Low Number Of Events Research Articles

986-P: Evaluation of Cardiovascular Risk and All-Cause Mortality in Type 1 Diabetes: Comparison of Risk Engines in a 10-Year Follow-up

Type 1 diabetes (T1D) has higher risk of death and CVD compared with general population. Effective risk stratification is essential to implement preventive strategies. We compare the performance of Steno Type 1 Risk Engine (ST1RE) and EURODIAB PCS Risk Engine (EURO-RE) in 733 T1D (M 52%; age 39.3±11.1; DD 18.5±11.6; A1c 7.8±1.2%) with no prior CVD over a 11-yr follow-up (IQR: 9.9-13.0). Both models include age, A1c and albuminuria; ST1RE includes 7 more variables (sex, DD, SBP, LDL-C, eGFR, smoking and exercise), EURO-RE only 2 more variables (WHR, HDL-C). By ST1RE, 453 T1D (61.8%) had low- (<10%), 179 (24.4%) moderate- (10-20%) and 101 (13.8%) high-risk (≥20%); for EURO-RE, estimates were 496 (67.7%), 161 (22.0%) and 76 (10.4%). Regression between 10-yr risks was 0.921 (p<0.0001); concordance of risk strata attribution was 82.5% (n = 605); 98 (13.4%); 30 (4.1%) T1D had higher and, respectively, lower risk by ST1RE vs. EURO-RE. C-statistic for all-cause death (n = 46) was 0.810 (95% CI 0.738-0.882) for ST1RE and 0.802 (0.729-0.875) for EURO-RE. Incidence of CVD was available for 697 T1D (95%). C-statistics for all CVD (n = 32) were 0.770 (0.699-0.841) and 0.777 (0.706-0.849) for ST1RE and EURO-RE, respectively; for coronary events (n = 23) 0.739 (0.650-0.828) and 0.765 (0.683-0.847); for coronary revascularization (n = 14) 0.802 (0.707-0.897) and 0.824 (0.742-0.905). With the limitation of low number of events, C-statistics for stroke (n = 8) were 0.764 (0.596-0.931) and 0.805 (0.654-0.955) for ST1RE and EURO-RE; for peripheral disease (n = 5) 0.794 (0.658-0.931) and 0.733 (0.518-0.948); for ESRD (n = 8) 0.719 (0.544-0.893) and 0.723 (0.529-0.917). Cox regression with backward variable processing selects EURO-RE as covariate for CVD and all other vascular events including ESRD, with ST1RE selected as the strongest covariate for all-cause death. Both ST1RE and the less-demanding EURO-RE are validated and widely available tools to identify high risk T1D individuals. Disclosure M. Garofolo: Consultant; Self; Eli Lilly and Company. E. Gualdani: None. D. Lucchesi: None. P. Falcetta: None. P. Francesconi: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.

Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).

4561 Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.

POS0652 SEX DIFFERENCES IN THE EFFICACY AND SAFETY OF TOFACITINIB IN RHEUMATOID ARTHRITIS PATIENTS: A POST HOC ANALYSIS OF PHASE 3 AND LONG-TERM EXTENSION TRIALS

Background:Differences in efficacy outcomes favouring males vs females with rheumatoid arthritis (RA) have been reported with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and tumour necrosis factor inhibitors; results with Janus kinase inhibitors are less clear.Objectives:To assess the impact of sex on efficacy, safety and persistence in tofacitinib RA clinical trials.Methods:Efficacy and safety analyses included data pooled from Phase (P)3 randomised controlled trials (RCTs) of patients (pts) with RA and an inadequate response (IR) to methotrexate (NCT00847613; NCT00853385) or ≥1 DMARD (NCT00856544) who received tofacitinib 5 or 10 mg twice daily (BID), adalimumab (ADA) 40 mg Q2W or placebo (PBO), with background csDMARDs. Persistence analyses of pts receiving tofacitinib 5 or 10 mg BID ± csDMARDs used data pooled from two long-term extension trials (NCT00661661; NCT00413699). Efficacy outcomes to Month (M)12 included: ACR20/50/70 responses, changes from baseline (Δ; BL) in DAS28-4(ESR), CDAI, HAQ-DI and FACIT-F, and DAS28-4(ESR) remission (<2.6). Safety was evaluated to M24 for tofacitinib and ADA. Kaplan-Meier persistence analysis estimated time to discontinuation.Results:2265 pts were included from P3 RCTs. Demographics and BL characteristics were comparable across sexes and treatments. Tofacitinib or ADA vs PBO generally led to significantly higher ACR20/50/70 responses in both sexes through M6. To M12, ACR20/50/70 responses were broadly comparable across active treatments and between sexes, with significant differences favouring males at some time points, including M3 (Figure 1). Statistically significant differences favouring males vs females were observed in DAS28-4(ESR) remission rates at most time points, including M3 (Figure 1); a similar trend was observed for ΔDAS28-4(ESR). ΔCDAI, ΔHAQ-DI and ΔFACIT-F significantly favoured males vs females receiving tofacitinib 5 mg BID at most time points, while ΔHAQ-DI and ΔFACIT-F tended to favour females receiving tofacitinib 10 mg BID. Rates of adverse events (AEs), serious AEs (SAEs), severe AEs and discontinuations due to AEs were slightly higher in females vs males with tofacitinib 5 mg BID; this was generally reversed with tofacitinib 10 mg BID and ADA (Table 1). AEs of special interest (AESI) were comparable between sexes with tofacitinib and ADA, although low event numbers limit interpretation (Table 1). Time to all-cause discontinuation and discontinuation due to AEs/lack of efficacy with tofacitinib 5 mg BID was similar between sexes. Numerical differences favouring females vs males were observed for time to all-cause discontinuation and discontinuation due to AEs with tofacitinib 10 mg BID.Table 1.Safety summary to M24 in pooled DMARD-IR P3 RCTsTofacitinib5 mg BIDTofacitinib10 mg BIDADAPts with events,n (%)Females(N=707)Males(N=133)Females(N=698)Males(N=137)Females(N=162)Males(N=42)AEs562 (79.5)85 (63.9)529 (75.8)107 (78.1)119 (73.5)30 (71.4)SAEs107 (15.1)17 (12.8)71 (10.2)24 (17.5)13 (8.0)6 (14.3)Severe AEs86 (12.2)12 (9.0)55 (7.9)22 (16.1)14 (8.6)5 (11.9)Discontinuations due to AEs87 (12.3)10 (7.5)88 (12.6)10 (7.3)17 (10.5)5 (11.9)Death6 (0.8)4 (3.0)03 (2.2)1 (0.6)2 (4.8)AESISerious infections28 (4.0)6 (4.5)27 (3.9)6 (4.4)2 (1.2)1 (2.4)All HZ (non-serious/serious)35 (5.0)7 (5.3)43 (6.2)5 (3.6)2 (1.2)3 (7.1)MACE5 (0.7)02 (0.3)3 (2.2)03 (7.1)Malignancies (excl. NMSC)7 (1.0)1 (0.8)9 (1.3)1 (0.7)01(2.4)NMSC2 (0.3)5 (3.8)4 (0.6)2 (1.5)1 (0.6)1 (2.4)Venous thromboembolism3 (0.4)03 (0.4)1 (0.7)00HZ, herpes zoster; MACE, major adverse cardiovascular events; NMSC, non-melanoma skin cancerConclusion:Efficacy outcomes with tofacitinib and ADA were generally higher in males and comparable in females vs previously reported mixed population response rates for advanced therapies. Safety findings did not reveal a consistent pattern between sexes. Tofacitinib persistence was similar between sexes.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:H Niall Jones Consultant of: Pfizer Inc, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Corrona, Eli Lilly, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Ichnos, Inmedix, Janssen, Kiniksa, Merck, Myriad Genetics, Novartis, Pfizer Inc, Regeneron, Samsung, Sandoz, Sanofi, Scipher, SetPoint Medical, UCB, Hendrik Schulze-Koops Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead Sciences, Hexal Sandoz, Hospira, Janssen-Cilag, MSD, Novartis, Pfizer Inc, Roche, UCB, Grant/research support from: Novartis, Pfizer Inc, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche, Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc, Roche, Cassandra Kinch Shareholder of: Pfizer Canada ULC, Employee of: Pfizer Canada ULC, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rebecca Germino Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lihi Eder Speakers bureau: AbbVie, UCB, Consultant of: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer Inc, UCB, Grant/research support from: AbbVie, Eli Lilly, Pfizer Inc, UCB

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

Genotype\u2013phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome

BackgroundAutosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either COL4A3 or COL4A4 genes. Reports on ARAS are rare due to small patient numbers and there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS.MethodsRetrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype–phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated.ResultsMedian age was 15 years (range 1.5–46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants.ConclusionsOur study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.

Efficacy of 3 Months vs. 6 Months of Valganciclovir Prophylaxis for Heart Transplant Recipients at Intermediate Risk (R+) for CMV Complications

<h3>Purpose</h3> Heart Transplant recipients previously exposed to CMV infection are considered intermediate risk for post-transplant CMV complications. Many centers therefore utilize "universal" prophylaxis for 3-6 months to mitigate this risk. However, it remains unclear how long prophylaxis should be continued post-transplant in this population. In the present analysis, we compared post-transplant CMV outcomes in patients receiving 3 vs. 6 months of valganciclovir prophylaxis in a multicenter, retrospective analysis. <h3>Methods</h3> Retrospective analysis of 321 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 treated with universal prophylaxis with valganciclovir for either 3 months (n = 277) or 6 months (n = 44). The primary endpoint was the development of CMV viremia or end-organ disease resulting in the escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. <h3>Results</h3> Of the 321 patients in the analysis, 13.4% (n = 43) developed CMV viremia or end-organ infection requiring escalation of anti-CMV therapy, and 3.4% (n = 11) were hospitalized for CMV infection. Overall, there was no significant difference in the primary endpoint in patients treated with 3 months of valganciclovir compared to 6 months (12.6% vs. 18.2%, p = 0.316; Figure 1A). There was a trend toward reduction in CMV hospitalization in the 6-month treatment group (Figure 1B), but this did not achieve statistical significance (3.6% vs. 2.3%, p = 0.651), potentially due to a low number of events. <h3>Conclusion</h3> We found no difference in the risk of CMV viremia or hospitalization for CMV using either a 3-month or 6-month regimen for prophylaxis in HTx recipients at intermediate risk for CMV (R+).

Life expectancy inequalities in Wales before COVID-19: an exploration of current contributions by age and cause of death and changes between 2002 and 2018

ObjectivesThe COVID-19 pandemic in Wales and the UK has highlighted significant and historic inequalities in health between social groups. To better understand the composition of these inequalities and inform planning after the pandemic, we undertook a decomposition of life expectancy inequalities between the most and least deprived quintiles for men and women by age and cause of death and explored trends between 2002 and 2018. Study designStatistical decomposition of life expectancy inequalities by age and cause of death using routine population mortality datasets. MethodsWe used routine statistics from the Office for National Statistics for the period 2002–2018 on population and deaths in Wales stratified by age, gender, Welsh Index of Multiple Deprivation (WIMD) 2019 quintile and cause of death, categorised by International Classification of Disease, version 10, code into 15 categories of public health relevance. We aggregated data to 3-year rolling figures to account for low numbers of events in some groups annually. Next, we estimated life expectancy at birth by quintile, gender and period using life table methods. Lastly, we performed a decomposition analysis using the Arriaga method to identify the specific disease categories and ages at which excess deaths occur in more disadvantaged areas to highlight potential areas for action. ResultsLife expectancy inequalities between the most and least WIMD quintiles rose for both genders between 2002 and 2018: from 4.69 to 6.02 years for women (an increase of 1.33 years) and from 6.34 to 7.42 years for men (an increase of 1.08 years). Exploratory analysis of these trends suggested that the following were most influential for women: respiratory disease (1.50 years), cancers (1.36 years), circulatory disease (1.35 years) and digestive disease (0.51 years). For men, the gap was driven by circulatory disease (2.01 years), cancers (1.39 years), respiratory disease (1.25 years), digestive disease (0.79 years), drug- and alcohol-related conditions (0.54 years) and external causes (0.54 years). Contributions for women from respiratory disease, cancers, dementia and drug- and alcohol-related conditions appeared to be increasing, while among men, there were rising contributions from respiratory, digestive and circulatory disease. ConclusionsLife expectancy inequalities in Wales remain wide and have been increasing, particularly among women, with indications of worsening trends since 2010 following the introduction of fiscal austerity. As agencies recover from the pandemic, these findings should be considered alongside any resumption of services in Wales or future health and public policy.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Pertuzumab and trastuzumab as adjuvant treatment for HER2-positive early breast cancer: outcomes in Chinese patients in the APHINITY study.

The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites. Patients were randomized to standard adjuvant chemotherapy plus 1year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39-1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm. Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.

Abstract PS10-31: Ribecca - a phase 3b, multi-center, open label study for women with estrogen receptor positive, locally advanced or metastatic breast cancer treated with ribociclib (lee011) in combination with letrozole: Final results

Abstract Introduction: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7, including premenopausal and postmenopausal patients without pretreatment as well as patients with up to 3 previous treatment lines for advanced disease. Here we present the final analysis for the primary endpoint. Methods:The study enrolled women or men with metastatic or locally advanced breast cancer irrespective of their menopausal status, who were not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of HR+, HER2- breast cancer was required. 502 patients were enrolled in two Cohorts. Cohort A (n=319): postmenopausal women and men without pretreatment for advanced disease; Cohort B (n=183): premenopausal women without pretreatment for advanced disease and pre- or postmenopausal women and men with ≤ 1 line of chemotherapy and/or ≤ 2 lines of endocrine therapy in the advanced situation. The primary endpoint was to assess the clinical benefit rate (CBR, defined as CR, PR or SD, or NCRNPD) at 24 weeks for the overall study population. Secondary endpoints included: progression free survival (PFS), overall survival (OS), safety, and changes in quality of life as assessed by EORTC QLQ-C30 and -BR23 questionnaires. Results: The study ended 84 weeks after the enrollment of the last patient. The median observation time was 10.6 months (0.1-38 months). Baseline characteristics: of 502 pts, 5 were male, 497 were female(46 pre-or perimenopausal, 451 postmenopausal); median age: 64 yrs; ECOG 0-1: 96.8%; 71.1 % of pts had bone metastases (40.8% bone only), 30.6% liver, 27.5% lung and 30.1% other metastases. 97.3% had at least 1 metastatic site: 48.7% had 1, 35.1% had 2, 12.9% had 3 and 1.6% had 4 metastatic sites, respectively. 78.9% received at least one prior antineoplastic therapy: 4.9% received neoadjuvant, 56.8% adjuvant and 37.8% palliative treatment as last antineoplastic therapy before study start. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (60.6%), nausea (42%), fatigue (39.2%), alopecia (35.1%), leukopenia or WBC decreased (30.7%), nasopharyngitis (28.5%), diarrhea (25.3%), ALT increased (22.9%) and AST increased (20.7%). The CBR at week 24 for the overall study population was 69.2%. Median PFS was 16.5 [95%CI 13.7; 19.3] months in the overall study population, 21.8 [15.4; 25.3] months and 9.3 [8.1; 16.3] months in Cohort A and B, respectively. At 72 weeks, the Kaplan-Meier estimate for OS was 86.8% [83.3; 89.6]. Because of the low number of events during the study period, median OS could not be determined. Conclusion: The results of the final analysis confirmed clinical benefit of ribociclib and letrozole in this patient population. No new safety signals emerged. Citation Format: Mattea Reinisch, Arndt Nusch, Thomas Decker, Andreas Hartkopf, Bernhard J Heinrich, Christian M Kurbacher, Roswitha Fuchs, Hans Tesch, Petra Krabisch, Sara Y Brucker, Tanja Fehm, Wolfgang Janni, Sherko Kuemmel, Diana Lüftner, Andreas Schneeweiss, Martin Schuler, Claudia Voges, Joerg Schubert, Peter A Fasching. Ribecca - a phase 3b, multi-center, open label study for women with estrogen receptor positive, locally advanced or metastatic breast cancer treated with ribociclib (lee011) in combination with letrozole: Final results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-31.

Impact of Adherence to Ibrutinib on Clinical Outcomes in Real-World Patients With Chronic Lymphocytic Leukemia.

BackgroundChronic lymphocytic leukemia (CLL) is a B-cell neoplasm with clonal expansion of small lymphocytes. Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a first-line treatment option, and recent data suggest that strict adherence is directly related to clinical outcomes.ObjectivesThe primary objective of this study was to quantify ibrutinib adherence rates in real-world patients with CLL on ibrutinib; secondary outcomes included progression-free survival and overall survival.MethodsThis retrospective study included subjects who were treated at a large academic medical center over approximately 5 years. Subjects were at least 18 years, diagnosed with CLL or small lymphocytic lymphoma, and treated with ibrutinib monotherapy for at least 6 months. Adherence was quantified using the medication possession ratio (MPR), which is the ratio of the sum of days’ supply of medication in a period over the number of days in that period, and was based on fill history from the medical center’s specialty pharmacy.ResultsFor the 32 subjects in this study, the mean ibrutinib adherence rate was 91.7% (range, 84.4%–100%). Only 3 subjects had disease progression, and 1 death was recorded while on therapy (all with MPR < 95%); therefore, analyses of clinical outcomes were unable to be assessed due to a low number of events. There were no statistically significant differences in rates of adherence based on baseline characteristics and adverse drug events.ConclusionIn patients with CLL treated with ibrutinib, mean adherence was 91.7%, which is lower than rates seen in clinical trials.

Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

Preterm Birth and Stillbirth During the COVID-19 Pandemic in Sweden: A Nationwide Cohort Study

Preterm Birth and Stillbirth During the COVID-19 Pandemic in Sweden: A Nationwide Cohort Study

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown.Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients.Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males.Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

Influence of colchicine prescription in COVID-19-related hospital admissions: a survival analysis.

Aims:To analyze the association between colchicine prescription and COVID-19-related hospital admissions in patients with rheumatic and musculoskeletal diseases (RMDs).Methods:Patients attending a rheumatology outpatient clinic from a tertiary care center in Madrid, Spain, from 1 September 2019 to 29 February 2020 were included. Patients were assigned as exposed or unexposed based on whether they were prescribed with colchicine in their last visit to the clinic during the 6 months before the start of the observation period. Treatment changes during the observation period were also considered. The primary outcome was COVID-19-related hospital admissions between 1 March and 20 May 2020. Secondary outcome included COVID-19-related mortality. Several weighting techniques for data balancing, based and non-based on the propensity score, followed by Cox regressions were performed to estimate the association of colchicine prescription on both outcomes.Discussion:The number of patients entered in the study was 9379, with 406 and 9002 exposed and unexposed follow-up periods, respectively. Generalized Boosted Models (GBMs) and Empirical Balancing Calibration Weighting (EBCW) methods showed the best balance for COVID-19-related hospital admissions. Colchicine prescription did not show a statistically significant association after covariable balancing (p-value = 0.195 and 0.059 for GBM and EBCW, respectively). Regarding mortality, the low number of events prevented a success variable balancing and analysis.Conclusion:Colchicine prescription does not play a significant protective or risk role in RMD patients regarding COVID-19-related hospital admissions. Our observations could support the maintenance of colchicine prescription in those patients already being treated, as it is not associated with a worse prognosis.Plain language title:Colchicine influence in COVID-19-related hospital admissions

Liraglutide and semaglutide: Pooled post hoc analysis to evaluate risk of dementia in patients with type 2 diabetes

AbstractBackgroundGlucagon‐like peptide 1 receptor agonists (GLP‐1 RA) have previously shown improved measures of memory and reduced phospho‐tau burden in preclinical animal models relevant to progressive cognitive impairment (Hansen. J Alzheimers Dis.2015;46:877‐88; Hansen. Brain Res.2016;1634:158‐70). Liraglutide and semaglutide are structurally similar GLP‐1 RAs associated with potent glucose‐lowering effect, body weight loss and cardiovascular benefits shown in large cardiovascular outcomes trials (CVOTs) (Marso. N Engl J Med.2016;375:311‐22; Marso. N Engl J Med.2016;375:1834‐44; Husain. N Engl J Med.2019;381:841‐51). In order to investigate the potential effects of GLP‐1 RA on dementia in a clinical setting, a post‐hoc analysis was conducted based on pooled data from three CVOTs.MethodLEADER, SUSTAIN 6 and PIONEER 6 were randomised, double‐blind, multicentre, placebo‐controlled CVOTs evaluating the cardiovascular effect of liraglutide or semaglutide vs. placebo, added to standard of care. The trials included patients with type 2 diabetes and established or high risk of cardiovascular disease. A post‐hoc analysis on pooled data from the three CVOTs was considered appropriate due to the similarities in trial design, patient population and treatment effects. Across all trials 15,820 patients with median follow‐up of 3.6 years were included in this analysis. Dementia‐related adverse events (AEs) were identified using Standardised MedDRA (version 21.1) Query for “dementia” narrow search terms. AE data collection across the trials differed in line with the regulatory requirements at the time of trial conduct. In LEADER and PIONEER 6 only serious AEs were systematically collected, while all AEs were collected in SUSTAIN 6. A time‐to‐event analysis based on the Cox proportional‐hazards model using treatment as covariate was used to estimate the hazard ratio for developing dementia.ResultAcross the three CVOTs, 15 GLP‐1 RA‐treated patients and 32 placebo‐treated patients were identified with development of dementia (Figure). Post‐hoc analysis on the pooled data showed a significant estimated hazard ratio of 0.47 [0.25; 0.86]95%CI in favour of the GLP‐1 RA treatment versus placebo.Conclusion Post‐hoc analysis based on pooled data from three double‐blinded CVOTs suggests, albeit with a low number of events, a reduced risk of dementia with liraglutide or semaglutide treatment in patients with type 2 diabetes.

Abstract 15129: Outcomes Related to Age of Elective Surgery and Age of Dissection Within Genetically Triggered Aneurysm Conditions: The Gentac Experience

Introduction: The GenTAC Registry ( G enetically Triggered T horacic A ortic Aneurysms and Cardiovascular C onditions) followed patients with aortopathies over 8 years among 8 centers with the goal of evaluating cardiovascular outcomes. Methods: Enrollment initiated in 2007, and data were collected until 2015. We included diagnoses with &gt;100 participants: Bicuspid aortic valve with aneurysm (BAV, n=879), Marfan syndrome (MFS, n=861), Familial thoracic aortic aneurysm or dissection (FTAAD, n=378), Other thoracic aortic aneurysm at &lt; 50 years of age (Other&lt;50, n=524), Turner syndrome (TS, n=298), Vascular Ehlers Danlos syndrome (VEDS, n=149), and Loeys-Dietz syndrome (LDS, n=121). We identified patients who underwent elective ascending aortic replacement, total unique dissections, and time to first dissection. With MFS as a reference population and adjusted for sex, endpoints were analyzed by a Firth penalized Cox-PH regression model to account for diagnosis groups with low event numbers. Results: LDS participants at a mean age of (24.5 ± 15.0y) were youngest at elective aortic surgery followed by MFS (32.3 ±12.3y), TS (37.6 ±13.6y), VEDS (35.0 ±SD 7.4y), Other&lt;50 (40.3 ±SD 10.3y), FTAAD (42.9 ±14.2y), and BAV(49.4 ± 13.8 y). Dissections were reported in all diagnosis groups with a total of 472 unique dissections in 3210 patients (14%). Mean age at first dissection was in the third decade for LDS, TS, MFS, VEDS and in the fourth decade for BAV, FTAD, and Other&lt;50. Adjusted hazard ratio for time to first dissection was higher in LDS, 1.77 (95%CI 1.14- 2.77), compared to MFS and other diagnosis groups (Figure 1). Conclusions: Reported aortic dissections were prominent in the GenTAC cohort. Despite elective surgery at a younger age, LDS patients had a higher hazard risk of dissection compared to other diagnosis groups.

HORIZON (OP-106): Melflufen Plus Dexamethasone (dex) in 55 Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) with Extramedullary Disease (EMD)-Subgroup Analysis

HORIZON (OP-106): Melflufen Plus Dexamethasone (dex) in 55 Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) with Extramedullary Disease (EMD)-Subgroup Analysis

Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical featuresin invasive micropapillary breast carcinoma with long-term outcomes.

We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features. Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS). We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001). Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.