Characterizing Iron Overload By Age in Patients Diagnosed with Pyruvate Kinase Deficiency - a Descriptive Analysis from the Peak Registry

Abstract Background: Pyruvate kinase (PK) deficiency is a rare, congenital, glycolytic enzyme defect that leads to chronic hemolytic anemia. Despite existing supportive therapies, many patients (pts) experience significant complications, including iron overload (FeO). FeO in PK deficiency is clinically underappreciated and may cause long-term organ damage and impact growth in children and adults. Objective: To describe characteristics and disease burden of pts with PK deficiency and a history of FeO by age group (pediatric cohort, <18 years [yrs]; adult cohort, ≥18 yrs) enrolled in the Peak Registry (NCT03481738). Methods: The Peak Registry is an ongoing, global retrospective and prospective observational study of adult and pediatric pts diagnosed with PK deficiency. For this analysis, pts were considered to have a history of FeO if they had ever received 1) chelation therapy; or 2) phlebotomy for removal of iron; or within 3 months of enrollment had 3) ferritin >1000 ng/mL; or 4) liver MRI >3 mg Fe/g dry weight; or 5) FerriScan® >3 mg Fe/g dry weight; or 6) cardiac T2* MRI ≤20 ms. Data on demographics, medical history, treatment, clinical assessment, and laboratory testing collected at study enrollment were summarized descriptively among pts with a history of FeO. Results: As of the 24Mar2020 data cut, 57/140 (40.7%) enrolled pts had a history of FeO (adult cohort N=28; pediatric cohort N=29); data from these 57 pts were used for this analysis. Average age at enrollment for adult and pediatric cohorts was 37.3 yrs (standard deviation [SD]: 14.80) and 7.7 yrs (SD: 4.64), respectively. PKLR genotype information was available for 21 adult and 15 pediatric pts; among the 21 adults, 13 (61.9%) had two missense mutations (M/M), 7 (33.3%) had one missense/one non-missense mutation (M/NM), and 1 (4.8%) had two non-missense mutations (NM/NM); among the 15 pediatric pts, 3 (20%) had M/M, 7 (46.7%) had M/NM, and 5 (33.3%) had NM/NM (Table). Among pts with known transfusion status, 6/56 FeO pts (10.7%) had never received a transfusion, with all other pts having received ≥1 prior transfusion (ever-transfused). Median hemoglobin (Hb) level at the time of enrollment was 8.6 g/dL (range: 6.7-12.5) in ever-transfused adults and 10.9 g/dL (9.3-11.3) in never-transfused adults. In pediatric pts (all ever-transfused), median Hb at enrollment was 8.3 g/dL (6.8-10.8). Most ever-transfused pts had received chelation therapy (18/20 [90.0%] adults, 28/29 [96.6%] pediatrics). Of the 6 pts who had never been transfused, 3 (50.0%) had received chelation therapy. Transfusion details for the 12 months prior to enrollment were available for 23 adults, of whom 5 (21.7%) had been regularly transfused (≥6 transfusions) and 18 (78.2%) had not been regularly transfused (0-5 transfusions); in the pediatric cohort (n=24), 8 (33.3%) pts had been regularly transfused and 16 (66.7%) had not. In the prior 12 months, regularly transfused adult and pediatric pts each received an average of about 10 transfusions whereas non-regularly transfused adult and pediatric pts received about 1 transfusion (Table). Additionally, 24/28 (85.7%) adult and 15/29 (51.7%) pediatric pts with FeO had a splenectomy, with median age at splenectomy of 6.5 yrs (range: 1-23 yrs) for the adult cohort and 6.0 yrs (4-12 yrs) for the pediatric cohort. Chelation therapy had been utilized by 20/23 (87.0%) splenectomized adults and 2/4 (50.0%) non-splenectomized adults, while 15/15 (100.0%) splenectomized pediatric pts and 13/14 (92.9%) non-splenectomized pediatric pts had received chelation therapy. Conclusion: These data indicate that FeO is a common complication affecting around 40% of PK deficient pts in this cohort, regardless of age, genotype, transfusion status, or severity. While a large proportion of these pts with PK deficiency and FeO have a high transfusion burden and/or have been splenectomized, FeO still occurs in both adult and pediatric pts without splenectomies, in pts who are not regularly transfused, and even in those who have never been transfused. This analysis supports the need for an initial evaluation and regular monitoring of FeO in all pts with PK deficiency, independent of transfusion status, splenectomy history, or genotype, starting early in life and continuing throughout adulthood. The longitudinal (up to 9 yrs) design of the Peak Registry will allow for continued monitoring and follow-up of FeO and related long-term complications in pts with PK deficiency. Figure 1 Figure 1. Disclosures Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grace: Novartis: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding. Glader: Agios: Consultancy. Glenthøj: Novo Nordisk: Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding. Kuo: Bluebird Bio: Consultancy; Pfizer: Consultancy, Research Funding; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy. Lander: Agios: Other: PK Deficiency Patient Advocacy Advisory Council - patient representative. Layton: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cerus: Membership on an entity's Board of Directors or advisory committees. Viprakasit: Agios: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Protagonist Therapeutics: Consultancy, Research Funding; Ionis Pharmaceuticals,: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding. Williams: Agios: Current Employment, Current holder of stock options in a privately-held company. Yan: Agios: Consultancy. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding.

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