CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

CONTEXT: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib-a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket-demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). OBJECTIVE: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. DESIGN: Patients with T315I-mutated CML-CP and treated with >=1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). RESULTS: 48 patients were included;25 patients (52.1%) received >=3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients;34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for >=96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS <=1% by week 96. The safety/tolerability profile of asciminib remained favorable after =9 months of added exposure (median duration of exposure, 2.08 years;range, 0.04-4.13 years). The most common (>=10%) grade >=3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%);none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. CONCLUSIONS: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP-a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

ASCIMINIB PROVIDES DURABLE MOLECULAR RESPONSES IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) WITH THE T315I MUTATION: UPDATED EFFICACY AND SAFETY DATA FROM A PHASE I TRIAL

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

Hospital-based Observational Study of Neurological Disordersin Patients Recently Vaccinated with COVID-19 mRNA Vaccines

Objective: To describe the spectrum of acute neurological disorders among hospitalized patients who recently received COVID-19 mRNA vaccination. Background: The unprecedented pace of COVID-19 vaccine development, use of novel mRNA technology and large-scale vaccination programs have engendered concerns of adverse events following immunization. Design/Methods: We performed a multi-centre prospective observational study in 7 public acute hospitals. Hospitalized patients who were referred for neurological complaints and had COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, in the last 6 weeks were classified into central nervous system(CNS) syndromes, cerebrovascular disorders, peripheral nervous system(PNS) disorders, autonomic nervous system(ANS) disorders and immunization stressrelated responses(ISRR). To contextualize our findings, data from National Immunization Registry was probed for the total number and demographic of individuals vaccinated in the corresponding period. Results: From 30 December 2020 to 20 April 2021, 1,398,074 persons (median age 59 years, 54.5% males) received COVID-19 mRNA vaccine (86.7% BNT162b2, 13.3% mRNA-1273);915,344 (65.5%) completed 2 doses. Four hundred and fifty-seven (0.03%) patients were referred for neurological complaints [median age 67 years, 61.5% males;95.8% received BNT162b2 and 4.2% mRNA-1273];classified into 73 (16.0%) CNS syndromes, 286 (62.6%) cerebrovascular disorders, 59 (12.9%) PNS disorders, 0 ANS disorders and 39 (8.5%) ISRRs. Twenty-seven had cranial mononeuropathy, 11 of whom had Bell's palsy. Of 33 patients with seizures, only 4 were unprovoked and occurred within 2 weeks of vaccination. All strokes occurred among individuals with pre-existing cardiovascular risk factors. We recorded 2 cases of cerebral venous thrombosis;none associated with thrombocytopenia. Five had mild flares of immune-mediated diseases. Conclusions: Our observational study does not establish causality of the described disorders to vaccines and is limited by lack of baseline incidence data of several conditions. Nevertheless, we did not observe any obvious signal of serious neurological morbidity associated with mRNA vaccination. The benefits of COVID-19 vaccination outweigh concerns over neurological adverse events.

Strategizing alumni to encounter financial sustainability issue: insights from public higher education institutions of Pakistan

Purpose: This practitioner paper intends to explore how Public Higher Education Institutions (PHEIs) in Pakistan could strategize alumni to encounter the financial sustainability challenges and achieve their organizational potential relevant to academic, research and public services. Design/methodology/approach: Employing a hermeneutic (interpretive) phenomenological approach, this study used interviews and focus group discussion data with 26 alumni from eight different PHEIs in Pakistan to explore their attitudes toward engagement with their institutions. Findings: This study shows a clear shift in institutional strategies between the developing and developed economies regarding the importance and value given to alumni and engagement practices employed. Practical implications: This study recommends that PHEIs in Pakistan can enjoy alumni engagement benefits to strengthen their organizational standing, provided they view alumni as a valuable entity and observe a proactive approach to engage alumni in a manner that may reflect the mutually beneficial and trustworthy relationship. Further, it would help institutions attain long-term financial sustainability, which is threatened by state-funding cuts and, more recently, COVID-19 pandemic-led recession. Originality/value: Scholarship shows that institutions in the developed economies have built a strong bond with their alumni to seek their support. However, the voices of institutions from the developing economies have not been heard yet. In this regard, this study appears to highlight the current alumni engagement practices and how institutions could improve on them to strategize alumni for a sustainable future. © 2022, Emerald Publishing Limited.

The shift to pediatric rheumatology telemedicine practice impacts the ability to assess and document critical JIA outcome data: A survey within the PR-COIN network

Introduction: The COVID-19 pandemic disrupted the traditional inperson healthcare delivery model, prompting a shift to telemedicine to ensure continuity of care for pediatric rheumatology patients. The change to virtual practice affected healthcare provider's assessments of disease activity in patients with juvenile idiopathic arthritis (JIA) as they were unable to perform hands-on physical assessments. Understanding the impact of this shift is critical to help address any care gaps that are faced during virtual visits for patients with JIA. Objectives: The objectives of the survey were four-fold: a) understand the impact of the switch from in-person to telemedicine visits from the healthcare provider perspective;b) identify the barriers and facilitators to collecting critical data elements that are important in monitoring JIA disease activity and outcomes;c) identify tools that providers are using during their telemedicine visits to perform disease activity assessments;and d) examine the impact of the telemedicine healthcare delivery on clinical research. Methods: A cross-sectional survey sent to members from all Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) centers (n=21) with total number of targeted respondents of 121. The survey was sent out for completion between 08/17/2020 - 09/ 02/2020. Quantitative responses were analyzed using descriptive statistics. Qualitative responses were analyzed by content and theme. Results: Survey ersponse rate was 98% (n=119) 90% fully completed. Most respondents (99%) indicated that they documented six critical data elements [CDE] (physician global assessment, patient global assessment, active joint count, morning stiffness, arthritis-related pain, and completion of uveitis screen) in 75% of telemedicine visits. Most respondents (74%) indicated that they documented active joint count over 70% of the time, while 30% of respondents reported barriers to documenting active joint count such as inability to palpate joints and the inability to visualize all joints on virtual examination. Identified barriers to assessment and visit documentation included challenges with assessing joint disease activity and platform technical issues. Ten percent of the respondents reported they often forgot to document CDE during telemedicine visits, indicating that setting up automated reminders in their electronic medical records may help with increasing their likelihood of documentation. A few centers reported having processes to assist with the collection of patient data in advance of the visit, such as pre-visitquestionnaires and planning. The ability to perform research activities was significantly impacted with only 37% of centers reported participating in research activities via telemedicine, and 29% reported their ability to consent patients via telemedicine visits. Conclusion: There are multiple barriers and facilitators to conducting successful clinical visits as well as performing clinical research over telemedicine. Our data suggests variation in telemedicine practice and process across centers, as well as within each center, reflecting the need to standardize the process of telemedicine visits. Given that a portion of patients with JIA will likely continue to be serviced over telemedicine post-pandemic, teams need to adapt their existing practices to continue providing quality care and integrating clinical research over this platform where appropriate.

Is intracardiac echo guided left atrial appendage occlusion a safe and cost effective alternative to transoesophageal guided left atrial appendage occlusion? A single centre retrospective review

57 Figure 1(Left to Right): lA Fluroscopic Image Showing ICE Catheter (Circled) On Left. lB: ICE Catheter on Left, Amplatzer Delivery Sheath On Right Deploying Amulet LAAO Device. 1C Contrast Image Post Deployment of LAAO Device Showing No Opacification of Left Atrial Appendage with Contrast, Indicative of Satisfactory Occlusion of LAA[Figure omitted. See PDF]Abstract 57 Table 1Baseline patient characteristicsICE Guided (n=25) TOE Guided (n=24) Age 76 ± 6.07 78.58 ± 6.63 Sex M(%)/F(%) 18(72%)/7(28%) 19(79%)/5(21%) CHA2DS2-VASc 3.84 ± 1.08 3.75 ± 0.92 HASBLED 2.96 ± 0.72 2.875 ± 0.88 Baseline Haemoglobin 12.53 ± 1.69 13.175 ± 1.48 Baseline Creatinine 91.72 ± 22.21 100.5 ± 28.57 Indication for LAA occlusion: -Intracranial Haemorrhage (%) 9(36%) 3 (12.5%) -GI Bleeding (%) 13 (52%) 15 (62.5%) -Epistaxis (%) 1 (4%) 1 (4.2%) -Stroke on NOAC Therapy (%) 1 (4%) 0 (0%) -Haematuria (%) 1 (4%) 2 (8.4%) -Other (%) 0 (0%) 3 (12.5%) ± Values Refer to Standard Deviation from the Mean Value.Abstract 57 Table 2Primary and second endpoints ICE Guided (n=25) TOE Guided (n=24) P Value* Primary Endpoints: Successful Implantation (%) 24 (96%) 24 (100%) 0.312 Procedure Related Death (%) 0 (0%) 0 (0%) N/A Secondary Endpoints: Fluroscopy Time (Mins) 41.64 ± 13.39 63.08±14.93 <0.001 Procedure Time (Mins) 127.56 ± 49.32 184.92 ± 63.16 <0.001 Haematoma (%) 0 (0%) 2 (8.33%) 0.235 LOS 2.6 ± 1.55 2.9 ± 1.15 0.03 Cardiac Arrest (%) 0 (0%) 1 (4.16%) 1.00 Pericardial Effusion (%) 1 (4%) 1 (4.16%) 1.00 Tamponade (%) 1 (4%) 0 (0%) 1.00 Peri-Device Leak (%) 1 (4%) 1 (4.16%) 1.00 Device Embolisation (%) 0 (0%) 1 (4.16%) 0.490 ± Vaules Refer to Standard Deviation from the Mean.*P Value from Mann Whitney U Test/Fishers Exact/T-Test as detailed in methods.*P Value <0.05 was determined to be statistically significant.ConclusionICE guided LAA occlusion leads to shorter hospital length of stay, procedure time and reduces time spent under fluoroscopy compared with TOE guided LAA occlusion. There was no statistically significant variations in the procedural complications between the two groups. ICE guided LAA occlusion removes the need for GA, making procedures logistically less challenging and eliminating the need for an aerosol generating procedure (TOE). In the current climate of a global Covid-19 pandemic which has limited access to ICU beds and anaesthetic support, ICE guided LAAO is a safe and cost effective alternative for stroke prevention to TOE guided LAAO in patients with high CHA2DS2-VASc scores and contraindications to oral anticoagulation. We will continue to follow these patients with gated CT Aorta to ascertain the incidence of device leak.

Neurological disorders associated with COVID- 19 in Singapore

Objective: To describe the neurological disorders associated with COVID-19 in Singapore. Background: Various neurological disorders have been reported in COVID-19 patients. Postulated mechanisms include hypercoagulopathy, dysimmunity, inflammation and direct viral invasion. The incidence and relationship to SARS-CoV-2, considering the confounding effect of a surge in COVID-19 cases on healthcare systems, are unclear. Design/Methods: This was a prospective, nation-wide, multi-centre, cohort study of patients with microbiologically-confirmed COVID-19 referred for any neurological complaints With in 3 months of infection. Neurological diagnoses and relationship to COVID-19 were made by consensus guided by contemporaneous published case definitions. Results: Between March-July 2020, 47,572 patients [median age 34 (1-102) years, 98% males] were diagnosed with COVID-19 in Singapore. Of 90 patients referred for neurological disorders, 39 [median age 41 (27-73) years, 97% males] were deemed related to COVID-19 and categorised as: i) Central nervous system syndromes - 3 encephalitis, 1 acute disseminated encephalomyelitis;ii) Cerebrovascular disorders - 19 acute ischemic stroke/transient ischemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT) and 2 intracerebral haemorrhage;iii) Peripheral nervous system - 7 mono/polyneuropathy;iv) Autonomic nervous system - 4 limited dysautonomia. Fifty-one other patients had pre/co-existent neurological conditions (headache, seizure, mononeuropathies and functional neurological disorders) unrelated to COVID-19. Encephalitis is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early and largely in mild infections. AIS/TIA was variable in onset;remarkably 63.2% had asymptomatic COVID-19. CVT was more frequent than expected and occurred in patients with mild/asymptomatic COVID-19. The pathophysiology of COVID-19 neurology appeared to be dysimmunity and/or prothrombotic tendency. There were no neurological complications in all 81 paediatric COVID-19 cases. Conclusions: COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. The relatively few cases recorded was probably because our outbreak affected mainly healthy young men with mild/asymptomatic COVID-19 and the pandemic did not unduly affect the Singapore healthcare system.

Impact of the COVID-19 pandemic on hyperacute stroke treatment: Experience from a comprehensive stroke centre in singapore

Background: The Coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving and affecting healthcare systems across the world. Singapore has escalated its alert level to Disease Outbreak Response System Condition (DORSCON) Orange, signifying severe disease with community spread. Objectives: We aimed to study the overall volume of AIS cases and the delivery of hyperacute stroke services during DORSCON Orange. Methods: This was a single-centre, observational cohort study performed at a comprehensive stroke centre responsible for AIS cases in the western region of Singapore, as well as providing care for COVID-19 patients. All AIS patients reviewed as an acute stroke activation in the Emergency Department (ED) from November 2019 to April 2020 were included. System processes timings, treatment and clinical outcome variables were collected. Results: We studied 350 AIS activation patients admitted through the ED, 206 (58.9%) pre- and 144 during DORSCON Orange. Across the study period, number of stroke activations showed significant decline (p =0.004, 95% CI 6.513 - -2.287), as the number of COVID-19 cases increased exponentially, whilst proportion of activations receiving acute recanalization therapy remained stable (p = 0.519, 95% CI -1.605 - 2.702). Amongst AIS patients that received acute recanalization therapy, early neurological outcomes in terms of change in median NIHSS at 24 hours (-4 versus -4, p = 0.685) were largely similar between the pre- and during DORSCON orange periods. Conclusions: The number of stroke activations decreased while the proportion receiving acute recanalization therapy remained stable in the current COVID-19 pandemic in Singapore. (Figure Presented).

Exploring Pediatric Tele-Rheumatology Practices During COVID-19: A Survey of the PRCOIN Network.

Healthcare providers were rapidly forced to modify the way they practiced medicine during the coronavirus disease 2019 (COVID-19) pandemic. Many providers transitioned from seeing their patients in person to virtually using telemedicine platforms with limited training and experience using this medium. In pediatric rheumatology, this was further complicated as musculoskeletal exams typically require hands-on assessment of patients. The objective of this study was to examine the adoption of telemedicine into pediatric rheumatology practices, to assess its benefits and challenges, and to gather opinions on its continued use. A survey was sent to the lead representatives of each Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) site to collect data about their center's experience with telemedicine during the COVID-19 pandemic. Quantitative data were analyzed using descriptive statistics, and qualitative data were thematically analyzed. Responses were received from the majority [19/21 (90%)] of PR-COIN sites. All respondents reported transitioning from in-person to primarily virtual patient visits during the COVID-19 pandemic. All centers reported seeing both new consultations and follow-up patients over telemedicine. Most centers reported using both audio and video conferencing systems to conduct their telemedicine visits. The majority of respondents [13/19 (68%)] indicated that at least 50% of their site's providers consistently used pediatric Gait Arms Legs and Spine (pGALS) to perform active joint count assessments over telemedicine. Over half of the centers [11/19 (58%)] reported collecting patient-reported outcomes (PROs), but the rate of reliably documenting clinical components varied. A few sites [7/19 (37%)] reported performing research-related activity during telemedicine visits. All centers thought that telemedicine visits were able to meet providers' needs and support their continued use when the pandemic ends. Benefits reported with telemedicine visits included convenience and continuity of care for families. Conversely, challenges included limited ability to perform physical exams and varying access to technology. Pediatric rheumatology providers were able to transition to conducting virtual visits during the COVID-19 pandemic. Healthcare providers recognize how telemedicine can enhance their practice, but challenges need to be overcome in order to ensure equitable, sustainable delivery of quality and patient-centered care.