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

Hanny Al-Samkari, Eduard J van Beers, D Holmes Morton, Stefan W Eber, Satheesh Chonat, Kevin H M Kuo, Nina Kollmar, Heng Wang, Vicky R Breakey, Sujit Sheth, Mukta Sharma, Peter W Forbes, Robert J Klaassen, Rachael F Grace, Hanny Al-Samkari, Eduard J van Beers, D Holmes Morton, Stefan W Eber, Satheesh Chonat, Kevin H M Kuo, Nina Kollmar, Heng Wang, Vicky R Breakey, Sujit Sheth, Mukta Sharma, Peter W Forbes, Robert J Klaassen, Rachael F Grace

Abstract

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic 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 used validated measures to assess the impact of disease on HRQoL (EuroQol 5-Dimension Questionnaire, Pediatric Quality of Life Inventory Generic Core Scale version 4.0, and Functional Assessment of Cancer Therapy-Anemia) and fatigue (Patient Reported Outcomes Measurement Information System Fatigue and Pediatric Functional Assessment of Chronic Illness Therapy-Fatigue). Significant variability in HRQoL and fatigue was reported for adults and children, although individual scores were stable over a 2-year interval. Although adults who were regularly transfused reported worse HRQoL and fatigue compared with those who were not (EuroQol-visual analog scale, 58 vs 80; P = .01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. HRQoL and fatigue significantly differed in children by genotype, with the worst scores in those with 2 severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. Additionally, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. Although current treatments for PKD are limited to supportive care, new therapies are in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
HRQoL as assessed by FACT-An in adults with PKD, by specific relevant subgroupings. Median hemoglobin (A), transfusion status (B), iron overload status (C), splenectomy status (D), and genotype (E). Higher FACT-An scores indicate higher HRQoL. The R479H/R479H genotype is primarily found in the Amish community. M/M, missense/missense; M/NM, missense/nonmissense; NM/NM, nonmissense/nonmissense.
Figure 2.
Figure 2.
Fatigue as assessed by Peds-FACIT-F in children with PKD, by specific relevant subgroupings. Including median hemoglobin (A), transfusion status (B), iron overload status (C), splenectomy status (D), and genotype (E). Higher Peds-FACIT-F scores indicate less fatigue. M/M, missense/missense; M/NM, missense/nonmissense; NM/NM, nonmissense/nonmissense.

References

    1. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. 2000;95(11):3585-3588.
    1. Carey PJ, Chandler J, Hendrick A, et al. ; Northern Region Haematologists Group . Prevalence of pyruvate kinase deficiency in northern European population in the north of England. Blood. 2000;96(12):4005-4006.
    1. Grace RF, Glader B. Red blood cell enzyme disorders. Pediatr Clin North Am. 2018;65(3):579-595.
    1. Grace RF, Zanella A, Neufeld EJ, et al. . Erythrocyte pyruvate kinase deficiency: 2015 status report. Am J Hematol. 2015;90(9):825-830.
    1. Grace RF, Bianchi P, van Beers EJ, et al. . Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Blood. 2018;131(20):2183-2192.
    1. Al-Samkari H, Van Beers EJ, Kuo KHM, et al. . The variable manifestations of disease in pyruvate kinase deficiency and their management. Haematologica. 2020;105(9):2229-2239.
    1. Rider NL, Strauss KA, Brown K, et al. . Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management. Am J Hematol. 2011;86(10):827-834.
    1. Pissard S, Max-Audit I, Skopinski L, et al. . Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. Br J Haematol. 2006;133(6):683-689.
    1. Zanella A, Fermo E, Bianchi P, Valentini G. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. 2005;130(1):11-25.
    1. Grace RF, Cohen J, Egan S, et al. . The burden of disease in pyruvate kinase deficiency: patients’ perception of the impact on health-related quality of life. Eur J Haematol. 2018;101(6):758-765.
    1. Singh SA, Bakshi N, Mahajan P, Morris CR. What is the future of patient-reported outcomes in sickle-cell disease? Expert Rev Hematol. 2020;13(11):1165-1173.
    1. Cappellini MD, Kattamis A, Viprakasit V, et al. . Quality of life in patients with β-thalassemia: a prospective study of transfusion-dependent and non-transfusion-dependent patients in Greece, Italy, Lebanon, and Thailand. Am J Hematol. 2019;94(10):E261-E264.
    1. Grace RF, Rose C, Layton DM, et al. . Safety and efficacy of mitapivat in pyruvate kinase deficiency. N Engl J Med. 2019;381(10):933-944.
    1. Garcia-Gomez M, Calabria A, Garcia-Bravo M, et al. . Safe and efficient gene therapy for pyruvate kinase deficiency. Mol Ther. 2016;24(7):1187-1198.
    1. Al-Samkari H, van Beers EJ, Morton DH, et al. . Characterization of the severe phenotype of pyruvate kinase deficiency [published online ahead of print 3 Jul 2020]. Am J Hematol.
    1. Al-Samkari H, Addonizio K, Glader B, et al. . The pyruvate kinase (PK) to hexokinase enzyme activity ratio and erythrocyte PK protein level in the diagnosis and phenotype of PK deficiency. Br J Haematol. 2021;192(6):1092-1096.
    1. Bunn HF, Briehl RW. The interaction of 2,3-diphosphoglycerate with various human hemoglobins. J Clin Invest. 1970;49(6):1088-1095.
    1. Lakomek M, Winkler H, Pekrun A, et al. . Erythrocyte pyruvate kinase deficiency. The influence of physiologically important metabolites on the function of normal and defective enzymes. Enzyme Protein. 1994-1995;48(3):149-163.
    1. Strømnes LA, Ree H, Gjesdal K, Ariansen I. Sex differences in quality of life in patients with atrial fibrillation: a systematic review. J Am Heart Assoc. 2019;8(8):e010992.
    1. van Wijk CM, Kolk AM. Sex differences in physical symptoms: the contribution of symptom perception theory. Soc Sci Med. 1997;45(2):231-246.
    1. Williams JB, Spitzer RL, Linzer M, et al. . Gender differences in depression in primary care. Am J Obstet Gynecol. 1995;173(2):654-659.
    1. Stordal E, Bjartveit Krüger M, Dahl NH, Krüger Ø, Mykletun A, Dahl AA. Depression in relation to age and gender in the general population: the Nord-Trøndelag Health Study (HUNT). Acta Psychiatr Scand. 2001;104(3):210-216.
    1. Bianchi P, Fermo E, Lezon-Geyda K, et al. . Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency. Am J Hematol. 2020;95(5):472-482.
    1. Salek MS, Ionova T, Johns JR, Oliva EN. Appraisal of patient-reported outcome measures in analogous diseases and recommendations for use in phase II and III clinical trials of pyruvate kinase deficiency. Qual Life Res. 2019;28(2):399-410.
    1. Salek S, Boscoe AN, Piantedosi S, et al. . Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: disease-specific assessments. Eur J Haematol. 2020;104(5):427-434.

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