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

Salek, Sam; Boscoe, Audra; Piantedosi, Sarah; Egan, Shawna; Evans, Christopher J.; Wells, Ted; Cohen, Jennifer; Klaassen, Robert J.; Grace, Rachael F.; Storm, Michael C.

doi:10.1111/ejh.13376

Cited by 9 publications

(8 citation statements)

References 25 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In patients with a congenital anemia, it may be difficult to assess fatigue or HRQoL except in the setting of a therapeutic intervention, such as pre/postsplenectomy, pre/posttransfusion, or pre/post a novel therapeutic. HRQoL instruments specific to the symptoms and impact of PKD have recently been developed 25 and are being validated in phase 3 clinical trials of a novel therapy. If these new instruments perform well, they may be optimal for future studies evaluating HRQoL in PKD.…”

Section: Discussionmentioning

confidence: 99%

Health-related quality of life and fatigue in children and adults with pyruvate kinase deficiency

et al. 2022

Self Cite

View full text Add to dashboard Cite

Pyruvate kinase deficiency (PKD) is the most common cause of congenital non-spherocytic hemolytic anemia. Although recognition of the disease spectrum has recently expanded, data describing its impact on health-related quality of life (HRQoL) are limited. In this prospective international cohort of 254 patients (131 adults and 123 children) with PKD, we assessed the disease impact on HRQoL (EuroQL-5D, PedsQL, FACT-An) and fatigue (PROMIS Fatigue, PedsFACIT-F) using validated measures. Significant variability in HRQoL and fatigue was reported for both adults and children although individual scores were stable over a 2-year interval. While adults who were regularly transfused reported worse HRQoL and fatigue compared to those who were not regularly transfused (EQ-VAS 58 vs. 80, p=0.01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. Both HRQoL and fatigue significantly differed in children by genotype with the worst scores in those with two severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in both children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. In PKD-specific symptom assessment, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. While current treatments for PK deficiency are limited to supportive care, new therapies are currently in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. (Clinicaltrials.gov number NCT02053480)

show abstract

Section: Discussionmentioning

confidence: 99%

Health-related quality of life and fatigue in children and adults with pyruvate kinase deficiency

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, the same Authors proposed two disease-specific PRO measures in 2020. 53 Twenty-one PKD patients underwent concept elicitation and then cognitive interviews to develop the PK deficiency daily diary (PKDD) and the PK deficiency-specific impact assessment (PKDIA) survey. The first is a 7-item tool that measure main PK signs and symptoms, whilst the latter is a 14-item measure of PKD impact on patients’ HR-QoL.…”

Section: Qol Evaluation In Pkdmentioning

confidence: 99%

Pyruvate Kinase Deficiency: Current Challenges and Future Prospects

Fattizzo¹,

Cavallaro²,

Marcello³

et al. 2022

JBM

View full text Add to dashboard Cite

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disease marked by chronic hemolytic anemia of various severity and frequent complications including gallstones, splenomegaly, iron overload, and others. Disease phenotype is highly heterogeneous and changes over time with children, adolescents and adult patients displaying different transfusion requirement and rates of complications. The diagnosis relies on the initial clinical suspicion in a patient with chronic hemolysis and exclusion of other more common congenital forms of hemolytic anemias; it is supported by the demonstration of reduced PK enzyme activity, and further confirmed by the detection of (homozygous or compound heterozygous) mutations of PKLR gene. Therapy is mainly supportive, with vitamin supplementation and transfusions (based on symptoms and patient growth rather than on fixed Hb thresholds). Splenectomy is widely performed, although it is less effective than in membrane defects and carries thrombotic and infectious risk. In the last decade, the allosteric PK enzyme activator mitapivat showed dramatic clinical benefit in clinical trials and gene therapy is also being studied to substitute the defective enzyme. In this review, we provide an insight in the current challenges of PKD diagnosis and management and discuss the future application of novel drugs and gene therapy, including a focus on quality of life.

show abstract

“…Secondary endpoints included the average change from baseline in hemoglobin, reticulocytes, and markers of hemolysis (bilirubin, lactate dehydrogenase, and haptoglobin) at weeks 16, 20, and 24, as well as the change from baseline to week 24 in two PKD-specific health-related quality-of-life patient-reported outcome (PRO) measures, the pyruvate kinase deficiency diary (PKDD), and the pyruvate kinase deficiency impact assessment (PKDIA). These two PRO measures are novel instruments developed specifically to assess health-related quality of life in PKD, 34 and they underwent internal validation in the ACTIVATE trial.…”

Section: Clinical Trials Of Mitapivat In Pkdmentioning

confidence: 99%

“…Preliminary results of the ongoing phase II ESTIMATE study have also been published in abstract form. 34 This open-label study is enrolling patients with sickle cell disease aged 16 years or older. Data on six enrolled subjects have been published, demonstrating no serious adverse events and overall comparable results thus far to the aforementioned phase I study.…”

Section: Clinical Trials Of Mitapivat In Thalassemia and Sickle Cell Diseasementioning

confidence: 99%

Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias

Al‐Samkari

Beers

2021

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Mitapivat (AG-348) is a novel, first-in-class oral small molecule allosteric activator of the pyruvate kinase enzyme. Mitapivat has been shown to significantly upregulate both wild-type and numerous mutant forms of erythrocyte pyruvate kinase (PKR), increasing adenosine triphosphate (ATP) production and reducing levels of 2,3-diphosphoglycerate. Given this mechanism, mitapivat has been evaluated in clinical trials in a wide range of hereditary hemolytic anemias, including pyruvate kinase deficiency (PKD), sickle cell disease, and the thalassemias. The clinical development of mitapivat in adults with PKD is nearly complete, with the completion of two successful phase III clinical trials demonstrating its safety and efficacy. Given these findings, mitapivat has the potential to be the first approved therapeutic for PKD. Mitapivat has additionally been evaluated in a phase II trial of patients with alpha- and beta-thalassemia and a phase I trial of patients with sickle cell disease, with findings suggesting safety and efficacy in these more common hereditary anemias. Following these successful early-phase trials, two phase III trials of mitapivat in thalassemia and a phase II/III trial of mitapivat in sickle cell disease are beginning worldwide. Promising preclinical studies have additionally been done evaluating mitapivat in hereditary spherocytosis, suggesting potential efficacy in erythrocyte membranopathies as well. With convenient oral dosing and a safety profile comparable with placebo in adults with PKD, mitapivat is a promising new therapeutic for several hereditary hemolytic anemias, including those without any currently US Food and Drug Administration (FDA) or European Medicines Agency (EMA)–approved drug therapies. This review discusses the preclinical studies, pharmacology, and clinical trials of mitapivat.

show abstract

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

Cited by 9 publications

References 25 publications

Health-related quality of life and fatigue in children and adults with pyruvate kinase deficiency

Health-related quality of life and fatigue in children and adults with pyruvate kinase deficiency

Pyruvate Kinase Deficiency: Current Challenges and Future Prospects

Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias

Contact Info

Product

Resources

About