7.091, P = 0.008, prevalence ratio = 1.24, 95% confidence interval = 1.03–1.50). The most commonly reported facilitator (49.9%) was “having a medical professional at the school,” and the main barrier (30.2%) was “my school would need more information, resources, assistance, etc.” Conclusions The findings identify areas for improvement in supporting the health and safety of children in high school participating in interscholastic athletics. Future dissemination and implementation research should develop strategies tailored to individual school community and need to improve SCIM policy adoption and implementation.

PLANNING OF THE ONE-YEAR CYCLE OF TRAINING ICE HOCKEY ATHLETES
 AT THE STAGE OF IN-DEPTH SPORT SPECIALIZATION

The material of the article contains information about the training of hockey athletes at the stage of in-depth sports
 specialization. According to a rational planning and distribution of training loads in game season 2021-2022 it was
 possible to increase the level of physical and technical fitness of the sportsmen participating in research. Reliable changes
 (p < 0,01 and p < 0,05) between the initial and final data in 20 control exercises, as well as an improvement in the
 average score to 1 point, indicate a good rate of increase in results, which, in turn, had a positive impact on the final
 place of the Bobruisk Arena youth sports school team in the standings of the 2021-2022 season.

Response to Subsequent Novel Therapies and Time to Second Progression-Free Survival Event in the MURANO Trial in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Previously Treated with Fixed-Dose Venetoclax Plus Rituximab

Background: The randomized Phase III MURANO trial (NCT02005471) assessed fixed-duration treatment with venetoclax (Ven) plus rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Despite improved clinical outcomes (progression-free survival [PFS], overall survival [OS] and time-to-next-treatment [TTNT], as well as minimal residual disease conversion and progressive disease [PD] association [Seymour et al. Blood 2022]) for pts randomized to VenR compared with bendamustine-R (BR), most pts will ultimately require subsequent therapies. However, the efficacy of subsequent treatment after relapse remains largely unexplored. This study was conducted prior to the widespread availability of other targeted therapies, so pts were not previously exposed to targeted therapies prior to MURANO treatment allocation. Here we report response rates to follow-up therapy with Ven-based regimens, or Bruton tyrosine kinase inhibitor (BTKi) therapy, as well as time to the second PFS events from the final analysis of the MURANO trial. Methods: Overall, 389 pts were randomized to VenR (2 years of Ven, with R for the first 6 months) or 6 months of BR. Pts in either arm with PD were followed for disease response to any subsequent anti-CLL therapeutic regimens, PFS and OS. A sub-study, introduced in 2018, allowed pts who developed PD following treatment with VenR or BR to receive the MURANO VenR regimen. Pts who initiated new anti-CLL therapy without a response assessment reported by the investigator, were considered unevaluable. Results : At the final clinical cutoff date of August 3, 2022, all pts had ceased study-specified treatment and the median follow-up of the main study was 85.7 (range: 0-99.2) months. PFS and OS benefits were maintained at the 7-year follow-up (Kater et al. EHA 2023). Overall, 73/194 (37.6%) pts in the VenR arm had not received a next-line therapy at the final cutoff, and 26 pts had died without subsequent therapy. Median TTNT or death with VenR was 63.0 months vs 24.0 months with BR (hazard ratio: 0.30). Following PD, 95/194 (49.0%) pts randomized to VenR and 131/195 (67.2%) pts randomized to BR had received subsequent anti-CLL therapy; the median (range) time off therapy in these pts was 28.3 months (-0.1-68.6) and 17.9 months (0.7-82.4), respectively. Of the 95 VenR pts receiving subsequent anti-CLL therapy, 30 (32.3%) received BTKi therapy (ibrutinib [n=25], acalabrutinib [n=4] and zanubrutinib [n=1]), with 18 ongoing at the time of the final cutoff; 47 (51.6%) received Ven-based therapy, with 12 ongoing at the time of the final cutoff; and 16 (17.2%) received chemoimmunotherapy (CIT). Two pts received a non-CLL therapy for another malignancy so were excluded from the subsequent analysis. Of the 131 BR pts receiving subsequent therapy, 79 (60.3%) received BTKi therapy (ibrutinib [n=69], acalabrutinib [n=6] and zanubrutinib [n=4]), with 20 ongoing at the time of the final cutoff; 17 (13.0%) received Ven-based therapy, with 3 ongoing at the time of the final cutoff; 24 (18.3%) received CIT; and 11 (8.4%) received other novel agents. Median time from randomization to second PFS event was 85.9 months (95% confidence interval [CI]: 81.8-88.2) in pts randomized to VenR and 48.4 months (95% CI: 44.5-56.6) in pts randomized to BR; p<0.0001 ( Figure). Best overall response (BOR; defined as complete remission [CR], CR with incomplete count recovery, partial remission [PR] and nodular PR) rates to first subsequent anti-CLL therapy for pts with evaluable responses were 75/93 (80.6%) for VenR and 85/107 (79.4%) for BR. Among evaluable pts previously treated with VenR and BR, the BOR rate to subsequent BTKi therapy was 19/22 (86.4%) and 51/65 (78.5%), respectively, while BOR rate to subsequent Ven-based therapies was 32/42 (76.2%) and 15/17 (88.2%), respectively. Conclusions: Final data from MURANO demonstrate that, despite the majority of BR pts receiving novel therapies after relapse on MURANO, there was a significantly prolonged time to second PFS event observed in favor of the VenR arm. Pts who had relapsed and received retreatment or crossed over to Ven-based regimens or subsequent BTKi therapy also demonstrated high response rates. These results indicate that early intervention with fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response.

Luspatercept for the Treatment of Anemia in Non-Transfusion-Dependent β-Thalassemia: Final Safety and Efficacy Data from the BEYOND Trial

Background: Suboptimal anemia management in patients (pts) with non-transfusion-dependent (NTD) β-thalassemia may lead to serious clinical complications. Improvements in hemoglobin (Hb) levels were shown to significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). There is a need for therapies that increase Hb levels besides red blood cell transfusions (RBCT), which lead to secondary iron overload. Primary and longer-term data from the BEYOND study showed that luspatercept led to significant increases in Hb levels and had a manageable safety profile in pts with NTD β-thalassemia (Taher AT, et al. Lancet Haematol 2022;9:e733-e744; Taher AT, et al. Blood 2022;140[suppl 1];8210-8212). Here we report the final data (up to last patient last visit [LPLV] date Nov 28, 2022), of the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (NCT03342404). Methods: Eligible pts (N = 145) had NTD (defined as receiving ≤ 5 RBC units in the 24 wk before randomization) β-thalassemia or HbE/β-thalassemia, Hb levels ≤ 10 g/dL. Pts were randomized to luspatercept (N = 96; 1.0-1.25 mg/kg) or placebo (N = 49) subcutaneously Q3W for ≥ 48 wk. Pts continued to receive best supportive care when required. Pts who crossed over from placebo to luspatercept were not included in this analysis. Mean Hb increase ≥ 1.0 g/dL (any 12-/24-wk interval) and ≥ 1.5 g/dL from baseline (any 12-wk interval), duration of mean Hb increase ≥ 1.0 g/dL and ≥ 1.5 g/dL from baseline, iron parameters, RBCT, and safety were evaluated up to the LPLV date. Results: As of Nov 28, 2022, 93/134 (69.4%) pts on luspatercept transitioned to the long-term follow-up study (NCT04064060): 66/96 (68.8%) pts in the luspatercept arm and 27/38 (71.1%) pts who crossed over from placebo to luspatercept after study unblinding. A total of 76/96 (79.2%) pts in the luspatercept arm completed 144 wk of treatment (tx), with 55/96 (57.3%) completing 192 wk of tx; 28/96 (29.2%) pts on luspatercept discontinued tx. The median (range) luspatercept tx duration was 202.8 (15.0-242.3) wk (Table) and 61.1 (3.0-138.0) wk with placebo. Pts had a durable increase in Hb ≥ 1.0 g/dL from baseline (by 12-wk interval) through wk 240 of luspatercept tx (Figure). In the luspatercept arm, 91/96 (94.8%) pts had a mean Hb increase ≥ 1.0 g/dL from baseline during any 12-wk interval (Table). The mean (standard deviation [SD]) total duration of mean Hb increase ≥ 1.0 g/dL from baseline (any 12-wk interval) with luspatercept was 1136.0 (491.9) days. The proportion of pts achieving a mean Hb increase ≥ 1.5 g/dL during any 12-wk interval over the entire tx period was 80/96 (83.3%) and 4/49 (8.2%) in the luspatercept and placebo arms, respectively. At baseline, 83/96 and 42/49 pts in the luspatercept and placebo arms, respectively, were RBCT-free. The proportion of pts who remained RBCT-free was 78.1% (75/96) and 57.1% (28/49) in the luspatercept and placebo arms, respectively. For pts who received RBCT, the mean time to first RBCT was 482.0 days with luspatercept and 202.6 days with placebo. The mean change from baseline in serum ferritin (SF) level at wk 96 was +76.45 µg/L with luspatercept (n = 90) and +211.51 µg/L with placebo (n = 35). The mean change from baseline in SF level stabilized with longer luspatercept tx (wk 192: 49.14 µg/L [n = 71]; wk 240: 52.19 µg/L [n = 51]). The mean change from baseline in liver iron content in the luspatercept arm was −1.23 mg/g dry weight (dw) at wk 96 (n = 8) and −0.79 mg/g dw at wk 144 (n = 54). The 10 most frequently reported adverse events (AEs; ≥ 5% of pts) with luspatercept were headache, back pain, bone pain, COVID-19, arthralgia, pyrexia, pain in extremity, fatigue, diarrhea, and hypertension. Rates of serious and grade 3-4 AEs in the luspatercept arm were 24.0% [23/96] and 34.4% [33/96]), respectively. In the luspatercept arm, thromboembolic events were reported in 2/96 pts, extramedullary hemopoietic masses in 10/96 pts (all grade 1-2), and there were no malignancies. Few AEs led to tx discontinuation in the luspatercept arm (5/96 [5.2%]); no new safety signals were identified. Summary: The final results from the BEYOND study show that pts with NTD β-thalassemia treated with luspatercept maintained clinically meaningful and durable erythroid responses. The safety profile of luspatercept was manageable, and extended luspatercept exposure did not raise new safety concerns.

Informed Representation of Persons Living with Sickle Cell Disease in the US and Factors That Influence Clinical Trial Participation

Rationale: Sickle cell disease (SCD) is a group of blood disorders that results in an abnormality in the protein hemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Sickle cell disease is typically inherited, and the most common type is ‘SS’ disease or sickle cell anemia. As of 2015, about 4.4m people have SCD, while 43m have the sickle cell trait. There is currently no pharmacological cure for SCD. The disease highlights racial and socioeconomic disparities in healthcare with treatment options, opportunities for clinical trial participation, and challenges associated with reimbursement. To enroll sufficient numbers of patients for SCD trials, drug developers need to identify enough patients with SCD, provide them with a compelling reason to enroll and complete these studies and make it possible for them to participate. Our proposed study aims to leverage a survey targeting patients, caregivers, patient advocacy groups (PAGs), and healthcare providers (HCPs) to ensure a representative understanding of the patient journey in the context of rare chronic diseases, focusing on: Overcoming trial participation constraints by identifying factors affecting patients' readiness to participate in SCD trials.Bridging the gap between the biopharma industry and patient needs to ensure patient-centered approaches.Evaluating select aspects of the economic impact of SCD to aid in more cost-effective treatment development.Promoting Diversity, Equity, and Inclusion in research by using feedback from diverse stakeholders.Addressing challenges in research such as the lack of a definitive pharmacological cure and instead focusing on disease management and quality of life improvements. Methods: A 20-question survey, developed by physicians with experience treating both adults and children with SCD, was distributed via social media and through purposeful distribution to subject matter experts on July 7 th, 2023, targeting patients, caregivers, PAGs, and HCPs in the US to seek a better understanding of the barriers to SCD clinical trial enrollment, retention, and access to current treatments. The range of questions covers: Barriers to clinical trialsBarriers and facilitators to clinical trial participationThe range of trials currently available to patientsBarriers to advocacyAccess to current treatmentsClinical trial impacts on the SCD communityStrategies of PAGs to advocate and provide resources to patients and caregiversLevel of the impact of PAGs on legislation and disease management considerationsEducational material resourcesCost of treatment and access to resourcesDrug safety and privacy concerns Results: Access to the survey will close on October 2 nd, 2023. Survey results will be analyzed and presented using descriptive graphics and text statistics. Interim analyses suggest individuals living with SCD hold safety and success of treatment in high importance. Final survey data are anticipated to further suggest the following: a diverse respondent demographic is vital for inclusive and relevant research efforts; acknowledgment of the importance of research and development (R&D) in creating novel treatments for chronic diseases; a need for resources to be directed towards diseases affecting marginalized communities; an understanding that chronic diseases usually lack a complete cure, focusing instead on disease modification and symptom control; and the importance of insights from a wide spectrum of respondents. The results aim to underline the necessity of patient-centric R&D, especially for vulnerable populations and disease-modifying treatments, given the difficulty of curing chronic diseases like SCD. By leveraging this data, stakeholders can better align their efforts toward creating impactful solutions for SCD patients, potentially leading to additional innovative, life-improving treatments.

Phase Ib/II Study (NCT02488408 / BGBC003) of Bemcentinib Monotherapy or in Combination with Cytarabine or Decitabine in Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): FINAL Results

Background: The standard of care (SOC) in newly-diagnosed (ND) AML patients (pts) unfit for intensive chemotherapy (IC) yields median overall survival (mOS) of 14.7 months. However, beyond 1 st line (1L), pts have limited treatment options and dismal mOS of 2.3 months (4.7 months in pre-venetoclax era), highlighting the need for more effective treatments in 2 nd line (2L) and beyond. Activation of AXL, a receptor tyrosine kinase, is associated with poor prognosis, resistance to chemotherapy and decreased antitumor immune response in AML. Bemcentinib (BEM) is a first-in-class, oral, highly selective AXL inhibitor. Aims: The BGBC003 PhIb/II trial studied the safety and efficacy of BEM as monotherapy in AML (cohort B1) and MDS (cohort B4) and in combination with decitabine (cohort B3) or low-dose cytarabine (LDAC) (cohorts B2 and B5) in ND and relapsed/refractory (R/R) AML pts unfit for IC. Pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted in pts treated with BEM monotherapy in the safety run-in phase (part A). Here, we present final efficacy and safety data, as well as PK/PD analysis from part A. Methods: In part A, 36 pts received BEM monotherapy in a dose escalation manner. In part B (cohorts B1-B5), pts received 3 loading doses at daily 400 mg BEM followed by 200 mg BEM daily. Study endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR) (ORR+unchanged [UC]). Plasma and peripheral blood (PB) samples were used for PK and phospho-AXL (pAXL) analyses. Results: From Oct-14 to Jul-21, 86 pts were enrolled in part B (72 efficacy evaluable), with a median age of 76 years (range 50-86), 77% being R/R at study entry. BEM monotherapy and in combination was well tolerated, with a safety profile comparable to the known safety profile of the combination agents. The ORR was 18% (B1), 0% (B3), 25% (B2+B5), and 19% (B4). The CBR was 45% (B1), 31% (B3), 31% (B2+B5) and 56% (B4). The mOS (months) was 18 (B1), 6.4 (B3), 8.0 (B2+B5) and 9.2 (B4). BEM+LDAC (B2+B5) showed promising survival benefit in ND (mOS 16.5 months, n=5) and R/R pts (mOS 7.8 months, n=27). The PK/PD analysis showed inhibition of the biological target pAXL in PB following monotherapy. BEM showed dose-dependent inhibition of pAXL and downstream targets of pAXL (pAKT, pERK and pNFkB) with EC 50 values of 89-162 ng/mL. Summary/Conclusions: BEM demonstrated on-target effect by inhibition of pAXL and downstream signalling in a concentration-dependant manner. BEM monotherapy and in combination was well tolerated across all cohorts. The overall efficacy observed is comparable with historical data in 2L AML and MDS. Although the shift in 1L SOC in AML during the study limits adequate comparisons, a survival benefit was observed both in ND and R/R AML, warranting further investigation. Keywords: Acute myeloid leukemia, Clinical trial, Receptor tyrosine kinase

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, >=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p<0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p<0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period > 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial of HH2853 in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, whereas treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. HH2853, the novel, potent and selective dual inhibitor of Enhancer of Zeste Homolog 1 and 2 (EZH1/2), has demonstrated a clinical benefit with a favorable safety profile in Phase 1 and Phase 2 trials in solid tumors and R/R non-Hodgkin's lymphoma (NHL) previously. Here we report the efficacy and safety data from phase 1b trial of HH2853 in r/r PTCL. Methods The Phase 1b clinical trial in PTCL (CTR20221416) was conducted from July, 2022 to June 15, 2023 at 15 sites in China. This study consisted of two parts. In part 1, 3+3 dose-escalation design with three dose levels of HH2853 (300mg, 400mg, 600mg BID) was used to identify the MTD and recommended Phase II dosage (RP2D) of HH2853. Part 2 was dose expansion at two dose groups (300mg and 400mg BID). HH2853 was orally dosed until disease progression, intolerable toxicity or withdrawal from the study. Safety was evaluated according to CTCAE v5.0. Tumor assessments were performed according to LUGANO 2014 every 2 treatment cycles (28-day/cycle). A final data cut off (DCO) on June 15, 2023 was conducted for safety and efficacy assessments. To that date, there were still 25 pts (73.5%) remained on HH2853 treatment. Results In this study in r/r PTCL, 34 pts enrolled with different PTCL histology types, including AITL (14 pts, 41.2%), PTCL-NOS (11 pts, 32.4%), ALK -ALCL (4 pts,11.8%), NKT (2 pts, 5.9%), TFH (2 pts, 5.9%), SKIN-PTCL (1 pt, 2.9%). Pts were a median age of 58 years (range: 34 to 79), ECOG 0-1 (ECOG 0, 9 pts, 26.5%, ECOG 1, 25 pts, 73.5%), had a median of 2 lines (range 1 to 5) prior systemic therapies, 6 pts (17.6%) had bone marrow involvement at the baseline. With 30 pts (88.2%) having prior CHOP or CHOP-like therapy，with 14 pts (41.2%) were refractory to their last treatment. 1pts (2.9%) had undergone hematopoietic stem cell transplantation. 32 patients (92.1%) had experienced a treatment related adverse event (TRAE), 7 pts (20.6%) experienced grade ≥3 TRAE. The most common TRAEs (≥10%) were PLT decreased (14 pts, 41.2%) , anaemia (13 pts, 38.2%)，and diarrhoea (11 pts, 32.4%). The frequently reported TRAEs of grade ≥3 with an incidence of ≥10% were PLT decreased (5 pts, 14.7%) and neutrophil count decreased (4 pts, 11.8%). 8 pts (23.5%) had dose interrupted due to TRAE. 3 pts (8.8%) had dose reductions due to TRAE from 600 to 400 mg BID, 1 pts (6.3%) had dose reductions from 400 to 200 mg BID, and 1 pts (2.9%) discontinued from the study due to TRAEs. The safety profile was consistent to that had been observed in HH2853 studies. 1 pt (2.9%) at 600mg BID experienced dose limiting toxicity (DLT)due to grade 4 PLT decreased. The majority of TRAEs were reversible or clinically manageable. Among the 34 enrolled pts, 28 patients had the evaluated response, the Overall Response Rate (ORR) was 60.7% (17 pts), including 21.4% (6 pts) Complete Responses (CR), 39.3% (11 pts) Partial Responses (PR) and 14.3% (4 pts) Stable Disease (SD), contributing to an 75.0% (21 pts) Disease Control Rate (DCR). The median time to response (mTTR) was 1.87 months (95% CI: 1.77, 2.17). At DCO the median follow up of the pts in the study was 2.79 month (IQR: 1.94, 5.88). The median Duration of Response (mDOR), the median Progression Free Survival (mPFS) and the median OS (mOS) had not reached. The 3-month PFS rate was 74.44% (95%CI:53.62%,86.95%). The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%). Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.

1582. Dolutegravir/Rilpivirine STR Switch Study in Persons with HIV-1 and Chronic Kidney Disease: 48-week Assessment of Viral Suppression, Treatment Adherence and Quality of Life

Abstract Background Single tablet regimens (STRs) are widely utilized in HIV treatment in the Western world largely because they improve convenience of oral regimens and eliminate differential adherence. US Blacks are disproportionately impacted by HIV, and are also disproportionately affected by chronic kidney disease (CKD) for a variety of reasons, especially in their later years. For PWH and CKD, STR options are limited due to pharmacokinetic considerations. We evaluate the impact on viral suppression, adherence, treatment satisfaction and quality of life (QOL) of switching to DTG/RPV STR for a largely Black aging US cohort with HIV and CKD. Methods In this 48-week open label single arm switch study conducted in a community health center setting, adults with HIV, a GFR< 60 mL/min/1.73m2, an HIV RNA < 50 copies/mL and no known prior resistance to DTG or RPV were switched to DTG/RPV STR. HIV RNA and CD4 were monitored per standard national clinical guidance following switch. Standardized tools for medication adherence, treatment satisfaction and QOL were administered at baseline, 24 weeks and 48 weeks. We present final 48-week data. Results Between August 2019 and December 2021, 35 participants were enrolled. One dropped out after 19 weeks and one after 22 weeks due to drug-drug interaction concerns following renal transplantation. 94% of participants were Black, 57% were female and 43% were 65 years and older. At baseline, 20% had a GFR < 30 mL/min/1.73m2 per race-based calculation (36% per race-free calculation). At 48 weeks, 97% of participants maintained viral suppression with an HIV RNA < 50 copies/mL in a per protocol analysis (91% in an intent-to-treat analysis). One participant with an HIV RNA of 62 copies/mL at 48 weeks subsequently re-suppressed on DTG/RPV. 69% reported an improvement in adherence, 77% noted an improvement in treatment satisfaction and 66% reported an improvement in QOL. The only adverse event reported in >5% of participants was nausea (5.7%). There were no serious adverse events. Conclusion For this diverse aging cohort with HIV and CKD in a real-life community health center setting, DTG/RPV STR was efficacious, well-tolerated and associated with improvements in adherence, treatment satisfaction and QOL, sustained over 48 weeks. DTG/RPV is a feasible oral ARV option for PWH and CKD. Disclosures Helena Kwakwa, MD, MPH, ViiV Healthcare: Grant/Research Support

Effects of the “ICU Support” team meeting concept on patient-centered and staff-centered outcomes: study protocol for a randomized controlled multicenter study

BackgroundProviding optimal care for critically ill patients is an extremely important but also highly demanding task, both emotionally and physically. The “ICU Support” team meeting concept aims to support intensive care unit (ICU) teams by promoting interprofessional communication, peer support, and patient safety by providing a structure for daily team meetings. This protocol describes a study to explore the effectiveness of “ICU Support” for patient- and staff-centered outcomes.MethodsICU Support will be implemented at nine university hospitals located in Germany, following a two-arm randomized parallel group design with an intervention and a control condition and three data collection periods. In the intervention arm, leading ICU personnel (physicians and nurses) will be trained in ICU Support and implement the ICU Support elements into the daily work routine of their units upon completion of data collection period T0 (baseline). In the control arm, ICU Support will not be implemented until the completion of the data collection period T1 (1 month after study start). Until then, the regular daily schedule of the ICU teams will be maintained. The final data collection period (T2) will take place 4 months after the start of the study. Primary outcomes include the number of intensive care complications per patient during their ICU stay during T1 and the sick-related absence of ICU staff during T1. Secondary outcomes include, among others, the average severity of intensive care complications per patient and employee self-reported data regarding their teamwork and patient safety behaviors.DiscussionThe need for healthy and well-trained ICU staff is omnipresent; thus, structured and evidence-based interventions aimed at supporting ICU teams and facilitating patient safety are required. This multicenter study aims to explore the effectiveness of ICU Support for patient- and staff-centered outcomes. The insights derived from this study have the potential to significantly improve ICU patient safety, staff communication, and connectedness and decrease sickness-related expenses and social costs associated with high work demands among ICU staff.Trial registrationGerman Clinical Trials Register DRKS00028642. Registered on 4 April 2022.

Visual Communication in Sustainability Action: Public understanding through human behavior and attitude

The study aims to explore the essential elements of an idea in designing visual marketing, advertising, or design developments to impose sustainable efforts. The final data is distributed into four categories: Behavior and Attitude in Visual Development, Mechanism in Public Information, Process of Public Understanding, and Public Understanding in Visual Sustainability. The research suggests creators of visual communications consider how their work shapes attitudes and behaviours about sustainability. With awareness around information, public understanding, and connections between visual media and sustainability, designers can promote responsible, eco-conscious messages. This framework proposes the development process should cultivate mindfulness about communicating sustainability effectively.

Evaluating a Public Health Information Service According to Users' Socioeconomic Position and Health Status: Protocol for a Cross-Sectional Study.

The increasing use of information technology in the field of health is supposed to promote users' empowerment but can also reinforce social inequalities. Some health authorities in various countries have developed mechanisms to offer accurate and relevant information to health care system users, often through health websites. However, the evaluation of these sociotechnical tools is inadequate, particularly with respect to differences and inequalities in use by social groups. Our study aims to evaluate the access, understanding, appraisal, and use of the French website Santé.fr by users according to their socioeconomic position and perceived health status. This cross-sectional study involves the entire French population to which Santé.fr is offered. Data will be collected through mixed methods, including a web-based questionnaire for quantitative data and interviews and focus groups for qualitative data. Collected data will cover users' access, understanding, appraisal, and use of Santé.fr, as well as sociodemographic and socioeconomic characteristics, health status, and digital health literacy. A validation of the dimensions of access, understanding, appraisal, and use of Santé.fr will be conducted, followed by principal component analysis and ascendant hierarchical classification based on the 2 main components of principal component analysis to characterize homogeneous users' profiles. Regression models will be used to investigate the relationships between each dimension and socioeconomic position and health status variables. NVivo 11 software (Lumivero) will be used to categorize interviewees' comments into preidentified themes or themes emerging from the discourse and compare them with the comments of various types of interviewees to understand the factors influencing people's access, understanding, appraisal, and use of Santé.fr. Recruitment is scheduled to begin in January 2024 and will conclude when the required number of participants is reached. Data collection is expected to be finalized approximately 7 months after recruitment, with the final data analysis programmed to be completed around December 2024. This study would be the first in France and in Europe to evaluate a public health information service, in this case the Santé.fr website (the official website of the French Ministry of Health), according to users' socioeconomic position and health status. The study could discover issues related to inequalities in access to, and the use of, digital technologies for obtaining health information on the internet. Given that access to health information on the internet is crucial for health decision-making and empowerment, inequalities in access may have subsequent consequences on health inequalities among social categories. Therefore, it is important to ensure that all social categories have access to Santé.fr. PRR1-10.2196/51123.

Evaluation of Factors Affecting the Competitive Advantage of Organizations in Establishing Sustainable Project Management Post Covid-19

Competitive advantage significantly matters for modern construction organizations as it promotes the sustainable development and safety management of projects. UK construction organizations have greatly suffered from a lack of safety and sustainability of project management in infrastructure development projects because of the COVID-19 pandemic. Post-COVID-19 UK infrastructure development projects are uncertain in the context of organizational competitive advantage as they cannot maintain sustainable project management. This study was conducted to identify, rank, and present a framework of factors influencing the competitive advantage of UK organizations. The study design involved identifying factors from the current literature, after which the most relevant factors were filtered with the help of semi-structured interviews with 15 experts. A pilot survey was conducted then, involving 192 respondents, after which a reliability test and exploratory factor analysis (EFA) were conducted on the results. A primary questionnaire survey involving 250 respondents was conducted, after which RII and confirmatory factor analysis (CFA) were conducted on the final data. A total of five subgroups were found to be significant in the CFA, such as Resources and Policies, Quality and Delays, Motivation and Expectation, Management and Environment, and Government and Business. It is recommended based on findings that the construction organizations of the UK have to consider working on identified factors to maintain a competitive advantage in establishing sustainable project management solutions for post-COVID-19 UK infrastructure development projects.

Determination of unknown shear force in transverse dynamic force microscopy from measured final data

Abstract In this paper, we present a new methodology, based on the inverse problem approach, for the determination of an unknown shear force acting on the inaccessible tip of the microcantilever, which is a key component of transverse dynamic force microscopy (TDFM). The mathematical modelling of this phenomenon leads to the inverse problem of determining the shear force g ⁢ ( t ) {g(t)} acting on the inaccessible boundary x = ℓ {x=\ell} in a system governed by the variable coefficient Euler–Bernoulli equation ρ A ⁢ ( x ) ⁢ u t ⁢ t + μ ⁢ ( x ) ⁢ u t + ( r ⁢ ( x ) ⁢ u x ⁢ x + κ ⁢ ( x ) ⁢ u x ⁢ x ⁢ t ) x ⁢ x = 0 , ( x , t ) ∈ ( 0 , ℓ ) × ( 0 , T ) , \rho_{A}(x)u_{tt}+\mu(x)u_{t}+(r(x)u_{xx}+\kappa(x)u_{xxt})_{xx}=0,\quad(x,t)% \in(0,\ell)\times(0,T), subject to the homogeneous initial conditions and the boundary conditions u ⁢ ( 0 , t ) = u 0 ⁢ ( t ) , u x ⁢ ( 0 , t ) = 0 , ( u x ⁢ x ⁢ ( x , t ) + κ ⁢ ( x ) ⁢ u x ⁢ x ⁢ t ) x = ℓ = 0 , ( - ( r ⁢ ( x ) ⁢ u x ⁢ x + κ ⁢ ( x ) ⁢ u x ⁢ x ⁢ t ) x ) x = ℓ = g ⁢ ( t ) , u(0,t)=u_{0}(t),\quad u_{x}(0,t)=0,\quad(u_{xx}(x,t)+\kappa(x)u_{xxt})_{x=\ell% }=0,\quad\bigl{(}-(r(x)u_{xx}+\kappa(x)u_{xxt})_{x}\bigr{)}_{x=\ell}=g(t), from the final time measured output (displacement) u T ⁢ ( x ) := u ⁢ ( x , T ) {u_{T}(x):=u(x,T)} . We introduce the input-output map ( Φ ⁢ g ) ⁢ ( x ) := u ⁢ ( x , T ; g ) {(\Phi g)(x):=u(x,T;g)} , g ∈ 𝒢 {g\in\mathcal{G}} , and prove that it is a compact and Lipschitz continuous linear operator. Then we introduce the Tikhonov functional J ⁢ ( F ) = 1 2 ⁢ ∥ Φ ⁢ g - u T ∥ L 2 ⁢ ( 0 , ℓ ) 2 J(F)=\frac{1}{2}\lVert\Phi g-u_{T}\rVert_{L^{2}(0,\ell)}^{2} and prove the existence of a quasi-solution of the inverse problem. We derive a gradient formula for the Fréchet gradient of the Tikhonov functional through the corresponding adjoint problem solution and prove that it is a Lipschitz continuous functional. The results of the numerical experiments clearly illustrate the effectiveness and feasibility of the proposed approach.

OGC P60 Impact of deprivation on treatment of oesophageal squamous cell carcinoma across a regional cancer network

Abstract Background Oesophageal cancer accounts for 8000 deaths per year in the United Kingdom, and 400,000 deaths globally. There are two main histological subtypes: oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC), with the former accounting for 90% of cases. Oesophageal cancer, particularly OSCC displays a strong correlation with deprivation, with females and males in the most deprived quintile having a corresponding 43% and 50% higher incidence rate compared to the least deprived. This study aims to look at whether deprivation across a regional network also affects treatment choice offered to patients, primarily definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy. Methods A total of 76 patients diagnosed with oesophageal squamous cell carcinoma were identified from the regional cancer network database from 2016 to 2019. Patients were ranked into 10 deprivation quintiles using the English indices of deprivation 2019 (IoD2019). Patients were subdivided into two groups based on treatment modality, definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy with a plan for surgery (nCRT). Statistical analysis was performed using R-statistical software with logistical regression and T-tests performed. Results A total of 76 patients were included in the final data set with 52 patients receiving dCRT and 24 receiving nCRT. Deprivation was associated with a statistically significant impact on treatment choice, with patients in higher deprivation quintiles more likely to be offered nCRT (logOR 0.40, 95%CI 0.11-0.75) p-value 0.013. Other important factors were gender, with male patients more likely to be offered dCRT (LogOR -1.8, 95%CI -3.7- -0.30) p-value 0.030. Important cofounders were cancer staging and gender with the dCRT group having a higher number of stage 4 cancers and males compared to the nCRT group. Conclusions In conclusion, deprivation had a statistically significant impact on treatment modality of OSCC, with patients in higher deprivation quintiles more likely to be offered nCRT. However, there are important confounders to take into consideration, particularly cancer staging and gender which may explain the results.

Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data

The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progressive central nervous system (CNS) metastases following radiotherapy. Primary analysis confirmed CNS objective response rate (ORR) was 11% (95% confidence interval [CI]: 3–25); clinical benefit rate (CBR) was 68% (4 months) and 51% (6 months). We report final efficacy data after a further 21-months of follow-up, updated safety, survival, and patient-reported outcomes (PROs). Patients received standard-dose pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Primary endpoint: confirmed ORR (CNS) per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary endpoints were response duration, CBR, progression-free survival (PFS), overall survival (OS), safety, and PROs. By clinical cut-off, 39 patients had completed or discontinued treatment. Confirmed ORR (CNS) was 11% (95% CI: 3.0–25.4). Median CNS-PFS was 4.6 months (95% CI: 4.0–8.9), as was median CNS-PFS or systemic PFS (95% CI: 4.0–8.9); median OS was 27.2 months (95% CI: 16.1–not reached). CBR in the CNS was 51% (19 patients, 95% CI: 34.4–68.1) at 6 months. Two patients remained on treatment until study closure, achieving stable disease for 4.1 and 4.8 years. Treatment-related grade 3/4 adverse events occurred in 7.7% of patients. Patients with confirmed partial response or stable disease (≥4 months) in the CNS had stable PROs over time. Pertuzumab plus high-dose trastuzumab represents a reasonable non-chemotherapeutic treatment option for selected patients with HER2-positive MBC with CNS metastases.