Clinical Monitoring Practices Among Adult Patients with Pyruvate Kinase Deficiency Who Have Never Been Transfused

Introduction: Pyruvate kinase (PK) deficiency is a rare, congenital, hemolytic anemia caused by mutations in the PKLR gene. Patients, including those never managed with blood transfusions, experience iron overload and other disease-related complications. In 2024, the first international expert guidelines for PK deficiency were published and included monitoring recommendations for patients never transfused (NT).

Aim: Todescribe the reasons provided by clinicians for not transfusing patients with PK deficiency who were NT and the disease monitoring activities in these patients, using data from two real-world studies: Peak Registry (NCT03481738) and PK deficiency Natural History Study (NHS; NCT02053480).

Methods: Both NHS and Peak were designed as global, longitudinal, observational studies enrolling patients with PK deficiency (NHS 2014-2017, Peak 2018-ongoing [data cut-off date: 15May2023]). This descriptive analysis used merged data from both studies and included patients aged ≥18 years, with a confirmed diagnosis of PK deficiency who were NT (defined as no lifetime history of blood transfusions before/during study follow-up). A subgroup analysis of patients with ≥12 months of retrospective data was performed to ensure adequate time for monitoring to occur. Results were evaluated relative to pertinent recommendations from the PK deficiency international expert guidelines.

Results: A total of 55 adult NT patients were included in the analysis. Median age (min-max) at the last visit was 39 years (18-81), 43.6% were female, 86.0% were White, 10.2% were Hispanic/Latino. Most patients resided in Southern Europe (43.6%), followed by North America (18.2%), Northern Europe (18.2%), Asia (12.7%), and Central Europe (7.3%). Overall, 18.9% (10/53; 2 unknown) had previously undergone splenectomy.

PKLR genotype distribution was 62.3% missense/missense, 34.0% missense/non-missense, and 3.8% non-missense/non-missense. Median (min-max) lab results at patients' last visit included hemoglobin 11.4 g/dL (6.8-18.3), reticulocytes 6.6% (2.6-63.0), and ferritin 312.0 ng/mL (16.6-6208.0).

The most common reason for not being transfused was “anemia not very severe” (71.1%), followed by “anemia not symptomatic” (20.0%), “iron-overload risks” (11.1%), “patient objection” (4.4%), “immune-associated risks” (2.2%), and “injection-related risks” (2.2%); rationale was only captured in Peak (n=45) and multiple response options were allowed.

Among the 42 NT patients with ≥12 months of retrospective data, clinical monitoring received during registry participation (and recent pre-baseline history) included lab assessments for hemoglobin (97.6%), reticulocytes (85.7%), and ferritin (95.2%). Bone health was monitored via 25-hydroxyvitamin D (23.8%, 10/42) and Dexa scan (12.9%, 4/31). Cardiovascular monitoring occurred in 37.5% and 19.4% of NHS and Peak participants, respectively. MRI for iron assessment (liver and/or cardiac) was performed for 20.8% of NHS patients and 25.0% of Peak patients. Among 5 patients with ongoing chelation therapy, all had registry documentation of ferritin monitoring, and none had a liver iron concentration evaluation via MRI.

Complications among the 42 NT patients with ≥12 months of retrospective data included iron overload (40.0%), osteoporosis (12.1%), extramedullary hematopoiesis (8.6%), left ventricular hypertrophy (7.4%), diabetes (5.7%), thromboembolic events (4.3%), hepatic cirrhosis (2.8%), and arrhythmia (2.7%). These complications, except for hepatic cirrhosis, were also observed in the subgroup reporting anemia not very severe and/or not symptomatic.

Conclusion: Among NT patients with PK deficiency, observed medical monitoring practices fall short of evidence-based recommendations in recently published guidelines. NT patients are at risk for complications, such as iron overload and osteoporosis, that require routine monitoring. Even patients classified as “not being very severe” and/or “not symptomatic” experienced disease complications. These findings emphasize the need for evidence-based disease monitoring to be consistently implemented for all patients with PK deficiency, enabling early detection and management of complications. Guidelines recommend annual screening for iron overload irrespective of transfusion status, highlighting that chelation therapy can potentially avoid further complications.

Eber:Agios Pharmaceuticals, Inc.: Other: Advisory board member. Glenthøj:Sanofi: Research Funding; Saniona: Research Funding; Novo Nordisk: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Pharmacosmos: Consultancy; Vertex: Consultancy. Glader:Agios Pharmaceuticals, Inc.: Consultancy. van Beers:Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Grace:Agios, Sobi, Novartis: Research Funding; Agios, Sanofi, Sobi: Consultancy. Kuo:Biossil: Consultancy; Alexion Pharmaceuticals: Consultancy, Honoraria; Agios Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Research Funding; Novo Nordisk: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Vertex Pharmaceuticals: Consultancy, Honoraria; Sangamo: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Consultancy. Bianchi:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. McGee:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yan:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Li:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Ford:Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Lander:Agios Pharmaceuticals, Inc.: Other: PK Deficiency Patient Advocacy Advisory Council - patient representative.