Disease monitoring and management among pediatric patients with pyruvate kinase deficiency: Real-world practices from pyruvate kinase deficiency registries prior to 2024 international expert guidelines

Abstract Introduction: Pyruvate kinase (PK) deficiency is a rare, genetic disease that leads to chronic hemolytic anemia and potentially life-limiting complications. To facilitate best management and improve patient outcomes, international expert guidelines for the diagnosis and management of PK deficiency were published in 2024 (Al-Samkari). Aims: To characterize the disease monitoring and management practices among pediatric patients with PK deficiency and compare the findings to the 2024 guideline recommendations. Methods: This study was a retrospective analysis of real-world data for pediatric patients (aged 1–17 years at the last documented visit [index date]) from the observational PK Deficiency Natural History Study (NHS; NCT02053480; 2014–2019) and the Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry (NCT03481738; 2018–ongoing). Data from the two registries were merged where possible and summarized descriptively for patients overall and by transfusion status in the year prior to the index: not regularly transfused (NRT; <6 transfusions) and regularly transfused (RT; ≥6 transfusions). Results are specific to documentation of clinical monitoring and disease management activities documented during registry participation; patients were required to have at least 1 year of retrospective data to ensure adequate time for monitoring to occur. Data were compared with the 2024 guidelines for the monitoring and management of pediatric patients, including recommendations concerning iron overload (IO), chelation, vitamin D and bone health, endocrine function, and splenectomy. Results: As of May 2023 (data cut-off), 140 pediatric patients were included (NRT, n=107; RT, n=33). At the index date, the median age of patients was 8.5 years (range 1–17), 47.9% were female, 82.4% were White, and PKLR genotype distribution was 53.3% missense/missense, 31.4% missense/non-missense, and 15.3% non-missense/non-missense. Patients who were NRT averaged less than one transfusion in the year prior to the index date (mean 0.9; standard deviation [SD] 1.5); 61.4% had a history of IO. In contrast, patients who were RT received an average of 10.2 transfusions (SD: 3.5); 90.6% had a history of IO. At the index date, patients who were NRT were older than patients who were RT (median age 10 and 5 years, respectively), and this cohort had a higher rate of splenectomy (NRT: 43.3%; RT: 27.3%). The data obtained during the registry did not allow for assessment of all practice monitoring or management recommendations. However, analysis showed that all patients who were RT (33/33) received ferritin monitoring in alignment with the recommendation to screen for IO in patients ≥3 years of age or after 12 transfusions, whichever occurs first. In contrast, not all patients who were NRT aged ≥3 years received ferritin monitoring (mean percentage for ages 3 to <6, 83%; for 6 to <12, 85%; for 12 to <18 years, 77%). Annual liver T2* MRI is recommended in all patients receiving chelation therapy, but only 31.6% (12/38) of those patients with ongoing chelation received liver T2* MRI monitoring. One-third (31.6%; 6/19) of patients who were RT and 52.6% (10/19) of patients who were NRT had a cardiac T2* MRI whilst on chelation therapy. Annual vitamin D monitoring is recommended from age 1 for those not on regular supplementation; monitoring occurred in 24.7% of patients (20/81; Peak registry data only), and 27.2% of patients received vitamin D supplementation (22/81; Peak registry data only). Guidelines advise endocrine monitoring for all patients who are RT and non-transfused patients with IO: 36.8% (7/19) of patients who were RT and 51.9% (14/27) of patients who were NRT with IO received such monitoring (NHS registry data only; thyroid hormone and sex hormones measured). Conclusions: Our review of the real-world practices reported in the NHS and Peak Registry prior to the publication of the 2024 guidelines in PK deficiency identified notable areas for improvement in patient management including monitoring of bone health, endocrine dysfunction, and IO in patients who were NRT. The findings emphasize the need for consistent care and appropriate monitoring for all pediatric patients with PK deficiency, regardless of transfusion status or perceived severity of disease.

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