Impact Of New Therapies Research Articles

Patient-Reported Outcomes in Early Phase Trials for Patients with Myelodysplastic Syndromes

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) experience a wide range of symptoms due both to their underlying disease and the effects of treatment. Designing early phase trials to explore effective therapies in these patients should not only examine anti-tumor activity, but also consider the effects of treatments on how patients feel and function. Assessing symptomatic toxicities associated with new therapies in early phase trials from the patient perspective is best measured using patient-reported outcomes (PROs) and offers valuable insight and complementary information to the traditional adverse event reporting in cancer clinical trials. This review describes PROs, highlights their importance in MDS drug development, and outlines the key psychometric properties and practical considerations that make PROs essential and desirable in evaluating the impact of new therapies. We will provide a general overview of PROs and follow with application of PROs in MDS/AML including strategies to be considered in early phase trials. Finally, we describe the creation of the Office of Patient-Centered Outcomes Research at the US National Institutes of Health which has developed a standardized PROs methodology for early phase trials conducted in the Center for Cancer Research at the US National Cancer Institute.

Effect of Finerenone on the KCCQ in Patients With HFmrEF/HFpEF: A Prespecified Analysis of FINEARTS-HF

BackgroundPatients with heart failure (HF) are limited by symptoms and have impaired quality of life. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported outcome measure that enables evaluation of the effect of HF and the impact of new therapies on health status in patients with HF. ObjectivesThis prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) assessed the efficacy and safety of finerenone according to baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS. MethodsFINEARTS-HF tested the efficacy of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone, compared with placebo, in patients with HF with mildly reduced ejection fraction/preserved ejection fraction. The primary endpoint was the composite of cardiovascular death and total worsening HF events. The KCCQ was completed by patients at randomization and at 6, 9, and 12 months after randomization. Change in KCCQ-TSS was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles at baseline. The association between KCCQ tertile and clinical outcomes was evaluated using semiparametric proportional-rates models for total events and Cox models for time-to-first-event data, and the effects of finerenone vs placebo on the primary endpoint were assessed across tertiles of KCCQ-TSS. ResultsOf the 6,001 participants in FINEARTS-HF, 5,986 (99.8%) had baseline KCCQ-TSS recorded (median score 69.8 of a possible 100; higher score = better health status). Lower (worse) KCCQ-TSS was associated with a higher risk of the primary endpoint. Finerenone, compared with placebo, reduced the risk of the primary endpoint across the range of KCCQ-TSS: tertile 1 (score 0-<57): RR: 0.82 (95% CI: 0.68-1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70-1.11); tertile 3 (81-100): 0.88 (95% CI: 0.69-1.14) (Pinteraction = 0.89). Compared with placebo, finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69-2.56 points) (P < 0.001). Numerically fewer finerenone-treated patients experienced clinically meaningful deterioration, and more had improvements in KCCQ-TSS. ConclusionsFinerenone significantly reduced HF events and improved health status in patients with HF and mildly reduced ejection fraction/preserved ejection fraction across the spectrum of KCCQ-TSS at baseline. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; EudraCT 2020-000306-29)

Disparities in Mortality Trends of Breast Cancer by Racial and Ethnic Status in the United States.

Breast cancer is the most commonly diagnosed malignancy for women and is a leading cause of mortality in women worldwide and in the United States. Recently, new interventions have been developed to improve its prognosis. The aim of this study was to assess the impact of new therapies on racial and ethnic groups in the United States for demographic-based disparities. We assessed the impact of these developments from 1999 to 2020 on age adjusted mortality rate (AAMR), mortality rate trend from 1999 to 2020, average annual percent change (AAPC), and temporal trends, by annual percent change (APC) in the United States for various demographic groups. We queried the CDC Wonder database to retrieve mortality rates by race and ethnic group from 1999 to 2020 with breast malignancy as a contributing cause of death. Between 1999 to 2020, all racial groups presented a significant overall decline in mortality rates: AI/AN [AAPC, -1.6% (95% CI=-2.2% to -1.0%); p<0.01], AAPI [AAPC, -0.5% (95% CI=-1.00% to -0.1%); p<0.01], Black/African American [AAPC, -1.4% (95% CI=-1.6% to -1.2%); p<0.01], and the white population [AAPC, -1.7% (95% CI=-1.8% to -1.5%); p<0.01]. The Black/African American population had a significant lower rate of decline compared to the white population (p<0.01) and Hispanic/Latinx populations had a lower rate of decline compared to those who are non-Hispanic/Latinx (p<0.01). We found that Black/African American population had a significant lower rate of decline compared to the white population and Hispanic/Latinx populations had a lower rate of decline compared to those who are non-Hispanic/Latinx. These differences in mortality trend rates in breast cancer emphasize the need for targeted interventions and resources tailored to specific demographic needs.

Abstract IA029: Expanding access and participation to early phase clinical trials for our underrepresented populations

Abstract The American Society of Clinical Oncology (ASCO) has a firm position that phase I trials provide trials participants potential benefit with improved quality of life, psychological and direct medical benefit. Disproportionate access to novel therapies through early phase clinical trials among underrepresented populations continues to exist. In fact, there is worsening disparity in accrual of patients from racial and ethnic minority groups in phase 1 trials of drugs for metastatic cancer. Access to cutting-edge clinical trials leading to paradigm-changing treatments is critical for cancer care and equity in society, as participation in clinical trials correlates with reduction in mortality. Stark disparities in access and participation to clinical trials impact underserved populations among racial and ethnic minorities, socioeconomically disadvantaged, and geographically isolated populations. The impact of newer therapies, if inadequately studied in underserved populations, may result in poor generalizability of study results and uncertain benefit for these groups. Further, evidence suggests that access to clinical trials narrows the gap in cancer care disparity among patients in urban and rural communities. In response to ethical, clinical, and biologic mandate, the National Cancer Institute’s (NCI) Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. This congressional mandate was a P30 administrative supplement awarded to eight NCI-designated cancer centers to enhance access to early phase precision medicine Experimental Therapeutics Clinical Trials Network (ETCTN) clinical trials for minority and underserved populations. The purpose of this presentation is to share best practices learned in CATCH-UP.2020 and discuss how this program helped create a roadmap to building a clinical trials ecosystem that allowed expanded access to early phase trials through cross-fertilization of successful tools among the CATCH-UP sites and within ETCTN. In our institution, learned best practices are applied across the spectrum of early phase clinical investigations to help overcome clinical trials disparities using the rural lens. With the goal of bringing precision medicine clinical trials close to home for our underrepresented populations, we aim to accelerate drug development without leaving anyone behind. Citation Format: Joaquina C. Baranda. Expanding access and participation to early phase clinical trials for our underrepresented populations [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA029.

Quality of Life in Childhood Immune Thrombocytopenia: Revision of the Kids' ITP Tools (KIT)

Introduction New treatment approaches have emerged for pediatric ITP over the years, potentially impacting the health-related quality of life (HRQoL) of affected individuals. The Kids' ITP Tools (KIT) (Child self-report/Parent proxy-report and Parent impact-report) have gained international attention as valid tools for monitoring HRQoL in children with ITP and the impact on their parents. The questionnaires were recently updated to reflect changes in clinical management. However, it has also become common practice to evaluate the impact of new therapies using domain scales of QOL (i.e., sub-categories), which are not yet available for the KIT. Thus, the primary objective of this study was to establish domain scales for the KIT 2.0 that accurately quantify and identify specific aspects of HRQoL that are impacted in children with ITP and their parents. Methods The study was conducted in two sequential phases. Phase 1 involved ITP experts identifying key conceptual domains for the KIT questionnaires based on their clinical experiences. An online survey (“card sort survey”) was distributed, and experts sorted the current KIT 2.0 questions into domains, with domain headings suggested as well. Phase 2 involved a statistical approach (i.e., exploratory factor analysis (EFA)) to yield models with different number of domains. Data from children with ITP and their parents was utilized to develop the models, and the data was specifically from three previous international multicentre studies: ITP Consortium of North America (ICON1 study), UK Children's Hospital (UK ITP Paediatric Registry), and the Children's Hospital of Eastern Ontario (KIT international validation). Results In Phase 1, 24 experts completed the Child self-report card-sort survey, while 12 experts completed the Parent impact survey. There were two models that were derived for the Child Self-Report, with one having three domain scales and the other with four domain scales. The Parent Impact resulted in only one model that had three domain scales. In Phase 2, exploratory factor analysis (EFA) resulted in three models for each of the three questionnaires (Table 1), with the final models selected from the EFA and based on clinical interpretability. The four-domain model was selected for the Child Self-Report. The model had a higher Tucker Lewis Index (TLI) score and cumulative percentage of variance compared to the three-domain model. Though the cumulative percentage of variance was higher for the six-domain model, the model had two domains that each contained only two questions, which is not ideal for face validity. The final domain headings for the Child self-report were derived from the expert card sort survey: ITP Uncertainty; General symptoms; ITP challenges/disruptions; and Loss of control. The four-domain model was also selected for the Parent proxy-report on the basis of the same factors as the Child self-report. Likewise, the four-factor model had higher TLI score and relatively lower root mean square error of approximation (RMSEA) compared to the three-factor. The six-factor model had an ideal RMSEA, but contained one domain that had only two questions. The final domain headings are the same as the Child self-report as the context of the questions are the same. The four-domain model was selected for the Parent impact-report. Though both the four- and six-factor models contained two domains with only two questions each, the two-factor model was not ideal clinically as the questions within each of the two domains were not all similar. The headings were also derived from the expert card-sort: ITP Uncertainty; Treatment; Functional well-being; and Activities. Conclusion The revised KIT 2.0 aims to comprehensively summarize health-related quality of life in pediatric patients with ITP and their parents. The introduction of a domain structure derived from expert- and patient-data to the KIT will enable identification of specific aspects of QOL that are affected, which is imperative given the introduction of novel pharmaceutical agents in ITP treatment.

Health‐economic innovation headroom in mild cognitive impairment due to Alzheimer’s diseas

AbstractBackgroundEstimating health‐economic impact of new therapies for prodromal Alzheimer’s disease (AD) requires extrapolating short‐term effects on surrogate markers of efficacy to long‐term clinically relevant outcomes. This requires assumptions on the nature of the treatment (symptomatic versus disease‐modifying) and depends on the target population (which varies in disease progression associated to biological subtypes). We aim to estimate the innovation headroom (potential value) of AD treatment in mild cognitive impairment (MCI), describe the impact of assumptions on treatment nature (symptomatic/disease‐modifying) and disease progression (fast/slow progressors), and discuss challenges for health‐economic evaluation of future AD treatments; to ensure patients timely access treatment innovations.MethodThe IPECAD open‐source decision‐analytic model was used to estimating time spent with MCI, mild, moderate and severe dementia, discounted quality‐adjusted life years (QALYs) and costs, under different treatment strategies. Innovation headroom was estimated by simulating a usual care strategy, and compare it with a strategy reflecting a fictive disease‐modifying treatment with 100% efficacy, and a strategy reflecting a fictive 100% efficacious symptomatic therapy; in preventing all individuals to progress to dementia.ResultThe innovation headroom analysis resulted in 4.1 additional QALYs and k€13 lower costs of care with disease‐modifying, and 0.8 additional QALYs and k€71 lower costs of care with symptomatic therapy. The higher QALY gain for disease‐modification is mainly explained by an indirect effect on mortality, resulting in a 5.5 year increase in life expectancy. The innovation headroom was about twice as large in the persons with fast progression compared to persons with slow progression in MCI. The disease‐modifying therapy mainly generated improved health (QALY gains), while the symptomatic therapy mainly generated savings in costs of care; which is contingent on their mortality assumptions.ConclusionThe potential health and economic benefit of (non‐)pharmacological interventions in MCI is substantial. However, its dependency on assumptions related to treatment nature argues for research efforts to better understand the relation between surrogate and long‐term outcomes. Its dependency on target population indicates a potential for individualized treatment based on profiles of disease progression. Finally, we recommend incorporating age‐related comorbidities as a result of the relatively large life years gained.

Clinical characteristics and initial treatment patterns of patients with HCC in Korea: A multi-center real-world database analysis from the LINK research network.

e16116 Background: In Korea, liver cancer is the fifth most frequently diagnosed cancer and has the second highest cancer mortality rate. Despite recent advances in systemic therapy, patients with Hepatocellular carcinoma (HCC) continue to have poor prognoses as many are diagnosed at an advanced disease stage. To better understand the current treatment landscape and contribute to improved patient outcomes, the LINK (Liver Cancer in Korea) research network was established as a longitudinal real-world HCC database with annual data refresh. The aim was to provide current and up-to-date real-world insights into HCC patient characteristics, treatment patterns, and outcomes. Methods: LINK’s data sources are the electronic medical records of three leading academic hospitals (Asan Medical Center, Samsung Medical Center, Severance Hospital). Extracted data are standardized using a study-specific common data model to ensure comparability across hospitals. Adult patients with primary diagnosis of HCC (ICD-10: C22.0) in 2015-2020 were included and followed until death, loss to follow-up, or June 2021, whichever occurred first. Patients without valid treatment records or morphology codes or with other primary cancer diagnosis were excluded. Data on key patient and clinical characteristics, treatments, such as systemic anti-cancer therapy (SACT) regimens, and real-world outcomes were collected. Rule-based algorithms were developed to define initial treatments and lines of therapy in palliative SACT. Results: Of 25,480 HCC patients identified, 10,298 (40%) met eligibility criteria and were included in the analysis. The median age was 60 years and 19% were female. There were 74% of patients classified as Child-Pugh (CP) class A, 16% as B, 1% as C, and 9% with unknown CP at diagnosis. For albumin-bilirubin (ALBI) grade at diagnosis, 49% of patients were classified as grade 1, 45% as 2, 5% as 3, and 1% unknown. Loco-regional therapy was the most common initial treatment, with 54% and 13% of patients receiving transarterial therapy and local ablation therapy, respectively. A total of 628 patients (6%) undergone liver transplantation regardless of preceding treatments and 15% of patients were initially treated with hepatectomy. Only 2% received radiation therapy (RT) or RT in combination with cytotoxic chemotherapy as initial treatment. Among 3,026 patients who received SACT either as an initial (10%) or subsequent treatment, 67%, 20%, and 13% received 1 line, 2 lines, and 3 lines of therapy. The most common first-line SACT was sorafenib, followed by lenvatinib. Conclusions: The LINK database can serve as a multi-center research platform to facilitate fast and reliable real-world evidence generation for HCC patients. Future updates and subgroup analyses of interest can further evaluate the impact of new therapies and changes to HCC treatment guidelines in Korea.

Patients’ epidemiology in stage III, unresectable non-small-cell lung carcinoma: A real-world analysis in Brazil.

e20589 Background: Although breakthrough therapy options for NSCLC have emerged in the last few years, lung cancer is still the principal cause of cancer-related deaths in both men and women worldwide. In Brazil, lung cancer is the major cause of cancer mortality – the second most common cause of cancer-related death in females and the first cause among males. The main factors contributing to the high burden of the disease remain the late-stage diagnosis and unequal healthcare access, which are most prevalent in low- and middle-income countries. This study aimed to describe lung cancer epidemiology – patients in stage III, unresectable NSCLC that could benefit from consolidation therapy after chemoradiation (CRT) treatment - in the Brazilian public health system for evaluating the future impact of new therapies. Methods: We gathered information on lung cancer procedures performed between January 2018 and October 2022 using the Brazilian public health system database (DATASUS). Since this is a claim medical database without clinical data, assumptions were specified based on procedures performed to determine the potential number of patients in Brazil who would benefit from these new treatment strategies in stage III NSCLC. The assumptions were the following: 1. Having received systemic therapy for a malignant tumor of the bronchi and lung (ICD-10 - C34); 2. Having received a pre-defined list of chemotherapy regimens (to define which patients were NSCLC); 3. Having started systemic therapy with a Stage III tumor; 4. Having not undergone surgery between three months before and two months following the start of systemic treatment 5. Treated with chemotherapy and radiotherapy (concomitantly or sequentially - until two months later); 6. Patients who died or progressed during treatment were classified as incomplete treatment. Results: Between 2018 and 2022, we identified an average of 9,340 patients each year who started therapies for lung cancer; 75% (7,023) of them performed specific procedures for NSCLC and were classified as such. 21% (1,472) of patients started treatment for stage III NSCLC, and 98% (1,438) of these cases were unresectable. Of these, 26% (377) received chemotherapy and radiation, 92% of whom finished the course of treatment. In Brazil, 346 patients per year with stage III unresectable NSCLC could be treated with consolidation therapy after CRT in the public health system. Conclusions: The number of NSCLC patients who can benefit from consolidation therapy after CRT (346) represents 3.7% of all lung cancer patients starting systemic treatment annually. It allows a better management of the possible economic impact of the addition of this new therapy in the Brazilian health public system. Increased screening for early diagnosis and improving access to CRT would expand the patient population eligible for this therapeutic approach.

Primary Biliary Cholangitis: Promising Emerging Innovative Therapies and Their Impact on GLOBE Scores.

Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.

The Muscular Dystrophy Association's neuroMuscular ObserVational Research Data Hub (MOVR): Design, Methods, and Initial Observations.

Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant clinical data shortage for these rare diseases. To maximize the development and impact of new therapies, the Muscular Dystrophy Association (MDA) created the neuroMuscular ObserVational Research Data Hub (MOVR) as an observational research study that collects disease-specific measures from individuals living with NMDs in the United States. This manuscript provides a description of MOVR, participants enrolled in MOVR, and longitudinal data availability. MOVR collects longitudinal data from individuals diagnosed with ALS, BMD, DMD, FSHD, LGMD, Pompe disease, or SMA, and who are seen for care at a participating MDA Care Center. Data are entered from medical records into standardized electronic case report forms (eCRFs). These eCRFs capture participants' demographics, diagnostic journeys, clinical visits, and discontinuation from the study. From January 2019 to May 2022, MOVR collected data from 50 participating care centers and 1,957 participants. Data from 1,923 participants who participated in MDA's pilot registry were migrated into MOVR, creating a total of 3,880 participants in MOVR. Initial analysis of aggregated data demonstrated that 91% of eCRFs were complete. Forty-three percent of participants had 3 or more encounters and 50% of all encounters were 5 months or less from the previous encounter. As a centralized data hub for multiple NMDs, MOVR serves as a platform that can be used to inform disease understanding, guide clinical trial design, and accelerate drug development for NMDs.

Beyond the Lungs-Emerging Challenges in Adult Cystic Fibrosis Care.

Cystic fibrosis (CF) is a multisystem disease. This article provides an up-to-date review of many of the nonrespiratory complications of CF, including mental health issues, nutritional and gastrointestinal problems, fertility issues, diabetes mellitus, bone health and musculoskeletal problems, liver disease, renal problems, and risk of malignancy. It highlights the recent impact of new therapies, including CF transmembrane conductance regulator modulators, on the nonrespiratory complications of CF and provides insights into the potential challenges faced by an aging population of adults with CF and their caregivers, including the potential future risk for cardiovascular disease.

Clinical and immunological factors associated with lupus nephritis in an Argentine patient population: A cross-sectional study

IntroductionIn recent decades, the prevalence of systemic lupus erythematosus (SLE) has increased thanks to early detection and the impact of new therapies on the survival of those affected. Up to 90% will have histopathological signs of kidney disease in the first 3 years of the disease, but lupus nephritis of clinical relevance will appear in 50% of cases, affecting kidney function and mortality. Despite aggressive therapeutic strategies, the prognosis of patients with LN remains unfavourable, mainly due to the high risk of progression to end-stage renal disease (10%–20%) and mortality from all causes. ObjectiveTo describe the clinical and immunological risk factors of a group of patients with lupus, comparing clinical and serological characteristics in relation to renal involvement to establish possible associations. Materials and methodsCross-sectional study in which 87 patients with SLE were included. Clinical and immunological variables were analyzed. Bivariate and multivariate analyses were performed using the presence of nephritis as an outcome. ResultsThe prevalence of lupus nephritis was 59%. The significantly associated variables were arterial hypertension (OR 3.1, 95% CI 1.02–9.40), age of onset of lupus less than 25 years (OR 2.7, 95% CI 1.08–6.73), the presence of reticular livedo (OR 4.1, 95% CI 1.09–15.7), positive anti-DNA (OR 2.9, 95% CI 1.18–7.24) and low levels of complement (OR 4.0, 95% CI 1.64–10.2). ConclusionsUrinary sediment abnormalities were the most common renal manifestation and lupus debut before the age of 25 seems to increase the risk of developing nephritis. Future research is required for a better explanation of the associations found.

Self-reported Severe and Nonsevere Hypoglycemia in Type 1 Diabetes: Population Surveillance Through the BETTER Patient Engagement Registry: Development and Baseline Characteristics

ObjectivesThe BETTER (BEhaviors, Therapies, TEchnologies and hypoglycemic Risk in Type 1 diabetes) registry is a type 1 diabetes population surveillance system codeveloped with patient partners to address the burden of hypoglycemia and assess the impact of new therapies and technologies. The aim of this report was to describe the baseline characteristics of the BETTER registry cohort. MethodsA cross-sectional baseline evaluation was performed of a Canadian clinical cohort established after distribution of an online questionnaire. Participants were recruited through clinics, public foundations, advertising and social media. As of February 2021, 1,430 persons ≥14 years of age and living with type 1 diabetes or latent-autoimmune diabetes (LADA) were enrolled. The trial was registered on ClinicalTrials.gov (NCT03720197). ResultsParticipants were (mean ± standard deviation) 41.2±15.7 years old with a diabetes duration of 22.0±14.7 years, 62.0% female, 92.1% Caucasian and 7.8% self-reporting as LADA, with 40.9% using a continuous subcutaneous insulin infusion (CSII) system and 78.0% using a continuous glucose monitoring (CGM) system. The most recent glycated hemoglobin ≤7% was reported by 29.7% of participants. At least 1 episode of hypoglycemia <3.0 mmol/L (level 2-H) in the last month was reported by 78.4% of participants, with a median (interquartile range) of 5 (3, 10) episodes. The occurrence of severe hypoglycemia (level 3-H) in the last 12 months was reported by 13.3% of participants. Among these, the median number of episodes was 2 (1, 3). ConclusionsWe have established the first surveillance registry for people living with type 1 diabetes in Canada relying on patient-reported outcomes and experiences. Hypoglycemia is a highly prevalent burden despite a relatively wide adoption of CSII and CGM use.

A preliminary application of a haemophilia value framework to emerging therapies in haemophilia.

Emergence of new therapies are anticipated to improve clinical outcomes and quality of life of persons with haemophilia. Challenges in conducting randomized clinical trials in rare diseases have resulted in a lack of direct head-to-head comparisons to support value-based decision-making between different treatments. We conducted a literature review for new and emerging haemophilia A and B therapies (extended half-life [EHL] replacement factor, non-replacement therapies [NRT], and gene therapies [GT]) to identify differentiating patient-centred outcomes defined previously in a haemophilia value framework. Since the literature included all publication types (e.g., surveys, modelling studies, commentaries/reviews), collected data were assigned level of evidence scores. Across different classes of therapies, bleeding was determined as the most frequently reported differentiating outcome, with EHL, NRT, and GT each demonstrating an advantage over comparator replacement therapies. EHL therapies for haemophilia A and B and NRT for haemophilia A showed good representation across Tier 1 outcomes (health status achieved/retained), while more publications were identified with Tier 2 (process of recovery) outcomes for NRT than EHL or GT. In Tier 3 (sustainability of health), frequency of breakthrough bleeds represented a differentiating outcome for EHL (both haemophilia A and B), NRT (haemophilia A only), and GT (haemophilia B only), whereas sustained good health was differentiating for most comparisons. We demonstrate the utility of the haemophilia value framework as a common core outcome set for effectively comparing therapies. Application of this framework will serve as a useful decision-making tool for patients, clinicians, and within health technology assessments. With the emergence of high-cost, paradigm changing treatments across multiple areas of medicine, we, the haemophilia community, need to be equipped to meet the growing demands for more rigorous evidence-based value assessments using the tools expected by assessors. The traditional access toolbox needs to evolve to meet the paradigm shift in treatment options. Value can no longer be defined by annualized bleed rates alone. To realize the full impact of new therapies, we need to utilize tools, such as a value framework, to organize evidence, identify data gaps, and assess patient-defined, meaningful outcomes across a multi-faceted dimension. The haemophilia value framework is an effective tool for organizing the available evidence and identifying gaps in the evidence. This can be used for assessing the value of emerging therapies in haemophilia utilizing data generated through randomized clinical trials and real world evidence generation. This is a call for incorporating the Value Framework into official submissions to authorities, as it captures a broader range of outcomes, including patient meaningful outcomes, in ways that better assess the potential benefits of new therapies.

P472 Changes in colectomy for Ulcerative Colitis during the last two decades: an in-depth retrospective analysis

Abstract Background The management of ulcerative colitis (UC) has been improved due to progresses in medical and surgical practices during the past twenty years. Yet the impact of new therapies on the evolution of the three colectomy’s indications in UC (severe acute colitis, refractory ulcerative colitis and (pre-)neoplastic complication) is still not well established. The aim of this study was to compare the evolution of the surgical indications within the last two decades. Methods This was an observational retrospective study carried out in two tertiary hospitals. All patients with UC who underwent total or segmental colectomy between 2001 and 2020 were included, without age restriction. Two periods were compared: 2001–2010 and 2011–2020. Endpoints were to compare the colectomy indications, patients’ characteristics, surgical procedures, and rates of postoperative complication between the two cohorts. Results Among the 286 patients included (57% were men; median age of 40 years; 60.5% of extensive and 35.7% of distal colitis), 87 (30.4%) underwent colectomy in 2001–2010 and 199 patients (69.6%) in 2011–2020. Patients’ characteristics were similar between the two periods, including duration of UC and the severity according to the global Mayo score. Colectomy rate for refractory UC significantly decreased over time (n=119) (50.6% vs. 37.7%; p=0.042), while it increased for acute severe colitis (n=116) (36.8% vs. 42.2%; p=0.390) and (pre-)neoplastic indication (n=51) (12.6% vs. 20.1%; p=0.130) (Figure 1). Regarding surgery, there was an increased use of laparoscopic colectomy (47.7% vs. 81.4%; p&amp;lt;0.001) during the latter period and the median length of stay in hospital after surgery has decreased from 13 to 10 days (p=0,098). There were less early (12.6% vs. 5.5%; p=0.038) and late severe complications (1.6% vs. 0.8%; p&amp;lt; 0.001) and less surgical revisions (38.6% vs. 19.5%; p&amp;lt;0.001) without change on 30-day mortality rate (2.3% vs. 1%; p=0.391). The rate of extraintestinal postoperative infections (especially urinary, pulmonary and catheters infections) increased during the second period (27% vs; 45.7%; p=0.018). As expected, the mean number of past biotherapies was higher during the second period (1.2 versus 0.6; p&amp;lt;0.001), as well as the rate of pre-operative exposition to TNFα antagonists (68.4% vs. 50.6%; p=0.016). Conclusion The rate of surgery for refractory colitis has significantly decreased while the rate of colectomy for cancer and acute severe colitis has risen during the last twenty years. In the same time, surgical technics have changed with more laparoscopic surgeries associated with a reduction of postoperative morbidity despite the larger use of biotherapies.

Impact of recommendations and new therapies on the prognosis of colon cancer with synchronous liver metastasis

To assess the prognostic impact of the new therapies recommended over the past twenty years for colonic cancers with synchronous hepatic metastasis (hmCC). From 1995 to 2016, 802 hmCC were identified in a tumor registry. An univariate and multivariate analysis looked for the impact of the different recommendations over three periods: chemotherapy without targeted therapy (p1CH), chemotherapy with targeted agent in 2nd line (p2TA2), chemotherapy with TA in 1st line (p3TA1) depending on anatomoclinical criteria and therapeutic sequences: chemotherapy then resection of the primary tumor (CR) (n=100), resection of the primary tumor then chemotherapy (RC) (n=541), chemotherapy alone with or without TC (onlyCH) (n=161). The rates of onlyCH, CR and RC had varied respectively during these 3 periods from 12% to 26%, 6% to 21% and from 82% to 53% (p=0.001). The medians of p1CH, p2TA2 and p3TA1 survival were 20.2, 22.7 and 23.6 months, respectively (p=0.12). The independent factors of poor prognosis were age ≥ 75 years (1.6 [1.35; 1.9] p=0.0001), chemotherapy only 2.3 [1.6; 3.5] p=0.0001), p1CH 1.7 [1.4; 2.1] p<0.0001), p2TA2 1.2 [1.02;1.6] p=0.04. The p2TA2 period had a worse prognosis than p3TA1 (1.25 [1.01; 1.5] p=0.03). In public health point of view, the recommendation of first-line TA improved survival and increased rate of primary tumor resection after chemotherapy.

Patient, family and productivity costs of end-stage renal disease in the Netherlands; exposing non-healthcare related costs

BackgroundHealthcare costs related to ESRD are well-described, but broader societal costs of ESRD are less known. This study aimed to estimate patient and family costs, including informal care costs and out-of-pocket costs, and costs due to productivity loss related to ESRD, for patients receiving dialysis and living with a kidney transplant, using a bottom-up approach.MethodsA total of 655 patients were asked to complete a digital questionnaire consisting of two standardised instruments (iMCQ and iPCQ) from November 2016 through January 2017. We applied a retrospective bottom-up cost estimation by combining data from the questionnaire with unit prices from the Dutch costing manual.ResultsOur study sample consisted of 230 patients, of which 165 were kidney transplant recipients and 65 received dialysis. The total annual non-healthcare related costs were estimated at €8284 (SD: €14,266) for transplant recipients and €23,488 (SD: €39,434) for dialysis patients. Costs due to productivity loss contributed most to the total non-healthcare costs (66% for transplant recipients and 65% for dialysis patients), followed by informal care costs (26% resp. 29%) and out-of-pocket costs, such as medication and travel expenses (8% resp. 6%).ConclusionBy exposing patient, family and productivity costs, our study revealed that dialysis and transplantation are not only costly within the healthcare system, but also incur high non-healthcare costs (18–23% resp. 35% of the total societal costs). It is important to reveal these types of non-healthcare costs in order to understand the full burden of ESRD for society and the potential impact of new therapies.

Detecting and preventing post-hematopoietic cell transplant relapse in AML.

Relapsed disease is the primary cause of mortality for acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (HCT). This review outlines the most recent advances in the detection and prevention of AML relapse following allogeneic HCT. Conventional methods for predicting post-HCT relapse rely on the molecular and cytogenetics features present at diagnosis. These methods are slow to reflect a growing understanding of the molecular heterogeneity of AML and impact of new therapies on post-HCT outcomes. The use of measurable residual disease (MRD) techniques, including multiparameter flow cytometry and molecular testing, may improve the prognostic ability of these models and should be incorporated into post-HCT surveillance whenever possible.In the post-HCT setting, FLT3 inhibitor maintenance data indicate that effective therapies can improve post-HCT outcomes. Maintenance data with DNA methyltransferase inhibitor monotherapy is less compelling and outcomes may improve with combinations. Early interventions directed at preemptive management of MRD may further improve post-HCT outcomes. Post-HCT AML relapse prevention has evolved to include more sensitive measures of disease detection and novel therapies that may improve outcomes of poor-risk AML patients. Additional work is needed to maintain this progress.

Factores clínicos e inmunológicos asociados con nefritis lúpica en una población de pacientes argentinos: un estudio transversal

IntroductionIn recent decades, the prevalence of systemic lupus erythematosus (SLE) has increased thanks to early detection and the impact of new therapies on the survival of those affected. Up to 90% will have histopathological signs of kidney disease in the first 3 years of the disease, but lupus nephritis of clinical relevance will appear in 50% of cases, affecting kidney function and mortality. Despite aggressive therapeutic strategies, the prognosis of patients with LN remains unfavourable, mainly due to the high risk of progression to end-stage renal disease (10%-20%) and mortality from all causes. ObjectiveTo describe the clinical and immunological risk factors of a group of patients with lupus, comparing clinical and serological characteristics in relation to renal involvement to establish possible associations. Materials and methodsCross-sectional study in which 87 patients with SLE were included. Clinical and immunological variables were analysed. Bivariate and multivariate analyses were performed using the presence of nephritis as an outcome. ResultsThe prevalence of lupus nephritis was 59%. The significantly associated variables were arterial hypertension (OR 3.1, 95% CI 1.02-9.40), age of onset of lupus less than 25 years (OR 2.7, 95% CI 1.08-6.73), the presence of reticular livedo (OR 4.1, 95% CI 1.09-15.7), positive anti-DNA (OR 2.9, 95% CI 1.18-7.24) and low levels of complement (OR 4.0, 95% CI 1.64-10.2.). ConclusionsUrinary sediment abnormalities were the most common renal manifestation and lupus debut before the age of 25 seems to increase the risk of developing nephritis. Future research is required for a better explanation of the associations found.

US Budget Impact Model for Selinexor, Bortezomib, and Dexamethasone for the Treatment of Previously Treated Multiple Myeloma.

PurposeTo estimate the budget impact of selinexor, bortezomib, and dexamethasone (XVd) in patients with previously treated multiple myeloma (MM) from the perspective of a private third-party payer and Medicare in the US.MethodsThe introduction of XVd as an option for patients with previously treated MM compared to no introduction of XVd was considered from a private third-party US payer (with 1,000,000 members) and a Medicare perspective in one-year increments for 3 years. Total annual treatment costs were calculated as the sum of drug costs, costs of treating serious treatment emergent adverse events (grade ≥3), ongoing best supportive care costs, and mortality costs.ResultsThe absolute budget impact (Millions, USD) of including XVd from a private third-party payer plan perspective was $0.06, $0.07, $0.08 and $0.22 for years 1, 2, 3, and overall, respectively. The relative budget impact of including XVd was 0.33%, 0.40%, 0.43%, and 0.38% for years 1, 2, 3, and overall, respectively. This translated to a per member per month (PMPM) budget impact of $0.005, $0.006, $0.007, and $0.006 (USD), for years 1, 2, 3, and overall, respectively. From a Medicare perspective, the absolute budget impact (Millions, USD) of including XVd was $29.68, $36.62, $39.42 and $105.72 for years 1, 2, 3, and overall, respectively. The relative budget impact of including XVd was 0.33%, 0.40%, 0.43%, and 0.38% percent for years 1, 2, 3, and overall, respectively. This translated to a PMPM budget impact of $0.041, $0.051, $0.054, and $0.049 (USD), for years 1, 2, 3, and overall, respectively. Sensitivity analyses showed general consistency with the base-case findings.ConclusionUnderstanding the potential budget impact of new therapies in MM is vital for payers to manage spending and assess treatment value. The introduction of XVd presents a manageable budget impact for a third-party US payer and Medicare.