Speaker Honorarium Research Articles

1602. Comparative Activity of Ceftolozane-Tazobactam (C/T) and Ceftazidime-Avibactam (CZA) against Pseudomonas aeruginosa (PSA) from Patients with Cystic Fibrosis (CF)

BackgroundAcute pulmonary exacerbations (APE) are a frequent cause of hospitalization for patients with CF. PSA is among the most common pathogen implicated in CF APE. Due to repetitive antibiotic courses, multidrug resistance (MDR) must be considered leaving few available intravenous antibiotic options. CZA and C/T are newer anti-PSA antibiotics that have been used to treat CF APE, but little data are available to compare their in vitro activity.MethodsNon-duplicate, contemporary, clinical PSA (n=105) isolates were acquired from 85 patients during CF APE from 3 US hospital systems. MICs were assessed in at least triplicate by reference broth microdilution for C/T, CZA, aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), ciprofloxacin (CIP), levofloxacin (LVX), meropenem (MEM), piperacillin/tazobactam (TZP), and tobramycin (TOB). Current CLSI breakpoints were used to define susceptibility. Activity was further assessed in MDR, CAZ and MEM non-susceptible (NS) phenotypes.ResultsThe mean patient age at isolate retrieval was 31 years (IQR: 21-43), and 20% were under 18 years. Mucoid morphology was observed in 48 (46%) isolates, and MDR defined in 41 (39%). Rates of susceptibility (MIC50/MIC90/%S) were: C/T (1/4/92%), CZA (2/8/90%), CAZ (4/64/68%), TZP (8/256/67%), TOB (2/32/63%), MEM (1/32/58%), ATM (8/64/57%), FEP (8/≥128/50%), CIP (2/8/27%), and LVX (4/16/24%). A mucoid phenotype did not alter %S (non-mucoid vs. mucoid) for C/T (93 vs. 92%) or CZA (91 vs. 88%). Among the 41 MDR PSA, activity was 2/16/83% and 4/16/76% for C/T and CZA, respectively. C/T, CZA, and MEM %S was 77, 69, and 23% for the 35 CAZ-NS isolates. C/T, CZA, and CAZ %S was 84, 77, and 39% for MEM-NS isolates.ConclusionThese contemporary PSA from patients with CF displayed low susceptibility rates to most β-lactams, fluoroquinolones, and tobramycin, and MDR was common. C/T and CZA retained similarly high susceptibility against these isolates, including MDR strains and CAZ-NS/MEM-NS phenotypes. These data justify that both CT and CZA may be considered for CF APE due to PSA non-susceptible to current standard of care treatment options.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))

13. Evaluation of Etest for Antibiotic Susceptibility and Minimum Inhibitory Concentration (MIC) Agreement Against pseudomonas Aeruginosa (psa) from Patients with Cystic Fibrosis (CF)

BackgroundCF acute pulmonary exacerbations are often caused by PSA, including multi-drug resistant strains. Optimal antibiotic therapy is required to return lung function and should be guided by in vitro susceptibility results. There are sparse data on the performance of Etest relative to reference broth microdilution (BMD) for many newer drugs against CF PSA. Herein, we describe Etest performance with 10 anti-PSA antibiotics against CF isolates.MethodsContemporary, clinical PSA (n=105) isolated during pulmonary exacerbation from patients with CF were acquired from 3 US hospitals. MICs were assessed by BMD (reference) and Etest for aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), ceftazidime/avibactam (CZA), ceftolozane/tazobactam (C/T), ciprofloxacin (CIP), levofloxacin (LVX), meropenem (MEM), piperacillin/tazobactam (TZP), and tobramycin (TOB). Each respective MIC was completed in at least triplicate using the same inoculum between methods. Modal MICs for each method were compared by rates of essential agreement (EA), categorical agreement (CA), minor error (miE), major error (ME), and very major error (VME) rates. All miE, ME and VME were adjusted if within EA.ResultsOf the 105 PSA, 46% had a mucoid phenotype. Results are summarized in the Table. Median modal Etest MICs read 0–1 dilution higher (IQR: 0–1) than BMD. CA and EA ranged from 64–93% and 63–86%, respectively. Single VMEs occurred for ATM (2.9%) and CAZ (4.2%). For CZA, 2 VMEs were observed and both were within EA. Major errors were ≤3% except for ATM (3.3%), MEM (3.3%), CZA (5.3% with adjusted ME 2.1%*), and FEP (13%). Minor error rates were < 10% except for TZP, CIP, LEV, TOB, and FEP (13–29%), for which majority of miE were within EA (3/14, 11/16, 10/18, 13/19, 20/31, respectively). Performance was similar for non-mucoid and mucoid populations.Etest PerformanceConclusionEtest methods performed well for most antibiotics against this challenging collection of PSA from CF patients. Laboratories should be cautious of miE and ME that may occur with certain antibiotics. Furthermore, our observations suggest laboratories confirm CZA results for isolates with MICs near the breakpoint. Disclosures Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials)) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

1308. Ex vivo Impact of Autologous Blood Transfusion (ABT) on Concentrations of Antibiotics used for Surgical Prophylaxis

BackgroundABT is widely employed during surgical procedures involving high blood loss, such as liver transplantation and open heart surgery. While ABT mitigates the need for allogeneic blood transfusions, an unintended consequence may be removal of drugs, including antimicrobials. Herein, we determined the ex vivo loss of antimicrobials utilized for surgical prophylaxis through an ABT system.MethodsExperiments were conducted in duplicate to simulate processing of ABT blood during surgery. Packed red blood cells and fresh frozen plasma (300ml) were acquired from banked blood and inoculated to achieve clinically-relevant plasma concentrations of vancomycin (VAN), the piperacillin (PIP) component of piperacillin/tazobactam, and the ampicillin (AMP) component of ampicillin/sulbactam. Inoculated blood was processed through a Cell Saver® Elite™ ABT system to fill a 125mL Latham bowl and washed with 500mL of normal saline. Processed fluid was directed to a reinfusion or waste bag; additional blood samples were collected from each. Drug concentrations were measured in all samples. The amount of VAN, PIP, and AMP infused through the Cell Saver (initial), and resulting in the reinfusion and waste bags was calculated.ResultsA range of 193-265mL of combined blood containing drug were processed in each experiment through the ABT system. Initial average plasma concentrations were 61, 107, and 172 mg/L for VAN, PIP, and AMP, respectively. When corrected for volume and hematocrit, plasma concentrations translated to a mean ± SD of 3 ± 1% of VAN in the reinfusion bag and 93 ± 2% in the waste bag. For PIP, plasma concentrations translated to 2 ± 1% of PIP in the reinfusion bag and 84 ± 13% in waste, while 2 ± 1% and 120 ± 5% of AMP was found in the reinfusion and waste bags, respectively. Unaccounted drug (0-14%) was considered sequestered in the device.ConclusionThese ex vivo assessments of antibiotic removal during ABT are the first to demonstrate significant loss of antibiotics (>95%) when processed through the ABT system. Further studies measuring impact of ABT on drug concentrations in patients undergoing surgery are warranted.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))

First Glimpse on Real-World Efficacy Outcomes for 2000 Patients with Systemic Light Chain Amyloidosis in Europe: A Retrospective Observational Multicenter Study By the European Myeloma Network

First Glimpse on Real-World Efficacy Outcomes for 2000 Patients with Systemic Light Chain Amyloidosis in Europe: A Retrospective Observational Multicenter Study By the European Myeloma Network

Light Chain Deposition Disease: First Analysis of an International Study in 359 Patients

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was &amp;gt;15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff &amp;gt;30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR &amp;lt;15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC&amp;lt;40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC &amp;lt;40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis

Background: There is no licensed therapy for light chain (AL) amyloidosis; however, bortezomib (B) is considered standard upfront treatment. Existing data on safety and efficacy of B in AL amyloidosis derive from clinical trials and retrospective series from few referral centers and only partly reflect real-world practice. In 2011, the Italian Medicines Agency (AIFA) started a program to grant access to upfront B to patients with AL amyloidosis. Treated patients had to be enrolled in an online registry and prospectively followed during therapy. We report the treatment experience in this real-world setting. Methods: AL amyloidosis diagnosis required tissue typing with mass spectrometry or immuno-electron microscopy. Patients samples could be sent to the Pavia specialized center for typing, but patients were not treated under the supervision of the referral center. Subjects with multiple myeloma were excluded. Variables were collected at baseline and hematologic and cardiac responses were assessed after 8 weeks (approximately 2 cycles) according to the International Society of Amyloidosis criteria. The cox proportional model has been adopted to assess the risk of treatment discontinuation according to the baseline characteristics. Results: A total of 754 patients were treated between May 2011 and October 2019 and 605 were included in the analysis. Most common reasons for exclusion were retrospective data collection (45%), and incomplete data set (31%). Median age was 67 years (range 26-89 years). 82% of patients had heart involvement. Cardiac stage was I in 18% of subjects, II in 45%, IIIa in 21%, and IIIb, in 16%. Sixty-seven percent of patients had renal involvement, and 13% and 14% had severe (glomerular filtration rate [eGFR] between 30 and 15 mL/min) and end-stage (eGFR &amp;lt;15 mL/min) renal insufficiency, respectively. Differential free light chain level (dFLC) was &amp;gt;180 mg/L in 41% of cases. Bortezomib was administered with dexamethasone (D) alone in 41% of patients, with cyclophosphamide and D (CyBorD) in 44%, and with melphalan and D (BMDex) in 13% of subjects. Other combinations were used in 2% of patients. In the overall population, the initial dose of B was attenuated (&amp;lt;1.3 mg/m2) in 22% of patients. The proportion of patients receiving attenuated dosage was higher in stage III patients (38%). Fourteen percent of subjects required B dose reduction during therapy, while B dosage could be increased in 7% of patients who started at a reduced dose. A twice-weekly B schedule at treatment initiation was used in 22% of all subjects and in 16% of stage III patients. Fourteen percent of patients initially treated with the twice weekly schedule needed to be shifted to the once weekly schedule. After 8 weeks (approximately 2 cycles) the overall hematologic response rate was 58% (CR 3%, VGPR 20%) and cardiac response was attained in 14% of patients. The median number of cycles performed was 3 (range 1-9), median duration of monitored treatment was 4.3 months. Treatment was discontinued during monitoring due to achievement of satisfactory response or completion of maximum (9) allowed number of cycles in 3% of cases, progression in 14%, death in 8%, and toxicity in 1% of patients. The cause of discontinuation was defined as independent of drug and disease in the remaining 25.1% of subjects. Risk of treatment discontinuation was lower in patients who could tolerate a 1.3 mg/m2 dose of B from cycle 1 (HR 0.70, 95%CI 0.54-0.91). Second-line therapy with immunomodulators (most commonly lenalidomide) was started in 14% of patients. Conclusions: Patients with AL amyloidosis start treatment at an advanced stage and early deaths are common. The rate of severe/end-stage renal failure was higher (27%) than expected, possibly indicating that these patients are less likely to be referred to specialized centers. Remarkably, outside referral centers B is commonly administered with D alone. Dose reductions are frequently applied, but dosage can be escalated during therapy. Response rates at 8 weeks are comparable to those reported in other large studies and early cardiac responses are possible. To the best of our knowledge this is the only study prospectively evaluating treatment with B in a real-world setting. Treatment registries under the supervision of regulatory agencies are precious tools to assess common therapeutic practice in rare disease, to evaluate candidate comparators for future trials, and to assess unmet medical needs. Disclosures Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Milani:Janssen: Other: Speaker honoraria; Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria. Nuvolone:Janssen: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis

Sars-Cov-2 Infection and Systemic Light Chain Amyloidosis: The International Society of Amyloidosis' Survey

Introduction: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global health crisis since it was first reported in December 2019. In a subset of infected subjects, pneumonia, multi-organ failure, and eventually death can occur. Frail patients and those with comorbidities are believed to be at increased risk of severe manifestations of SARS-CoV-2 infection. Patients with light chain (AL) amyloidosis have a hematologic malignancy that causes multi-organ dysfunction and can be at higher risk of complications and death. The International Society of Amyloidosis (ISA) has issued a guidance (Kastritis et al. BJH 2020, https://cms.cws.net/content/isaamyloidosis.org/files/ISA%20recommendations%20Covid-19%20v_%203_3.pdf) for patients with amyloidosis during the pandemic and called for an international data collection in April 2020. Aim of this study is to report the preliminary data of the ongoing international survey regarding systemic AL amyloidosis and COVID-19.Methods: The survey was proposed by the ISA Board and approved by the coordinating institution's Ethics Committee. All members of the ISA were invited to participate by email and a link for participation is online on ISA website. RedCap software was used for the data collection.Results: Twelve Institutions requested the access to the data collection system from 7 countries. At the data lock of July 26, 2020, 29 patients with systemic amyloidoses were collected from 7 different Institutions. Systemic AL amyloidosis patients reported so far were 19: 12 from the Pavia Amyloidosis Research and Treatment Center (Italy), 3 from the Boston Medical Center (USA), and 1 patient each from the Columbia University Hospital (New York, USA), Hospital Clinic (Barcelona, Spain), Clinica Universitaria de Navarra (Navarra, Spain) and Amyloidosis Centrum (Heidelberg, Germany). Eleven (58%) had heart involvement, 8 (42%) had kidney and two or more organs were involved in 9 patients (47%). The most frequent comorbidities reported were history of hypertension in 7 (37%) and cardiovascular diseases in 3 (16%). Four (21%) patients were newly diagnosed and treatment-naïve at the time SARS-CoV-2 infection was documented. The remaining 15 patients had received a median number of 2 previous lines of therapy (range 1-3). Nine (47%) patients were on active chemotherapy at the time of COVID-19 infection. Five were receiving daratumumab combinations, and the 4 remaining patients were on cyclophosphamide, bortezomib and dexamethasone, oral melphalan and dexamethasone, lenalidomide and ixazomib. Relevant concomitant medications were anti-hypertensive drugs in 26% of cases and diuretics in 21%. One patient was on dialysis. COVID-19-related symptoms were fever 11 (58%), cough 8 (42%), anosmia and ageusia. Pneumonia was documented in 10 (53%) patients, 5 of whom had acute respiratory distress syndrome (ARDS) (26%). Four of them were treated with non-mechanical ventilation and one accessed intensive care support. Three of the 5 patients with severe COVID-19 had heart involvement, 2/5 had concomitant heart and kidney involved and 3 was infected while on active chemotherapy. Azytromicin was used in 6 (26%) cases, which was in combination with hydroxycloroquine in 4 of them. Three patients received steroids as treatment for SARS-CoV-2 infection, while anticoagulant therapy was used only in two cases. Lopinavir, tocilizumab and sarilumab were used in one patient each. Four patients (21%) died in the whole cohort. Three had ARDS and one patient died few weeks after the recovery of COVID-19 infection. All deceased patients had heart involvement, 2 were on active therapy (daratumumab plus bortezomib and ixazomib plus dexamethasone). Two patients with kidney involvement at diagnosis, one with ARDS and one with a radiological documented pneumonia treated with non-mechanical ventilation recovered from COVID-19 but developed subsequent worsening of renal function, requiring dialysis in one case.Conclusions: The fatality rate and the proportion of patients with severe COVID-19 in this series is in the higher range of reports from the general population. Severe SARS-CoV-2 infection can result in renal failure in patients with renal AL amyloidosis.DisclosuresMilani:Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria; Celgene: Other: Travel support. Sanchorawala:Oncopeptide: Research Funding; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Prothena: Research Funding; Takeda: Research Funding; Janssen: Research Funding; UpToDate: Patents & Royalties; Caelum: Research Funding; Celgene: Research Funding. Cibeira:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Educational lectures; Akcea Therapeutics: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Other: Educational lectures; Amgen: Honoraria, Other: Educational lectures. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other.

FOLFOX as Second-Line Chemotherapy for Advanced Biliary Tract Cancer

Background: Advanced biliary tract cancer (ABC) has a poor prognosis for which cisplatin-gemcitabine is the reference first-line chemotherapy. No robust evidence is available for second-line chemotherapy. Methods: Patients with ABC who progressed on first-line cisplatin-gemcitabine were randomised to active symptom control (ASC) and oxaliplatin and 5-fluorouracil (FOLFOX) or ASC alone. The primary end-point was overall survival (OS); recruitment of 162 patients was required, to deliver 148 events (hypothesised hazard ratio (HR) 0.63; 80% power; 5% two-sided alpha). Secondary end-points included progression-free survival (PFS) and response rate (ASC+FOLFOX arm only). Results: A total of 162 patients were randomised (81 in each arm) between 27-Mar-2014 and 04-Jan-2018). The median age was 65 years (range 26-84); 80 (49%) were male and the primary tumour sites were intrahepatic cholangiocarcinoma (CCA) 72 (44%), extrahepatic CCA 45 (28%), gallbladder 34 (21%) and ampullary cancer 11 (7%). After 150 OS events, the adjusted HR was 0.69 (95%CI-0.50-0.97; p=0.031; ASC+FOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+FOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. The median PFS was 4.0 months (95%-CI 3.2-5.0); the response rate was 5% and the disease control rate 33%. Grade 3-5 adverse events were reported in 56 (69%) and 42 (52%) patients in the ASC+FOLFOX and ASC arm, respectively, including two chemotherapy-related deaths. Conclusion: FOLFOX improved OS after progression to cisplatin-gemcitabine with a clinically-meaningful increase in 6m and 12m OS rate. FOLFOX should become standard-of-care in second-line for ABC. Trial Registration: NCT01926236, EudraCT: 2013-001812-30. Funding Statement: The study was sponsored by The Christie NHS Foundation Trust. The ABC-6 study was funded by Cancer Research UK (CRUK/13/004), StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity) and The Christie Charity. The Cholangiocarcinoma Foundation provided funding translational research. Dr Angela Lamarca received funding from ESMO (European Society for Medical Oncology), SEOM (Sociedad Espanola de Oncologia Medica) and Conquer Cancer Foundation (Young Investigator Award) fellowship programs and from The Christie Charity. Declaration of Interests: Dr Angela Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Prof Daniel H Palmer declares research grants from AstraZeneca, Bayer, BMS, Nucana, Sirtex; and Consulting or Advisory roles for AstraZeneca, Bayer, BMS, Eisai, MSD, Servier, Roche. Harpreet Singh Wasan declares no conflict of interest associated to this work. Dr Paul J Ross declares research grants from research grants from Sanofi, Bayer; Consulting or Advisory roles for Bayer, BMS, Eisai, Sirtex, Roche; speaker fees from Amgen, Roche, Servier; Travel grants from Bayer, Roche, Servier. Dr Yuk Ting Ma declares speaker honoraria and advisory roles for Bayer, Eisai and Roche. Dr Arvind Arora declares no conflict of interest. Dr Stephen Flak declares no conflict of interest. Dr Roopinder Gilmore declares no conflict of interest. Prof Jon Wadsley declares research grants from AstraZeneca and Sanofi-Genzyme and Consulting or Advisory roles for Lilly, AstraZeneca, Sanofi Genyme, Eisai, AAA, Roche, Novartis, Ipsen. Dr Kinnari Patel declares no conflict of interest. Alan Anthony declares no conflict of interest. Prof Anthony Maraveyas declares research grants from Pfizer, BMS and Bayer. Speaker fees from BMS. Bayer Ipsen, EUSA Pharma, Daiichi Sankyo and Pfizer and advisory roles for Bayer ,BMS, Leo, Pfizer, Merck and Ipsen. Dr Tim Iveson declares no conflict of interest. Dr Justin S Walters received educational support for travel and conference attendance from Mylan and Ipsen, and speaker honoraria from Mylan. Dr Claire Hobbs declares no conflict of interest. Safia Barber declares no conflict of interest. David Ryder declares no conflict of interest. Prof John Ramage declares research grants, speaker fees and advisory roles for Ipsen, Novartis and AAA. Linda M Davies declares no conflict of interest. Prof John Bridgewater declares Consulting or Advisory role for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD oncology, Merck Serono, Servier and BMS. Prof Juan W Valle declares Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, PierisPharmaceuticals, QED and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited Ipsen Novartis Nucana; and Travel Grants from Celgene and Nucana. Ethics Approval Statement: The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by a research ethics committee and all patients were required to provide written informed consent.

Associations of DMT Therapies with COVID-19 Severity in Multiple Sclerosis: An International Cohort Study

Associations of DMT Therapies with COVID-19 Severity in Multiple Sclerosis: An International Cohort Study

The ovarian sensitivity index is predictive of live birth chances after IVF in infertile patients.

STUDY QUESTIONDoes the ovarian sensitivity index (OSI) predict embryo quality, pregnancy and live birth in patients undergoing FSH/hMG stimulation for IVF?SUMMARY ANSWERThe OSI is predictive of pregnancy and live birth in older women with a more unfavorable prognosis undergoing FSH/hMG stimulation for IVF.WHAT IS KNOWN ALREADYThe OSI was previously reported to reflect gonadotrophin requirements among high, normal and poor responders and to predict pregnancy potential in younger patients undergoing ovarian stimulation with FSH.STUDY DESIGN, SIZE, DURATIONA retrospective cohort study that included 1282 women undergoing IVF with FSH/hMG stimulation was carried out between January 2010 and December 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSWe evaluated 1282 women who underwent fertility treatment with FSH/hMG stimulation and oocyte retrieval at an academically affiliated private fertility center. OSI was calculated as (oocytes ×1000)/total gonadotrophin dose and grouped into two classes based on a receiver operating characteristic (ROC) curve analysis of a randomly selected development sample comprising one-third of the cycles. The remaining cycles comprised the validation group. ROC curves were also used to compare the predictive value of OSI to that of baseline FSH and anti-Müllerian hormone (AMH). Logistic regression models evaluated the effect of high (OSI >0.83) and low (OSI ≤0.83) on clinical pregnancy and live birth in the validation group. Models were adjusted for female age, baseline FSH, AMH and oocyte yield and gonadotrophin dose.MAIN RESULTS AND THE ROLE OF CHANCEWomen presented with a mean ±SD age of 38.6 ± 5.4 years and showed median AMH levels of 0.65 (95% CI 0.61–0.74) ng/ml. They received 5145 ± 2477 IU of gonadotrophins and produced a median 5.2 (95% CI 5.0–5.5) oocytes. Pregnancy and live birth rates per oocyte retrieval for all women were 20.6% and 15.8%, respectively. Patients with higher OSI (less gonadotrophin required per oocyte retrieved) produced significantly more high-quality embryos than patients with low OSI (3.5 (95% CI 3.2–3.8) versus 0.6 (95% CI 0.5–0.7) (P = 0.0001)) and demonstrated higher pregnancy (23.2% versus 9.7%) and live birth rates (8.8% versus 5.3%) than their counterparts (P = 0.0001 and P = 0.0001, respectively). After adjustments for age, baseline AMH and FSH, total gonadotrophin dosage and oocyte yield, an OSI >0.83 was associated with greater odds of pregnancy (odds ratio 2.12, 95% CI 1.30–3.45, P < 0.003) and live birth (odds ratio 1.91, 95% CI 1.07–3.41, P < 0.028).LIMITATIONS, REASONS FOR CAUTIONThe results may not be applicable to women with excellent pregnancy potential or FSH-only stimulation.WIDER IMPLICATIONS OF THE FINDINGSThe predictive capacity of OSI for embryo quality, pregnancy and live birth, which is independent of AMH or FSH, may help in counseling patients about their pregnancy potential and live birth chances.STUDY FUNDING/COMPETING INTEREST(S)Intramural funding from the Center for Human Reproduction and the Foundation for Reproductive Medicine. A.W., V.A.K., D.F.A., D.H.B. and N.G. have received research grant support, travel funds and speaker honoraria from various pharmaceutical and medical device companies: none, however, related to the topic presented here. D.H.B. and N.G. are listed as inventors on already awarded and still pending US patents, claiming beneficial effects on diminished ovarian reserve and embryo ploidy from dehydroepiandrosterone supplementation.TRIAL REGISTRATION NUMBERN/A.

Infection Control, Antimicrobial Consumption, and Hospital-Acquired Clostridioides difficile Infection in Acute-Care Hospitals in Catalonia

Background: Hospital-acquired Clostridioides difficile infection (HA-CDI) is a major infection control challenge. Using whole-genome sequencing, &lt;40% of HA-CDI cases have been estimated to have been acquired from other inpatient cases. Huge regional variations have been described depending on the prevalence of epidemic ribotypes. We hypothesized that, according to the geographical area, variations in HA-CDI rates between hospitals could be attributable either to differences in infection control policies or to antimicrobial consumption. Objectives: To assess the association of HA-MRSA rates (a surrogate marker of infection control policies) and antimicrobial consumption with HA-CDI incidence from 2011 to 2018 in hospitals reporting at the VINCat-program (Infection Control and Antimicrobial Stewardship Catalan Program). Methods: Data on 45 hospitals in Catalonia (with 70.5% of all adult acute-care hospital beds) reporting antimicrobial consumption, HA-MRSA, and HA-CDI new cases to the VINCat-program since 2011 to 2018 were analyzed. To report antimicrobial consumption, the Anatomical Therapeutic Chemical Classification (ATC) defined daily dose (DDD) index 2018 was used. Participating hospitals were classified into 3 groups according to size: group 1 (&gt;500 beds), 9 hospitals; group 2 (500–200 beds), 15 hospitals; and group 3 (&lt;200 beds), 21 hospitals. The number of hospitalization days recorded at the participating hospitals increased from 2,828,101 in 2011 to 3,201,680 in 2018. To analyze the association between HA-MRSA rate, antimicrobial consumption and the rate of CDI-HA, a Poisson regression model was used. HA-CDI annually new cases have been defined as a dependent variable, the stays as an offset of the model and the HA-MRSA rates and antimicrobial consumption (measured in DDD) as independent factors. The exponents of model coefficients are equal to incidence rate ratios (IRR). Results: The regression model showed an association of with antimicrobial consumption with HA-CDI (IRR,1.05; 95% CI, 1.03–1.07; P &lt; .001) and a lack of association with HA-MRSA (IRR, 0.83; 95% CI, 0.46–1.48; P = .52). Conclusions: The HA-CDI incidence rate grew annually by 5% for an increase of 1 DDD in annual antibiotic consumption. No association HA-MRSA rates was detected, suggesting that antimicrobial stewardship programs are urgently needed to improve the control of HA-CDI in Catalonia, a geographical area with a low prevalence of epidemic ribotypes.Funding: NoneDisclosures: Juan Pablo Horcajada reports consulting fees from MSD, Pfizer, and Menarini and speaker honoraria from MSD, Pfizer, and Zambon.

Improvement of Adequacy of Empirical Antimicrobial Therapy in Escherichia coli Bacteremia of Urinary Source in Catalonia (VINCat-PROA)

Background: The antibiotic use optimization program (PROA) in Catalonia (Spain) is part of the surveillance program for nosocomial infections in hospitals in Catalonia (VINCat). Despite the existence of guidelines for the treatment of urinary tract infections in hospitals, adherence to them is not guaranteed. Objective: Our objective was to evaluate the adequacy of empirical antimicrobial therapy to local guidelines in bacteremia caused by Escherichia coli of urinary source within the PROA-VINCat program during a 3-year period. The impact of a voluntary survey asking for evaluating local results and implementing correction measures was also analyzed. Methods: Multicentric prospective observational study including all episodes of E. coli bacteremia of urinary source between May 2017 and September 2019, in adult hospitalized patients in 45 Catalan hospitals. Adequacy of the empirical therapy to local guidelines was one of the prospectively recorded items. A survey evaluating local results of 2017–2018 and asking for possible correcting measures was sent to the participating centers at the end of 2018. Percentages of adequacy of empirical antimicrobial therapy in 2017, 2018, and 2019 were compared by means of χ2 test. Results: Overall, 3,804 episodes of bacteremia were recorded: 845 in 2017, 1,861 in 2018 and 1,098 until September 30, 2019. Globally, adequacy of empirical therapy to guidelines increased from 73.7% in 2017 to 78.2% in 2019 (P = .06). Interestingly, in the 24 hospitals that responded to the voluntary survey, the adequacy of empirical therapy increased significantly from 72.9% in 2017 to 79.9% in 2019 (P = .009). In hospitals that did not respond, adequacy remained the same over the years (76.7% in 2017, 75.1% in 2019; P = .90). Correction measures applied were: meeting with the antimicrobial stewardship team to evaluate the results (100%), review of local resistance rates (62%), review of local guidelines (58.3%), improving guidelines dissemination (75%), sessions for improving guidelines adherence (58%), and analysis of adherence to guidelines after education (65%). Conclusions: In the empirical treatment of E. coli bacteremia of urinary source, adequacy to local antimicrobial therapy guidelines improved from 2017 to 2019, but only in hospitals answering a voluntary survey regarding correcting measures for improving adequacy. Adherence to antimicrobial stewardship proposals improves indicators at local and regional level.Funding: NoneDisclosures: Juan Pablo Horcajada reports consulting fees from MSD, Pfizer, and Menarini and speaker honoraria from MSD, Pfizer, and Zambon.

Trends of Adult Antimicrobial Hospital Consumption in Catalonia (Spain) from 2008 to 2018

Background: Antimicrobial resistance is a disturbing problem in the health system. A relationship between the use of certain antimicrobials and a resistance increase has been proposed. Since this phenomenon is not usually attributed to specific uses of antimicrobials but preferably to its evolution over the years, the analysis of the antimicrobial consumption over time can justify the epidemiological situation of a given region in terms of resistance and possible increases and decreases for specific microorganisms. The objective of this study was to analyze the evolution of the use of antimicrobials in Catalonia during 2008–2018 through the VINCat program (Infection Control and Antimicrobial Stewardship Catalonian Program). Methods: The number of hospitals participating in the VINCat increased from 46 in 2008 to 63 in 2018 (ie, 68.8% and 85.7% of all adult acute-care hospital beds in Catalonia, respectively). Hospitalization days recorded at the participating hospitals increased from 2,991,053 in 2008 to 3,714,938 in 2018. The Anatomical Therapeutic Chemical Classification (ATC) defined daily dose (DDD) index was used for monitoring antimicrobial consumption. Simple linear regressions were performed, the linear relationship was checked by ANOVA tests, and the Pearson correlation (Pc) coefficients were obtained. Values of P ≤ .05 were considered statistically significant. Results: From 2008 to 2018, there was a statistically significant increase of global antibacterial consumption (65.50 vs 71.73 DDD per 100 bed days; P = .001) and antimycotic consumption (3.09 vs 3.45 DDD per 100 bed days, P = .012) due to an increase of consumption in the surgical units. At the same time, there was a decrease in the consumption of antimycotics in the medical units (4.35 vs 3.90 DDD per 100 bed days; P =.029). Cephalosporins and carbapenem consumption increased both globally (10.88 vs 13.86 DDD per 100 bed days; P &lt; .001) and in medical and surgical units (3.26 vs 5.38 DDD per 100 bed days; P &lt; .001). This increase was mainly associated with ceftriaxone (3.45 vs 5.46 DDD per 100 bed days; P &lt; .001) and meropenem (1.12 vs 3.08 DDD per 100 bed days; P &lt; .001). There was a global decrease in the consumption of penicillins (26.10 vs 24.24 DDD per 100 bed days; P = .012) and quinolones (11.63 vs 9.61 DDD per 100 bed days; P = .004). This trend was observed also in ICUs and medical units but not in surgical units, for which only quinolones showed a significant decrease. Decreases in the use of amoxicillin/clavulanate acid (17.80 vs 14.24 DDD per 100 bed days; P &lt; .001) and ciprofloxacin (5.68 vs 4.01 DDD per 100 bed days; P &lt; .001) were observed. Conclusions: The increase in the use of antimicrobials in Catalonia is concerning. This increase is attributable to the use of these drugs in surgical units. Antibiotic stewardship measures should be aimed primarily at these units. The increasing use of carbapenems should be analyzed.Funding: NoneDisclosures: Juan Pablo Horcajada reports consulting fees from MSD, Pfizer, and Menarini as well as speaker honoraria from MSD, Pfizer, and Zambon.

Age-Related Outcomes after Transcatheter Aortic Valve Implantation: Insights from the SwissTAVI Registry

Age-Related Outcomes after Transcatheter Aortic Valve Implantation: Insights from the SwissTAVI Registry

Robustness of Simultaneous Lesion and Neuroanatomy Segmentation in Multiple Sclerosis Using Deep Neural Networks

Background: Segmentation of white matter lesions and deep grey matter structures is an important task in the quantification of magnetic resonance imaging in multiple sclerosis. In this paper we explore segmentation solutions based on convolutional neural networks (CNNs) for providing fast, reliable segmentations of multimodal magnetic resonance images into lesion classes and normal-appearing grey and white-matter structures. We also explore the ability of such methods to transfer between institutions. Methods: We trained two state-of-the-art CNN architectures in cross-validation on the 2016 MSSEG training dataset: a reference implementation of a 3D Unet, and a more recently proposed architecture (DeepSCAN), to set a baseline for MS lesion segmentation performance. We then retrained those methods on a larger dataset from a single centre, with and without labels for other brain structures, and compared performance with the reference methods, and with other reference methods from recent publications. Results: Both CNN methods substantially outperform other approaches in the literature when trained on the MSSEG dataset, showing agreement with human raters in the range of human inter-rater variability. Both showed small drops in performance when trained on single-centre data and tested on the MSSEG dataset instead. When trained with the addition of anatomical labels, the performance of the 3D Unet degraded, while the performance of the DeepSCAN net improved. Overall, the DeepSCAN network predicting both lesion and anatomical labels was the best-performing network. A retrospective study of this classifier found that the classifier successfully identified several lesions missed by human raters. Interpretation: We present a method for simultaneously segmenting MS lesions and neuroanatomical structures, whose performance on lesion segmentation is close to that of human raters. The drop in performance when evaluated on external data is less drastic than reported by other researchers. Performance of 3D Unets, while excellent on datasets with small numbers of structures labelled, may suffer when the number of labels increases. Funding Statement: This research was supported by the Swiss Multiple Sclerosis Society and a grant from the Novartis Forschungsstiftung. Declaration of Interests: Richard McKInley, Rik Wepfer, Fabian Aschwanden, Lorenz Grunder, Raphaela Muri, CHristian Rummel, Rajeev Verma, Christian Weisstanner, Mauricio Reyes, Franca Wagner and Roland Wiest have no interests to declare. Anke Salmen has recieved speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme, none related to this work. Andrew Chan received honoraria for board and speaker honoraria from Actelion, Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche, Teva, all for hospital/university research funds. He has recieved reserach funds from Research funds: UCB, Biogen, Sanofi-Genzyme, and is an editor for European Journal of Neurology, and Clin Transl Neurosci. Ethics Approval Statement: Ethical approval for the study was granted by the local ethical commission (Cantonal Ethical Commission Bern, ’MS segmentation disease monitoring’, approval number 2016-02035).

COVID-19: A global transplant perspective on successfully navigating a pandemic.

The COVID‐19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID‐19 has impacted transplantation worldwide. The impact has not been just restricted to issues pertaining to donors or recipients, but also health‐care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID‐19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant‐related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.

P258 Real-world secukinumab retention, response rates and adverse events in the treatment of PsA and axSpA

Abstract Background Secukinumab, an IL-17A inhibitor, has been licensed for use in the United Kingdom for both axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) for several years. Despite this there is minimal published data on its use out with randomised controlled trials. We present here the collated real-world rheumatology experience of secukinumab use in Glasgow. Methods Patients who have ever received secukinumab for any rheumatology indication were identified using available medical records (from 14/05/2012 to 18/09/2019). Diagnosis, baseline demographics, disease activity at baseline and at 6 months, and whether patients are still currently on secukinumab was recorded. Primary inefficacy was defined as stopping treatment due to inefficacy ≤6 months. Reasons for discontinuation were also recorded. As disease activity scores were variably recorded, the primary outcome was retention rate as a surrogate for efficacy and lack of adverse event. Patients only included in disease scores if scores available both at baseline and 6 months. Results 352 patients (with 530 patient-years of exposure) identified. 251 (71.3%) patients currently remain on secukinumab. 301 of 336 (89.6%) patients remained on drug at six-month review (16 await review). Characteristics and response of two main diagnostic groups listed in Table 1 (Note: 3 patients had SAPHO, 5 had Juvenile Idiopathic Arthritis, 1 had reactive arthritis). Common adverse events were infections (11 patients), rash and/or pruritis (6 patients), mood change and/or fatigue (4 patients). Three patients developed inflammatory bowel disease (IBD) subsequent to starting secukinumab. Five patients had pre-existing IBD, none of which flared on secukinumab. Two patients required hospitalisation for abscesses whilst on secukinumab. One patient had a stroke and one patient had a myocardial infarction whilst on secukinumab - both patients had multiple risk factors for cardiovascular disease. No malignancies identified. Three patients died, with none felt related to secukinumab (cerebellar haemorrhage in warfarinised patient with high INR; pneumonia six months after switching from secukinumab to tocilizumab; one out of hospital death over one year after stopping secukinumab). Conclusion In this real world cohort of patients with axSpA and PsA, secukinumab retention rates at 6 months are high with no new safety signals identified. Disclosures A. Tindell None. S. Batool None. A. McGucken None. S. Siebert Consultancies; S.S. has received speaker or consultation fees or honoraria from AbbVie, UCB, Janssen, Boehringer Ingelheim, Novartis, Celgene. Honoraria: S.S. has received speaker or consultation fees or honoraria from AbbVie, UCB, Janssen, Boehringer Ingelheim, Novartis, Celgene. Grants/research support; S.S has received funding for research/ grants from Pfizer, Janssen, BMS, Celgene, UCB, Boehringer Ingelheim, Novartis, GSK.

P71 Working collaboratively with patients as research partners in the co-production of the WASTEd: a measure of fatigue and energy in axial spondyloarthritis (axSpA)

Abstract Background The last decade has witnessed significant growth in the active involvement of patients as research partners (PRPs) in health and social care research to facilitate a stronger patient-focus in research endeavours and outputs. Whilst general guidance is available - e.g. INVOLVE - there is limited guidance pertaining to how one should collaborate with patients as partners in the development of patient-reported outcome measures (PROMs). Here, we describe our active collaboration with patients as research partners in the co-production of a new PROM: the Warwick Axial Spondyloarthritis measure of faTigue and Energy (WASTEd). Methods An established PRP group contributed to the development of the initial funding application, whom received training and support from the PRP group facilitator (JM). The key stages for PRP collaboration throughout the PROM development process were jointly agreed and included: developing qualitative research topic guides and supporting data analysis; supporting development and refinement of the measurement framework to underpin the new PROM, and; supporting question (item) generation and refinement following both qualitative and quantitative explorations. All key decisions were made following face-to-face meetings between the lead research and the PRP group. Results Six face-to-face meetings were held over 2.5 years (average meeting duration 2 hours; range 1.5 to 3 hours) with between three and eight PRP members attended each meeting. Additional e-mail correspondence and summary reports were shared between meetings. The group contributed across all project stages including: developing ethics applications which included assessing the acceptability of the study to patients; generating interview topic guides and verbal probes for key issues identified by the PRP group; interpreting qualitative data with the lead researcher; co-designing and editing the draft PROM and refining the long form version of the PROM using both qualitative and statistical data. PRP collaboration was particularly integral to the appropriate use of relevant language and, most substantively, in providing a clearer understanding of the distinction between fatigue and energy. Conclusion The active collaboration with PRPs has supported the co-production of a relevant and acceptable PROM, driven by the needs and perspectives of patients. Additionally, the PRP groups were able to ensure all refinement decisions made to the PROM did not undermine the content validity of the measure. Finally, their involvement has sought to act as a check, support and challenge on inferences drawn by the researchers, enriching the process and study outcomes. Disclosures N.A. Pearson None. G. Strickland None. J. Thompson None. J. Martindale Honoraria; JM has received speaker fees and/or honoraria from Abbvie Ltd, Novartis, Pfizer and UCB. Grants/research support; JM has received a research grant from Pfizer. E. Tutton None. H. Parsons None. J. Packham None. K. Haywood None.

It's time to phase out "serologic weak D phenotype" and resolve D types with RHD genotyping including weak D type 4.

CDS, JTQ, LMK, SGS and WAF have disclosed no conflicts of interest. CMW has received speaker honorarium from Grifols and Immucor and consulting honorarium from Quotient, Cerus, and ArchOncology with renumeration to New York Blood Center. GAD and MAK are on the Grifols Speakers Bureau. MD has received speaker honorarium from Grifols. RV receives financial support from bioMérieux, Cerus, Fresenius-Kabi, Hemanext, and Hemastrat. STJ receives speaker honorarium from Grifols and Immucor.

Psychosis Relapse During Long-Acting Injectable Antipsychotic Treatment: An Individual Participant Data Meta-Analysis of 19 Trials and 5,111 Individuals with Schizophrenia-Spectrum Disorders

Background: Most individuals with schizophrenia-spectrum disorders experience relapses, which increases the risk of morbidity and mortality. Since non-adherence with antipsychotic maintenance treatment may affect up to half of individuals, psychosis relapse can often be confounded by unnoticed treatment interruption. Research of relapse during confirmed antipsychotic exposure has basic clinical and neurobiological implications, yet data are limited. Methods: Systematic review and individual participant data meta-analysis (IPDMA) of clinical trials of long-acting injectable antipsychotics (LAIs) for psychosis relapse-prevention, following IPD-PRISMA guidelines. Datasets were identified by searching relevant repositories up to August/01/2019. Each LAI arm was re-analyzed as a separate cohort, further identifying sub-cohorts of individuals with and without prospectively determined symptom remission (PSR). Pooled incidence rates, incidence rate ratios (IRRs) and hazard ratios (HRs) were derived from within-cohort Poisson, Kaplan-Meyer and Cox regression analyses. Outcomes: Nineteen treatment cohorts (n=5,111), of which 2,938 had PSR, while 2,173 did not (non-PSR), with 3,959·53 actual observed participant years were meta-analyzed. Pooled incidence of relapse was 22·97 per 100 patient-years, being 14·76 per 100 patient-years for the PSR sub-cohort and 31·51 per 100 patient-years for the non-PSR sub-cohort (IRR=0·39, 95%CI=0.29-0·53). The strongest predictors of relapse were having tardive dyskinesia (HR=2·39, 95%CI=1·05-5·42) and comorbid substance use disorder (HR=1·55, 95%CI=1·15-2·10) at treatment onset. Predictors were similar between the PSR and non-PSR sub-cohorts, except for greater impact of substance use disorder in PSR (p<0·01). Interpretation: A sizeable proportion of individuals with schizophrenia-spectrum disorders relapses during confirmed antipsychotic treatment. This risk doubles in individuals not achieving symptom remission, but even in remitted patients, 1 out of 7 patients relapsed in <1 year. Developing tardive dyskinesia and comorbid substance use may have pathophysiological implications for relapse on confirmed antipsychotic treatment. Funding Statement: This study was funded by Northwell Health. Declaration of Interests: Dr Rubio has been a consultant or has received speaker honoraria from: Lundbeck, Teva. He has also received royalties from UpToDate, and grant support from Alkermes. Dr Tiihonen reports personal fees from the Finnish Medicines Agency (Fimea), European Medicines Agency (EMA), Eli Lilly, JanssenCilag, Lundbeck, and Otsuka; is a member of advisory board for Lundbeck, and has received grants from the Stanley Foundation and Sigrid Juselius Foundation. Dr Taipale reports personal fees from JanssenCilag. Dr. Tiihonen and Dr. Taipale have participated in research projects funded by grants from JanssenCilag and Eli Lilly to their employing institution. Dr Malhotra has served as a consultant for Forum Pharmaceuticals and has served on a scientific advisory board for Genomind, Inc. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a stock option holder of LB Pharma. Dr Kane has been a consultant and/or advisor for or has received honoraria from Alkermes, Allergan , LB Pharmaceuticals, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva and UpToDate and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. Dr Schoretsanitis, John and Guinart declare no conflict of interest. Ethics Approval Statement: Each data owner obtained ethics committee approval prior to sharing the de-identified data.