Age of Onset of Complications in Patients with Pyruvate Kinase Deficiency: Analysis from the Peak Registry

Background: Pyruvate kinase (PK) deficiency is a rare, hereditary anemia. Chronic hemolysis is the primary consequence of PK deficiency, which leads to a spectrum of complications. Patients (pts) may develop certain complications at an early age, due to the disease or side effects of supportive treatments, and they may have greater prevalence of complications at an earlier or later age than experienced by the general population.

Aim: To describe the age of onset of select comorbidities and complications in pts with PK deficiency enrolled in the Peak Registry (NCT03481738) and the age distribution of pts at enrollment with ongoing jaundice.

Methods: The Peak Registry is an ongoing, global, retrospective, and prospective observational study of pts with a diagnosis of PK deficiency. This analysis included pts with available age data as of 01Dec2021. Data on demographics, laboratory values, and medical history, inclusive of comorbidities and complications and their onset dates, were summarized descriptively for all pts. Data on comorbidities and complications represented the lifetime history (from birth through most recent registry follow-up visit), except for iron overload, which was evaluated up to registry enrollment only. Continuous variables were summarized using number of known values, mean, SD, median, and range. Categorical variables were summarized by number and percentage of pts within a category, using the number of pts with known data as the denominator.

Results: A total of 218 pts (101 pediatric, <18 years [yrs]; 117 adults, ≥18 yrs) with available age data were included. The median (range) age at enrollment was 19 yrs (0-77). Of the 211 pts with available splenectomy data, 44.5% (94/211) had been splenectomized prior to or at enrollment, at a median (range) age of 7 yrs (2-28). In addition, 44.6% (90/202) had received chelation therapy prior to enrollment. Approximately one-quarter (25.6%) of 207 pts with available transfusion history information had never received a transfusion in their lifetime. Of the pts with available transfusion frequency data in the 12 months prior to enrollment, 18.0% (33/183) of pts were regularly transfused (≥6 transfusions) and 82.0% (150/183) were non-regularly transfused (0-5 transfusions).

The most common comorbidities in the cohort included iron overload (48.6%), mental health issues (14.2%), cholecystitis (14.1%), liver disease (10.2%), osteopenia (5.5%)/osteoporosis (2.5%), deep vein thrombosis (5.3%), and pulmonary hypertension (4.6%) (Table). For the 85 pts who had experienced iron overload and had available onset age, iron overload often occurred at an early age (65.9% were at <12 yrs), with a median (range) age of 5 yrs (0-68). However, many pts also had onset of iron overload in adulthood (14.1% were 18-<40 yrs and 11.8% were 40-<65 yrs at onset). In pts who were regularly transfused in the 12 months prior to enrollment (n=33), onset of iron overload was experienced by 75.8% of pts (median [range] age of onset: 3 yrs [1-45]). For pts who were non-regularly transfused in the 12 months prior to enrollment (n=51), onset of iron overload was experienced by 42.2% of pts (median [range] age of onset: 6 yrs [1-68]). The median (range) age of onset for other comorbidities was 27 yrs (9-74) for mental health issues, 15 yrs (3-58) for cholecystitis, 1 yr (0-57) for liver disease, 35 yrs (9-76) for osteopenia, 33 yrs (9-64) for osteoporosis, 35 yrs (29-66) for deep vein thrombosis, and 8 yrs (0-77) for pulmonary hypertension.

Of 67 pts with jaundice and known onset age, median (range) age at onset was 0 yrs (0-54). Forty-six of these pts had ongoing jaundice as of enrollment, 41.3% of whom were aged 18-<40 yrs. The overall median (range) age for these 46 pts was 16 yrs (0-50).

Conclusions: This analysis shows that pts with PK deficiency developed a wide range of comorbidities/complications throughout their life, many of which occurred at an early age. Iron overload, osteopenia/osteoporosis, liver disease, and cholecystitis tended to be observed at younger ages than would be expected in the general population. These findings indicate that the disease burden associated with PK deficiency starts early in life. Clinicians, including pediatric specialists, should be aware of these risks and of the importance of early, regular monitoring for complications in these pts, which could lead to improvements in prevention and outcomes.

Glenthøj:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Saniona: Research Funding; Pharmacosmos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: 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; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Grace:Novartis: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy; Agios Pharmaceuticals: Consultancy, Research Funding. van Beers:Sobi: Research Funding; Sanofi: Consultancy; RR Mechatronics: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Consultancy. Glader:Agios: Consultancy. Kuo:bluebird bio: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Celgene/BMS: Consultancy; Novartis: Consultancy, Honoraria; Bioverativ/Sanofi/Sangamo: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lander:Agios Pharmaceuticals, Inc.: Other: PK Deficiency Patient Advocacy Advisory Council patient representative. Williams:Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yan:Agios Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. McGee:Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Bianchi:Agios Pharmaceuticals, Inc.: Other: Scientific advisor.