Comorbidities and complications in adults with pyruvate kinase deficiency.

OBJECTIVES: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified. METHODS: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency. RESULTS: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort. CONCLUSIONS: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.

Prevalence of pyruvate kinase deficiency: A systematic literature review.

OBJECTIVES: Pyruvate kinase deficiency (PK deficiency) is a rare disorder caused by compound heterozygosity or homozygosity for > 300 mutations in the PKLR gene. To understand PK deficiency prevalence, we conducted a systematic literature review. METHODS: We queried Embase and Medline for peer-reviewed references reporting PK deficiency prevalence/incidence, PKLR mutant allele frequency (MAF) among the general population, or crude results from which these metrics could be derived. RESULTS: Of 1390 references screened, 1296 were excluded after title/abstract review; 60 were excluded after full-text review. Four of the remaining 34 studies were considered high-quality for estimating PK deficiency prevalence. Two high-quality studies identified cases from source populations of known sizes, producing estimates of diagnosed PK deficiency prevalence of 3.2 and 8.5 per million. Another high-quality study derived an estimate of diagnosed PK deficiency prevalence of 6.5 per million by screening jaundiced newborns. The final high-quality study estimated total diagnosed and undiagnosed PK deficiency prevalence to be 51 per million through extrapolation from observed MAFs. CONCLUSIONS: We conclude that prevalence of clinically diagnosed PK deficiency is likely between 3.2 and 8.5 per million in Western populations, while the prevalence of diagnosed and undiagnosed PK deficiency could possibly be as high as 51 per million.

Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: Disease-specific assessments.

INTRODUCTION: Currently recommended patient-reported outcome (PRO) measures for patients with pyruvate kinase (PK) deficiency are non-disease-specific. The PK Deficiency Diary (PKDD) and PK Deficiency Impact Assessment (PKDIA) were developed to be more targeted measures for capturing the symptoms and impacts of interest to this patient population. METHODS: The instruments were developed based on concept elicitation interviews with 21 adults and modified based on 20 cognitive interviews. The domain structure and item concepts of the PKDD and PKDIA were compared with currently recommended measures, the EORTC QLQ-C30 and the SF-36v2®. RESULTS: The PKDD is a seven-item measure of the core signs and symptoms of PK deficiency. The PKDIA is a 14-item measure of the impacts of PK deficiency on patients' health-related quality of life (HRQoL). Minimal similarities were found between the new measures and the EORTC QLQ-C30 (eg, 43% of concepts were similar to the PKDD; 42% were similar to the PKDIA) and SF-36v2® (57% of concepts were similar to the PKDD; 17% were similar to the PKDIA). CONCLUSIONS: The PKDD and PKDIA fill a gap in the existing outcomes measurement strategy for PK deficiency. Future work includes psychometric evaluation of these newly developed measures.

Understanding side effects of therapy for myasthenia gravis and their impact on daily life.

BACKGROUND: Myasthenia gravis is a chronic, autoimmune, neuromuscular junction disorder characterized by skeletal muscle weakness. Current therapies for myasthenia gravis are associated with significant side effects. The objective of this study was to characterize the side effects, and associated health-related quality of life and treatment impacts, of traditional myasthenia gravis treatments. METHODS: This study had two phases; a Phase 1 interview and a 2-part web-based survey in Phase 2 that included brainstorming (Step 1) and rating (Step 2) exercises using group concept mapping. In Phase 1, all 14 participants reported experiencing side effects from myasthenia gravis treatments which had significant impacts on daily life. In Phase 2, 246 participants contributed to Step 1; 158 returned for Step 2. RESULTS: The brainstorming exercise produced 874 statements about side effects and their impact, which were reduced to 35 side effects and 23 impact-on-daily life statements. When rating these statements on severity, frequency, and tolerability, blood clots, infections/decreased immunity, weight gain, and diarrhea were the least tolerable and most severely rated. The most frequent and severe impacts were sleep interference and reduced physical and social activities. CONCLUSIONS: Based on these findings, there appears to be a need for better and more tolerable treatments for myasthenia gravis patients.

Mortality among US veterans with a physician-documented diagnosis of pyruvate kinase deficiency.

Real-world studies of pyruvate kinase (PK) deficiency and estimates of mortality are lacking. This retrospective observational study aimed to identify patients with PK deficiency and compare their overall survival (OS) to that of a matched cohort without PK deficiency. Patients with ≥1 diagnosis code related to PK deficiency were selected from the US Veterans Health Administration (VHA) database (01/1995-07/2019); patients with a physician-documented diagnosis were included (PK deficiency cohort; index: date of first diagnosis code related to PK deficiency). Patients in the PK deficiency cohort were matched 1:5 to patients from the general VHA population (non-PK deficiency cohort; index: random visit date during match's index year). OS from index was compared between the two cohorts. Eighteen patients in the PK deficiency cohort were matched to 90 individuals in the non-PK deficiency cohort (both cohorts: mean age 57 years, 94% males; median follow-up 6.0 and 8.0 years, respectively). At follow-up, patients in the non-PK deficiency cohort had significantly longer OS than the PK deficiency cohort (median OS: 17.1 vs. 10.9 years; hazard ratio: 2.3; p = 0.0306). During their first-year post-index, 75% and 40% of the PK deficiency cohort had laboratory-confirmed anemia and iron overload, respectively. Among patients who died, cause of death was highly heterogeneous. These results highlight the increased risk of mortality and substantial clinical burden among patients with PK deficiency. While the intrinsic characteristics of the VHA database may limit the generalizability of the results, this is the first real-world study to characterize mortality in patients with PK deficiency.

Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry: rationale and study design.

INTRODUCTION: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry. METHODS AND ANALYSIS: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations. ETHICS AND DISSEMINATION: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications. TRIAL REGISTRATION NUMBER: NCT03481738.

Burden of illness for patients with cholangiocarcinoma in the United States: a retrospective claims analysis.

BACKGROUND: Advanced cholangiocarcinoma (CCA) is associated with considerable morbidity and mortality. Novel second-line treatments for advanced CCA underscore the need to understand treatment patterns and economic burden of illness in clinical practice. METHODS: This retrospective, claims-based study using Optum's de-identified Clinformatics® Data Mart Database [2007-2019] selected patients with CCA who experienced failure of a line of therapy containing either gemcitabine or fluorouracil. The index date was defined based on evidence of treatment failure: date of last administration of the gemcitabine- or fluorouracil-based regimen plus 28 days, or initiation date of the next-line systemic therapy. Treatment patterns, healthcare resource use (HRU), costs, and survival were assessed during the follow-up period (index until death or end of eligibility). RESULTS: A total of 1,298 patients met inclusion criteria and had a mean age of 69.1 years. There were 958 patients (73.8%) with intrahepatic and 275 patients (21.2%) with extrahepatic CCA. Average follow-up was 7.5 months. Almost 40% of patients did not receive another line of therapy after the index date. Among the 784 patients who received another line of therapy, 40.3% used fluorouracil-based therapy, 30.7% used gemcitabine-based therapy, and 29.3% used capecitabine-based therapy. Total mean per patient per month CCA-related healthcare costs were $7,743, with medical services ($6,685) a larger driver of monthly costs relative to treatment costs ($1,058). Median overall survival (OS) was 5.3 months among all patients. CONCLUSIONS: Many patients with advanced CCA do not initiate additional therapy after failure of gemcitabine or fluorouracil treatment, and there is considerable variation in treatments among those who do. This study highlights the high costs and unmet need for a standard of care in this patient population.

Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review.

BACKGROUND: The recognition of distinct molecular subgroups within cholangiocarcinoma (CC), along with the increasing availability of targeted therapies, suggests that further characterization of the prevalence and prognosis of frequently occurring subgroups may assist with the development of more effective treatment approaches for the management of CC. A systematic review was performed to investigate the prevalence of isocitrate dehydrogenase 1 (IDH1) mutations (mIDH1) in patients with CC, the possible clinical and prognostic significance of mIDH1, and the presence of co-mutations in tumors with mIDH1. METHODS: This review was conducted using the Cochrane dual-reviewer methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol (PRISMA-P) guidelines. Searches were performed in Embase, MEDLINE, the Cochrane Central Trials Register and Database of Systematic Reviews, and other Cochrane Library assets using terms for CC and mIDH1 with no language or date restrictions for articles published up to December 31, 2017. Searches were also performed of abstracts presented at the following conferences in 2016 and 2017: American Society of Clinical Oncology (ASCO), ASCO-Gastrointestinal Cancers Symposium (ASCO-GI), the European Society for Medical Oncology (ESMO), and ESMO-Asia. Screening was performed separately by two reviewers and cross-checked. Any discrepancies between reviewers were resolved by a senior researcher. Data from all selected references were recorded in a data extraction grid. RESULTS: A total of 46 publications met the inclusion criteria and were included in the systematic review. Of these publications, 45 reported the frequency of mIDH1 among a total sample of 5,393 patients with CC. mIDH1 was enriched in intrahepatic CC (ICC), with 552 (13.1%; 95% CI, 12.1-14.2) of the 4,214 patients with ICC having the mutation compared with 9 (0.8%; 95% CI, 0.4-1.5%) of the 1,123 patients with extrahepatic CC (ECC). The percentage of females with mIDH1 CC (66.2%; 95% CI, 57.7-73.7%) was higher than in the overall CC population (44.4%). The frequency of mIDH1 in patients with ICC reported in individual studies ranged from 4.5-55.6%, and a significantly higher frequency was reported in non-Asian centers compared with Asian centers (weighted mean, 16.5% vs. 8.8%; P<0.001). The prevalence of mIDH1 in patients with ICC at USA centers was 18.0% (95% CI, 16.4-19.8%). Eleven publications reported the prevalence of co-mutations in patients with mIDH1 ICC, with the most frequent being AT-rich interactive domain-containing protein 1A (ARID1A) (22.0%), BRCA1-associated protein 1 (BAP1) (15.5%), and PBRM1 (13.3%). Eight publications investigated the possible prognostic significance of mIDH1. None of the studies reported a statistically significant association between mIDH1 and overall survival (OS), progression-free survival (PFS), or time to progression. CONCLUSIONS: This systematic review substantiates the prevalence of mIDH1 in CC and further characterizes clinical, pathologic, and genetic covariates within this sub-population. Co-mutation data may inform future studies of mechanisms of response and resistance to mIDH1-targeted therapies.

Impact of Refractory Myasthenia Gravis on Health-Related Quality of Life.

OBJECTIVES: Myasthenia gravis (MG) may be refractory to traditional therapies. Quality of life (QOL) and disease burden in patients with refractory and nonrefractory MG were compared using Myasthenia Gravis Foundation of America MG Patient Registry data. METHODS: Adults aged 18 years or older with MG diagnosed ≥2 years before enrollment were included. Participants with refractory MG had received ≥2 previous and 1 current MG treatment and had MG Activities of Daily Living Scale total score ≥6 at enrollment; other participants had nonrefractory MG. MG QOL 15-item scale (MG-QOL15) scores were compared. RESULTS: In total, 56 participants with refractory and 717 participants with nonrefractory MG enrolled. Participants with refractory MG had significantly higher mean (SD) MG-QOL15 total scores [31.4 (11.1) vs. 20.8 (15.0), P < 0.0001] and were more likely to have had exacerbations, emergency department visits, and recent hospitalizations. CONCLUSIONS: Participants with refractory MG experience worse QOL and greater clinical burden than those with nonrefractory disease.

Understanding Drivers of Employment Changes in a Multiple Sclerosis Population.

BACKGROUND: Qualitative data are lacking on decision making and factors surrounding changes in employment for patients with multiple sclerosis (MS). This study aimed to increase our understanding of the key symptoms and factors leading patients with MS to leave work or reduce employment. METHODS: Adults with MS who reported leaving the workforce, reducing work hours, or changing jobs due to MS in the past 6 months were recruited from four US clinical sites. Patients participated in semistructured interviews to discuss MS symptoms and reasons for changing employment status. All interviews were transcribed and coded for descriptive analyses. RESULTS: Twenty-seven adults (mean age = 46.3 years, mean duration of MS diagnosis = 10.9 years) with a range of occupations participated; most were white (81.5%) and female (70.4%). Physical symptoms (eg, fatigue, visual deficits) (77.8%) were the most common reasons for employment change; 40.7% of patients reported at least one cognitive symptom (eg, memory loss). Fatigue emerged as the most pervasive symptom and affected physical and mental aspects of patients' jobs. Most patients (85.2%) reported at least two symptoms as drivers for change. Some patients reported a significant negative impact of loss of employment on their mental status, family life, and financial stability. CONCLUSIONS: Fatigue was the most common symptom associated with the decision to leave work or reduce employment and can lead to a worsening of other MS symptoms. Comprehensive symptom management, especially fatigue management, may help patients preserve their employment status.

Cardiometabolic risk and health care utilization and cost for Hispanic and non-Hispanic women.

Cardiometabolic risk (CMR) is a specific set of risk factors that are associated with an increased chance of developing diabetes and cardiovascular disease. We conducted a retrospective study of female members of a health maintenance organization in the southwestern United States to: determine the prevalence of CMR for 4 different groupings of CMR factors, identify differences between Hispanics and non-Hispanics, and quantify differences in 2-year health care utilization and costs of CMR. Subjects were females who had bone mineral density tests during 2003-2004, and thus a measure of height and weight, allowing body mass index (BMI) calculation (n = 2578; 27.6% Hispanic). Risk factors used to define CMR groupings were: obesity (BMI), triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and fasting glucose. Results showed that Hispanics had higher prevalence rates than non-Hispanics (65.8% versus 52.3%, respectively; P < 0.0001). Adjusting for age and ethnicity, total costs for CMR patients in the groupings that required the presence of diabetes were twice the costs of those without CMR (approximately $11,500 versus $5500, respectively; P < 0.0001). In all other groupings, costs for patients with and without CMR were approximately $7000 versus $5500, respectively (P < 0.0001). Non-Hispanics had significantly higher visit costs than Hispanics. There were no differences in pharmacy costs. Higher utilization and costs associated with CMR suggest the need to identify and monitor patients with CMR. Our findings suggest diabetes prevention could yield substantial cost savings. Higher costs for non-Hispanics, despite higher prevalence among Hispanics, may indicate underutilization of health care resources by Hispanics. Future research in CMR should explore ethnic differences in access to care and disease management programs.

Association of cardiometabolic risk factors and prevalent cardiovascular events.

BACKGROUND: Although cardiovascular disease causes substantial morbidity and mortality, how individual and groups of risk factors contribute to cardiovascular outcomes is incompletely understood. This study evaluated cardiometabolic risk factors and their relationship to prevalent diagnosis of acute myocardial infarction (AMI) and stroke. METHODS: We used retrospective data from 3 integrated health-care systems that systematically collect and store detailed patient-level data. Adult enrollees were eligible for inclusion if they had all of the following clinical measurements: weight, height, blood pressure, high density lipoproteins, triglycerides, and fasting blood glucose or evidence of diabetes from July 1, 2003, to June 30, 2005. We used National Cholesterol Education Program Adult Treatment Panel III guidelines to determine qualifying levels for cardiometabolic risk factors. RESULTS: A total of 170,648 persons met the inclusion/exclusion criteria; 11,757 had no qualifying risk factors, 25,684 had 1, 38,176 had 2, and 95,031 had 3 or more risk factors. Compared to those without risk factors, persons with any 1 risk factor were 2.21 (95% confidence interval [CI], 1.78-2.74) times more likely to have had a diagnosis of AMI or stroke. The risk increased to 2.79 (95% CI, 2.26-3.42) for persons with 2, 3.45 (95% CI, 2.80-4.24) for persons with 3, 4.35 (95% CI, 3.54-5.35) for persons with 4, and 5.73 (95% CI, 4.65-7.07) for persons with 5 risk factors. The highest risk was conferred by having the combination of risk factors of diabetes, hypertension, and dyslipidemia, with or without weight risk. CONCLUSIONS: This study demonstrates a direct association between an increasing number of cardiometabolic risk factors and prevalent diagnosis of AMI and stroke. The combination of risk factors conferring the highest risk was diabetes, hypertension, and dyslipidemia.