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

Background: Pyruvate kinase (PK) deficiency is a rare, congenital, glycolytic enzyme defect that leads to chronic hemolytic anemia and other 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. Aims: Describe characteristics of patients (pts) with PK deficiency and history of FeO by age (pediatrics, <18 years [yrs]; adults, ≥18 yrs) enrolled in the Peak Registry (NCT03481738). Methods: The Peak Registry is a 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 (including FerriScan®) >3 mg Fe/g dry weight; or 5) cardiac T2* MRI ≤20 ms. Data collected at study enrollment were summarized descriptively among pts with a history of FeO. Results: As of 24Mar2020, 57/140 (40.7%) enrolled pts had a history of FeO (28 adult and 29 pediatric pts); data from these 57 pts were used for this analysis. PKLR genotype information was available for 21 adult and 15 pediatric pts; among 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 pediatric pts, 3 (20%) had M/M, 7 (46.7%) had M/NM, and 5 (33.3%) had NM/NM (Table). Among FeO pts with known transfusion status, 6/56 (10.7%) had never been transfused, 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, 8/24 (33.3%) pts had been regularly transfused and 16/24 (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. Additionally, 24/28 (85.7%) adult and 15/29 (51.7%) pediatric pts with FeO had a splenectomy, with median age (range) at splenectomy of 6.5 yrs (1–23) and 6.0 yrs (4–12), respectively. Chelation therapy had been utilized by 20/23 (87.0%) splenectomized adults and 2/4 (50.0%) non-splenectomized adults, while 15/15 (100%) splenectomized pediatric pts and 13/14 (92.9%) non-splenectomized pediatric pts had received chelation therapy. Image:Summary/Conclusion: FeO is a common complication affecting 41% of pts with PK deficiency in this cohort, regardless of age, genotype, transfusion status, or splenectomy status. 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. Evaluation and regular monitoring of FeO in all pts with PK deficiency should begin early in life and continue throughout adulthood.