Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study

Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Using Cross-Cultural Collaboration to Establish a Working Coalition for An Equitable COVID-19 Vaccine Program

Coalitions and collaborations with African Americans in the United States are often between people with equal humanity but unequal power. Endeavors between historically harmed communities and representatives of systems that continue to harm them frequently lead to intentional and unintentional miscommunication, mistrust, and distrust. The causes for health inequity are complex and should include consideration of systemic racism. In most standard public health models, departments typically take the lead and invite select members of the community to help. This article describes a collaboration that took place in Marin City, California, between African American churches, the department of public health, and community-based organizations during the COVID-19 pandemic. This example focuses on the value of African American history and cosmology as a foundation for respectful cross-cultural collaboration in implementing a COVID-19 vaccination effort. A cross-cultural collaborative model was developed for use by this coalition to guide the development and implementation of community response teams. Unique and shared responsibilities provided by the coalition partners are examined. Humanistic principles, including empathy, positive regard, trust, and grace, are held as central to the model when planning, implementing, and evaluating activities undertaken by cross-cultural coalitions. Sustainability issues are considered concerning staffing, funding, and public policy. © The Author(s) 2023.

Gig Work and the Pandemic: Looking for Good Pay from Bad Jobs During the COVID-19 Crisis

COVID-19 led to work hour reductions and layoffs for many Americans with wage/salary jobs. Some gig work, however, which is usually considered precarious, remained available. We examine whether people doing gig microtasks right before the pandemic increased their microtask hours during COVID-19 and whether those changes helped them financially. Using data from workers on Amazon's Mechanical Turk platform from February, March, and April of 2020, we find that roughly one third of existing workers increased their microtask hours. Increases were larger for people who lost household income or wage/salary hours. Spending more time on microtasks, however, did little to help workers financially. Furthermore, the people most reliant on microtasks before the pandemic had worse financial outcomes than others. In short, even though microtask work might seem like a good way for people to recoup lost income during the pandemic, it was of limited utility even for the experienced workers in our sample.

Neuromodulatory Effects of Sars-Cov2 on Blood Brain Barrier Integrity and Function: E-Poster Viewing

Introduction: Autopsies of COVID-19 patients demonstrate the presence of SARS-CoV-2 in the brain endothelium, cerebrospinal fluid, glial cells, and neuronal tissue;while emerging clinical data suggest that ~40% of COVID-19 patients develop neurological symptoms. We examined the effects of SARS-COV-2 RBD spike protein on blood brain barrier (BB) integrity, and on the expression of tight junction proteins (TJP) that maintain BBB permeability and function. Materials / Methods: Primary human BMVEC were treated with recombinant SARS-COV-2 Spike protein (BEI Resources Inc) for 24-48 hrs, followed by immunofluorescent staining to quantify ACE2 receptor expression. Pro-inflammatory cytokines were quantified in culture supernatants using BioLegend's LEGENDLplexTM bead-based immunoassay. Additionally, a well validated 2D in-vitro BBB model was used to examine the effects of SARS-COV-2 on BBB integrity as measured by transendothelial electrical resistance (TEER) across the membrane, and TJ protein gene expression levels were measured using real time quantitative PCR. Result(s): Data demonstrates that primary human BMVEC express the ACE2 receptor and treatment with SARS-COV-2 spike protein significant increases in ACE2 receptor expression. We observed a significant increase in the levels of the pro-inflammatory cytokines TNF-alpha (p<0.01), IL-6 (p<0.0001), IL-10 (p<0.05), IL-23 (p<0.05) and IL-33 (p<0.01) in BMVEC treated with SARS-COV-2 spike protein compared to untreated controls. A 30% (p<0.05) decrease in TEER occurred in the BBB treated with SARS-COV-2 spike protein as compared to untreated controls, and SARS-COV-2 decreased TJP expression. Data demonstrates that SARS-COV-2 treatment decreased gene expression for the TJPs- ZO-1 (52%;p<0.05), ZO-2 (92%;p<0.001), Claudin-5 (97%;p<0.001) and JAM-2 (45%;p<0.05) as compared to untreated controls. Discussion(s): SARS COV-2 mediates its effects via the ACE2 receptor and therefore an increase in ACE2 expression on BMVEC suggests that neuroinvasion by SARS- COV2 is mediated via endothelial inflammation. Further, SARS-COV-2 induced levels of pro-inflammatory cytokines IL-6, TNF-alpha, IL-8, and IL-10 corroborates the induction of a neuroinflammatory response, confirming hypercytokinemia, which may underlie neuroinflammation in COVID-19 associated encephalopathy. Our data suggest that the significant decrease in TJP gene expression levels directly affect BBB integrity and function thus enabling neuro-invasion and potential subsequent COVID-19 associated neuropathology. Conclusion(s): BMVEC have a paracrine-autocrine role in maintaining CNS homeostasis and the SARS-COV2 associated endothelial cell dysfunction preludes the neuropathology observed in COVID-19 infected patients. Potentially, anti-cytokine based therapeutics may be effective in treating patients with COVID- 19 associated neurological disease. Acknowledgements: Authors gratefully acknowledge funding from SUNY Research Seed Grant Program 2019-20 -RFP #20-03-COVID that was crucial to obtain data for this pilot project. Learning Objectives: Examine the basic neuromodulatory mechanisms that underlie SARS-COV-2 mediated neuropathology. Keywords: SARS-COV2;transendothelial electrical resistance;Blood Brain Barrier;permeability, Tight junction Copyright © 2022

A novel approach to monitoring lithium blood levels and renal function in patients receiving lithium during the COVID-19 pandemic

Introduction: Lithium is commonly administered to patients in an outpatient department (OPD) setting. Regular monitoring of lithium levels and renal function in accordance with published guidelines is required. In our unit, this is usually performed at OPD review. During the COVID-19 pandemic, reviews were either postponed or done remotely. Objective(s): 1. To devise a system to ensure that patients receiving lithium had appropriate blood test monitoring in the absence of traditional OPD appointments. 2. To assess the efficacy of this intervention by recording blood test dates and comparing with pre-COVID compliance. Method(s): All outpatients receiving lithium, identified from the hospital database, received (1) a letter summarising the monitoring guidelines and (2) prospectively dated blood request forms. Patients at higher risk of contracting COVID-19 were advised to attend their primary care setting. Others were encouraged to attend primary care or our phlebotomy department. Compliance was measured by accessing the hospital's laboratory enquiry computer based system and compared with pre-COVID-19 figures. Information was anonymised, as per General Data Protection Regulations. Result(s): 57 patients receiving lithium were identified. Prior to the first Irish lockdown in March 2020, 16 (28%) were overdue testing. Three months into the pandemic, 15 patients (26%) were overdue testing. Conclusion(s): In the absence of routine outpatient appointments during the COVID-19 pandemic, the provision of written guidelines and completed blood request forms for patients receiving lithium was effective in ensuring monitoring of lithium levels and renal function. This system can be utilised as an alternative/adjunct to OPD review benefitting patients and health service delivery.

Comparison of Math Assessment Modalities for Students with Autism Spectrum Disorder

Little is known about the impact of testing modality on math performance, particularly for students with autism spectrum disorder (ASD). In the current study, a multielement, single-case design was used with three students with ASD across three math fluency assessment modalities: paper-pencil, iPad with a stylus, and iPad with a keyboard. Each student alternated 1-minute math fluency probes in each modality, taking two assessments per day. Visual analysis showed minimal differences between the three modalities, and the modality with the highest mean score varied across students. Although the iPad stylus modality did not produce significantly higher scores for any student, all three students rated it as their favorite assessment. Implications for educators are discussed.

Immunogenicity and Safety of SARS-CoV-2 Vaccines and Breakthrough Infections Among Solid Organ Transplant Recipients: Systematic Review and Meta-Analysis

Purpose: The SARS-CoV-2 pandemic has had a significant impact on the field of solid organ transplant(SOT). Immunization against SARS-CoV-2 is globally available since 2021. SOT recipients represent a vulnerable group with a higher risk of infection and worse outcomes from COVID-19 compared with the general population. There is a concern for the efficacy of SARS-CoV-2 vaccination amongst SOT recipients. We aimed to assess immunogenicity, safety and breakthrough infections after SARS-CoV-2 vaccination. Method(s): We conducted a systematic review and a meta-analysis using articles from 8 databases published from January 1,2020 to July 13,2021. We included studies reporting data regarding SOT and SARS-CoV-2 post vaccine antibody response or cellular response;safety of vaccination;and SARS-CoV-2 infection after at least one vaccine dose. A meta-analysis of postvaccine antibody response and death in breakthrough infections was conducted using a random-effects model. Result(s): Initially, we identified 572 potential studies. After careful review, we included 64 studies for systematic review and 46 studies for meta-analysis. We identified 6,710 SOT recipients. Pooled incidence of antibody positivity after completion of any vaccine schedule was 28.3% (95% confidence interval[CI] 22.5-34.8%). Pooled incidence of antibody positivity after messenger RNA vaccination with 2 doses and 3 doses were 29.3%(95%CI 23.58%-35.74%) and 57.4%(95%CI 48.63-65.78%), respectively. Twelve reports on interferon-gamma response to SARS-CoV-2 spike antigen peptides showed a positivity between 30.4% and 55.0% after messenger RNA vaccines. The most common side effect after vaccination was site pain. Only 5 cases developed rejection but no graft loss. The pooled incidence of death in breakthrough infections was 17.1%(95%CI 10.2%-27.2%). Conclusion(s): Our findings show that only 29% of SOT recipients could mount antibodies after 2 doses of messenger RNA vaccines, with an improved response seen after 3 doses (57%). Even with 3 doses, the immunogenicity is still suboptimal and further studies to investigate the optimal vaccination strategies in this population are needed.

The influence of COVID-19 upon perceptions of parent identity and role among youth sport spectators

Parent experiences in youth sport settings during the COVID-19 pandemic are a notable and understudied phenomenon. Parents had varied experiences as a result of safety mandates and protocols that limited physical presence and engagement in their child's sports activities. These limitations proved to be an emotional challenge for parents - balancing the responsibilities of protecting the safety of their families and providing sports experiences to promote both normalcy and acquire the life skills gained from sports participation in a fluid environment. In some instances, parents engaged in virtual spectating experiences which sought to minimize physical risks associated with COVID-19, but also did not require their physical presence to participate. Research on the virtual experience of parents is novel and from a sample of 112 parents across youth sport sectors in 18 states how the spectating modality influenced parental roles and identities was examined. Virtual spectating experiences reflected many challenges for parents, but also prompted much gratitude for allowing continued engagement in their child's sports activities. This exploratory research prompts larger questions urging sport-based professionals to examine the influences of spectating modalities on experiences of parents. The authors captured retrospective parent reactions to their personal spectating experience and generated a grounded theory diagram to demonstrate relationships between factors shaping the parent identity and role in this context. Implications for sport-based professionals are discussed.

ELECTROCONVULSIVE THERAPY (ECT): A CLINICAL AND TECHNICAL UPDATE

Background: Electroconvulsive therapy (ECT) remains most effective treatment for mood and other psychiatric disorders. New techniques are emerging, while others are being refined based on evidence to maximise benefits and reduce side effects. Research, real-life data and lived experience are integral elements of such progress. The Royal Australian and New Zealand College of Psychiatrists, Section of ECT and Neurostimulation (RANZCP SEN) have developed guidelines to nurture culture of academic rigour and clinical utility. Major challenges face neurostimulation such as utilisation in adolescents and children, which remains somewhat controversial and regulated in legislations in most jurisdictions, and the new COVID-19 pandemic challenge to clinical practice over past 2 years. Objectives: To present clinical and technical aspects of ECT, such as factors affecting efficacy and side effects, and to improve knowledge of the latest evidence from research and real-life data. The symposium will provide an opportunity for clinicians to understand the latest evidence while allowing a personalised treatment approach. Methods: Relevant literature and naturalistic data will be presented to illustrate the potential role of neuroimaging as a neuronavigational tool in ECT electrode placement, the impact on efficacy and side effects and proposing guidance for more accurate dosing, Case reports pertinent to ECT in adolescents and children, in addition to results from an international survey on the impact of COVID-19 on ECT practice, will be presented. Findings: Neurostimulation therapies are evolving fields. Ongoing research, naturalistic data and lived experience can guide new techniques and refinements. Conclusion: Psychiatrists and clinicians are encouraged to develop evidence-based personalised treatment plans for patients.

INTERSTATE TELEMEDICINE FOR UROLOGIC ONCOLOGY CARE DURING THE COVID-19 PANDEMIC

INTRODUCTION AND OBJECTIVE: Access to urologic care can be a significant challenge to rural patients. Due to policy changes related to telemedicine during COVID-19, restrictions on interstate telemedicine were waived by several states beginning in March 2020. The aim of this study is to evaluate telemedicine as a means of extending care to patients in rural areas in a cost-effective manner. We collected information on in-person and telemedicine visits for instate and out-of-state patients to provide insight on delivery of care to rural patients. METHODS: From August 2019 to October 2021, all patients seen for urologic cancer care and related complaints (e.g., elevated PSA) at the University of Washington and Seattle Cancer Care Alliance in-person and via telemedicine were sent a survey after each visit. The survey queried patients about travel time, travel costs, and days of work missed. We compared out-of-state (OOS) patients (patients residing in Oregon, Alaska, Idaho, or Montana) seen in-person with those seen via telemedicine. RESULTS: We collected complete surveys for 1094 patient visits, both in-person (N=207) and telemedicine (N=887), excluding repeat visits for established patients. Among established OOS patients, those receiving care via telemedicine had decreased patientestimated travel costs per appointment compared with those receiving care in-person (80.4% telemedicine vs 4.4% in-person visits patients reported no cost). Similarly, 82.1% of patients receiving care via telemedicine, vs 6.7% of in-person visits, reported $0 in cost for their visit. Telemedicine patients reported fewer missed days of work compared with in-person patients (2+ days of work missed for 7.9% of telemedicine patients vs 40.7% of in-person patients). Median selfreported costs for in-person visits among OOS patients were significantly higher than costs reported by Washington State residents (median $500 vs $50, respectively, p= <0.05). CONCLUSIONS: Telemedicine appointments for urologic oncology care for OOS patients increase access to subspecialty care for rural patients at lower cost. Extending OOS exemptions beyond the COVID-19 telemedicine waivers would permit continued delivery of high-quality urologic cancer care to rural patients.

INTERRUPTIONS IN BLADDER CANCER CARE DURING THE COVID-19 PUBLIC HEALTH EMERGENCY

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic has impacted various clinical and research processes in urologic care. As part of a pragmatic clinical trial in bladder cancer, we collected information regarding the impact of COVID-19 at participating sites, which provides insight into how the pandemic has imposed constraints on clinical bladder cancer care and research. METHODS: Starting in May 2020, we distributed a monthly survey to sites participating in CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer, NCT0393382). The survey included questions about interruptions in routine clinical bladder cancer care, specifically assessing elective surgery restrictions, impact on radical cystectomy, TURBT, office cystoscopies, intravesical therapy, and intravesical bacillus Calmette- Guerin (BCG) supply. We report survey responses for sites that responded to > 50% of the monthly surveys from May 2020 to October 2021. RESULTS: From May 2020 through October 2021, 21 sites (66%) had > 50% monthly response rate. The time periods of greatest limitations on bladder cancer procedures (Figure 1) were May-July 2020, Dec-Jan 2020/2021, and Sept-Oct 2021, corresponding to the peak waves of COVID-19 infections. Elective surgery was most affected, with limitations or holds in those time periods at up to 76%, 38%, and 28% of CISTO sites, respectively. Most of the restrictions involved surgeries that required inpatient stays, potential intensive care unit admission, and staffing shortages. 9 sites (28%) experienced transient BCG shortages during the survey period. CONCLUSIONS: Clinical activity was most limited during the initial COVID-19 surge in Spring/Summer 2020. Despite higher COVID- 19 infection rates in subsequent waves, bladder cancer clinical activity has been maintained at CISTO sites throughout the COVID pandemic. Periodic BCG shortages continue to affect bladder cancer care across the US. (Figure Presented).

COVID-19 in Lung Transplant Recipients: Outcomes and Long-Term Follow Up

Purpose The COVID-19 pandemic represents a major global health burden, and an important cause of morbidity and mortality nowadays. Data remains scarce on COVID-19 in lung transplant recipients (LTR). The purpose of this study was to understand impact of infection with COVID-19 in this population, to investigate different variables that contributed to the prognosis, and to assess the long-term clinical outcomes. This represents the largest cohort of continuously followed LTR with COVID-19 to date. Methods We conducted an observational retrospective cohort study of LTRs infected with COVID 19 at a major transplant center between June 2020 and April 2021. Infection was defined by having a positive diagnostic polymerase chain reaction (PCR) test. Patients’ characteristics, COVID severity and management were retrieved. Changes in individual patient's FEV1, imaging and trans-bronchial lung biopsies (TBLB) performed at 3, 6, and 12 month intervals after infection were compared to the baseline prior to infection. Results Fifty-three LTRs were identified as having COVID infection. Median age was 64 years, 31 (58.5%) were males, and 48 (90.5%) were double-LTR. Average BMI was 26.71 and 9 patients had diabetes. 38 (71.7%) patients were on three immunosuppression agents, and 4 (7.5%) patients had an augmented immunosuppression prior to COVID infection. 7 (13.2%) patients had at least one dose of mRNA COVID vaccine. 29 (54.7%) patients were treated as outpatient. Among admitted patients, 13 (24.5%) were treated in the ICU, and 7 (13.2%) required mechanical ventilation. Mortality rate was 15.1%. 26 patients had follow up on their FEV1 in 3 months, 33 in 6 months, and 7 up to 12 months. 14 (26.4%) patients had at least >10% drop in their FEV1, of which 10 patients had >20% drop. 18 patients had TBLB in 3 months, 19 in 6 months, and 4 in 12 months. Overall, 7 (13.2%) patients had acute cellular rejections (ACR). 23 patients had chest imaging at time of infection, with CT scan available for 10. Out of these, 6 showed pure ground glass opacities (GGO), and 4 showed mixed GGO and nodular opacities. Conclusion Out of our 53 LTR with COVID infection, 24.5% had severe disease. Mortality was high in our cohort at 15.1%. PFT decline was common, with 26.4% having an FEV1 drop of over 10% at follow up, suggesting persistent complications are common.

Case Report of Donor Transmitted SARS-CoV-2 Infection During Lung Transplantation

Avoiding SARS-CoV-2 infection in the peri-operative period is a challenge for lung transplantation during the COVID19 pandemic. Testing donor lung BAL samples for SARS-CoV-2 as part of pre-transplant workup may avoid donor-derived infections. A 36-year-old woman with interstitial lung disease secondary to desquamatous interstitial pneumonia during infancy underwent bilateral lung transplant. She was highly allosensitized (cPRA >89%, ccPRA 97%) prompting intra-operative plasmapheresis (PLEX) and rabbit thymoglobulin induction immunosuppression. Post-operatively, her immunosuppression consisted of institution-standard tacrolimus, mycophenolate, and methylprednisolone. For HLA desensitization belatacept, rituximab, intravenous immunoglobulin (IVIG), and carfilzomib regimens were added. She was extubated post-op day 2. Her course was complicated by worsening hypercarbia, hypoxia and respiratory secretions. Post-op day 11, she was reintubated with tracheostomy placement. Chest imaging showed bilateral heterogeneous pulmonary opacities. BAL sampling was positive for SARS-CoV-2 with concern for donor transmission given adherent hospital precautions. Pre-transplant donor and recipient nasopharyngeal (NP) SARS-CoV-2 screenings were negative. Donor transmission was confirmed by positive PCR testing of banked pre-operative donor lung BAL samples. Dexamethasone and remdesivir were started. Tacrolimus and mycophenolate were continued for immunosuppression. She developed acute antibody-mediated rejection (AMR) with new donor specific antigens (DSA) likely related to her SARS-CoV-2 infection. Her AMR was managed with IVIG and PLEX x 10 with PLEX followed by SARS-CoV-2 convalescent plasma. Her DSA's resolved and ventilatory support was weaned. She was discharged home post-op day 56 and was doing well on room air 6 months out. This case emphasizes a potential to miss donor SARS-CoV-2 infection in standard pre-operative evaluation. Despite absence from the NP mucosa viable SARS-CoV-2 virions may be present in donor lung tissue, increasing risk of infection to recipients. Peri-transplant SARS-CoV-2 infection carries a high risk of morbidity. Of note, our case occurred prior to the UNOS mandate for donor lung SARS-CoV-2 screening by lower respiratory sampling. This mandate will decrease risk for similar cases in the future. [ FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Preliminary analysis of the MM21 trial: Response adaptive salvage treatment with daratumumab-lenalidomide-dexamethasone (DRD) for newly diagnosed transplant eligible multiple myeloma patients failing front-line bortezomib-based induction therapy

BACKGROUND Bortezomib-based induction (V-IND) approaches are used in >90% of Australian newly diagnosed transplant eligible multiple myeloma (NDTE MM) patients (pts) with a maximum of 4 cycles of V-IND therapy available via the pharmaceutical benefits scheme (PBS) prior to a planned autologous stem cell transplantation (ASCT). However, NDTE MM patients failing V-IND (defined as best response < partial response [PR]) demonstrate shortened survival and continue to represent a sub-group of MM where a clear unmet medical need persists. The ALLG MM21 was designed to evaluate the efficacy of an early response adapted approach with a switch to an intensive Daratumumab-lenalidomide-dexamethasone (DRd)-based salvage-ASCT- consolidation strategy in patients failing V-IND. METHOD We present the results of a planned interim analysis of the multi-centre single arm study MM21 (ACTRN12618001490268). Eligible pts were NDTE MM who had received V-IND pre-ASCT and demonstrated either a sub-optimal response (SOR - defined as <minimal response [MR] after 2 cycles or <PR after 4 cycles of V-IND) or primary refractoriness (1REF - defined as disease progression while on or within 60 days of completing V-IND). Pre-ASCT DRd was DARA 16mg/kg IV days 1, 8, 15 and 22 for cycles 1 (C1) and 2, and on days 1 and 15 of C3 and C4;Lenalidomide 25mg OD D1-21;and, dexamethasone 40mg PO on D 1, 8, 15 and 22 of each 28-day cycle for C1 to C4. Anti-thrombotic and anti-viral prophylaxis was as per individual institutional practice. Between C3 and C4, patients underwent a G-CSF mobilised PBSC collection with a melphalan 200mg/m2 conditioned ACST after C4. Patients underwent D100 post-ASCT disease response assessment including EuroFlow minimal residual disease (MRD) testing. In the absence of disease progression, patients then received 12, 28-day cycles of consolidation comprising DARA IV 16mg/kg on D1, 15 of C1 and C2 and on D1 of C3 to C12, lenalidomide 25mg PO on D1-21 of C1 and C2 and 10mg OD on days 1-28 of C3 to C12;dexamethasone 40mg was weekly from C1 to C12. RESULTS Fifty patients were recruited from 7 Australian sites between March 2019 and July 2020. Median age was 61 years with 66% males. Disease status at study entry was SOR in 72% (<MR n = 9, <PR n = 27) and 1REF in 28%. Data cut-off date was June 30 2021. 45 patients (90%) received 4 complete cycles of salvage DRd. 11/50 (22%) patients did not undergo ASCT and 4 patients failed stem cell collection. Two pts were withdrawn due to treatment related gastrointestinal toxicity - persistent oesophagitis (n =1) and recurrent colitis (n=1). There were two deaths, due to COVID-19 pneumonia (n =1) and septic shock (n =1). Pre-ASCT response was evaluable in 43 patients, overall response rate (ORR) was 70% - complete response (CR) 6%, very good partial response (VGPR) 18%, partial response (PR) 46%, clinical benefit rate (CBR) 83% - MR 11% and stable disease (SD) 2% on Intention to Treat (ITT n = 50) analysis. 33 patients were assessed for MRD - MRD negative 6% on ITT (3/33 9%). Pre-consolidation disease assessment was evaluable in 37 pts, both ORR and CBR were 72% - stringent complete response (sCR) 4%, CR 14%, VGPR 24%, PR 30% ITT analysis. 31 pts were evaluated for MRD - MRD negative 28% ITT (14/31 45%). In 6 patients, MRD was omitted or could not be performed due to pre-analytical issues. Post-C2 consolidation assessment was evaluable in 37 pts, ORR 72% - sCR 2%, CR 24%, VGPR 26%, PR 20%, CBR 74% - SD 2% ITT analysis. To date, 22 patients have been evaluated for MRD with 4 patients awaiting results, MRD negative rate of 38% ITT (10/22 45%). MRD sample collection at this time-point was omitted in 7 patients, potentially skewing MRD negativity on ITT analysis. CONCLUSION Preliminary analysis of the MM21 trial demonstrates early response-adaptive escalation to DRd facilitated ASCT in the majority patients with robust ORR post-autologous stem cell transplant and substantial improvement in disease control, as reflected in improved rates of MRD and disease response to treatment. At both post-ASCT time-p ints there was significant drop off in MRD testing due to testing omission, potential skewing results of MRD analysis. MRD and duration of response analysis following C12 consolidation is planned and will be of interest. Current data suggests this drug combination shows potential for substantial benefit in the study population. (Figure Presented).

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

"Bugs as drugs" in medicine encompasses the use of microbes to enhance the efficacy of vaccination, such as the delivery of vaccines by Leishmania-the protozoan etiological agent of leishmaniasis. This novel approach is appraised in light of the successful development of vaccines for Covid-19. All relevant aspects of this pandemic are summarized to provide the necessary framework in contrast to leishmaniasis. The presentation is in a side-by-side matching format with particular emphasis on vaccines. The comparative approach makes it possible to highlight the timeframe of the vaccine workflows condensed by the caveats of pandemic urgency and, at the same time, provides the background of Leishmania behind its use as a vaccine carrier. Previous studies in support of the latter are summarized as follows. Leishmaniasis confers life-long immunity on patients after cure, suggesting the effective vaccination is achievable with whole-cell Leishmania. A new strategy was developed to inactivate these cells in vitro, rendering them non-viable, hence non-disease causing, albeit retaining their immunogenicity and adjuvanticity. This was achieved by installing a dual suicidal mechanism in Leishmania for singlet oxygen (O-1(2))-initiated inactivation. In vitro cultured Leishmania were genetically engineered for cytosolic accumulation of UV-sensitive uroporphyrin I and further loaded endosomally with a red light-sensitive cationic phthalocyanine. Exposing these doubly dye-loaded Leishmania to light triggers intracellular production of highly reactive but extremely short-lived O-1(2), resulting in their rapid and complete inactivation. Immunization of susceptible animals with such inactivated Leishmania elicited immunity to protect them against experimental leishmaniasis. Significantly, the inactivated Leishmania was shown to effectively deliver transgenically add-on ovalbumin (OVA) to antigen-presenting cells (APC), wherein OVA epitopes were processed appropriately for presentation with MHC molecules to activate epitope-specific CD8+ T cells. Application of this approach to deliver cancer vaccine candidates, e.g., enolase-1, was shown to suppress tumor development in mouse models. A similar approach is predicted to elicit lasting immunity against infectious diseases, including complementation of the spike protein-based vaccines in use for COVID-19. This pandemic is devastating, but brings to light the necessity of considering many facets of the disease in developing vaccination programs. Closer collaboration is essential among those in diverse disciplinary areas to provide the roadmap toward greater success in the future. Highlighted herein are several specific issues of vaccinology and new approaches worthy of consideration due to the pandemic.