Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Sickle Cell Disease, Health outcomes research, Clinical Research, Thalassemia, Hemoglobinopathies, Diseases, Real-world evidence, Registries
Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world, but their varying degree of clinical severity may be partly influenced by genetic modifiers. Despite the identification and characterization of several genetic modifiers by previous studies, these are, as yet, insufficient to guide treatment recommendations or stratify patients reliably. The International Hemoglobinopathy Research Network (INHERENT) will investigate the role of genetic modifiers in hemoglobinopathies, through a large, multi-ethnic genome-wide association study (GWAS), with the aim to identify and validate further disease modifiers that can be used for patient stratification and personalized treatment.
Aims
This pilot study aims to test the operational feasibility of the INHERENT study across different geographic and healthcare settings and, thus, identify and address challenges in performing the envisioned GWAS within INHERENT.
Methods
INHERENT members participating in the pilot study were selected based on their geographic location, disease group distribution (SCD/thalassemia) and hemoglobinopathy-specific healthcare policies. The following steps of study implementation were tested: (a) obtaining local bioethics approval (b) patient enrollment and data collection using a common case report form (CRF), (c) sample collection and shipment, (d) genotyping of globin genes, (e) centralized GWAS experiments, and (f) statistical analysis. The completeness of the collected dataset was also assessed. Informed consent was obtained prior to any research activities.
Results
The pilot study enrolled 772 subjects from 14 centers spanning 8 countries, namely Angola, Cyprus, Denmark, DR Congo, Greece (3), Malaysia (3), Nigeria (3), and the USA. An additional thirteen centers obtained bioethics approval but have not initiated participant enrollment yet. The distribution by disease group is 52.3% SCD and 40.9% thalassemia, while the median age is 22 (mean 25.3) years, with 53.9% adult and 28.5% children (<18 years), and the remaining records being incomplete for age and disease.
Data completeness (affirming presence, absence, or not enough data) of key parameters related to medical complications is approximately 80%, while the range of completeness for laboratory parameters was wide, with a maximum at 70%. Pain is a common complication in SCD with approximately 60% of participants presenting with at least one presentation of acute or chronic pain. Surprisingly, a higher percentage of children (65%) versus adults (55%) had this complication. Acute anemia is observed in 30% of children with SCD, but in only 10% of adults with SCD and not commonly in any thalassemia participants, even those living in low-resource settings. While end organ damage is common in both conditions, this seems better captured within the adult thalassemia population. Notably, a higher rate of cardiac/pulmonary, kidney/liver, endocrinological and bone complications is observed in adult thalassemia participants. Biological material for 600 participants has been shared centrally and GWAS experiments have been performed using the Illumina GSA SNP array.
Key challenges identified in the pilot study include:
- unavailability of key phenotypic data in routine clinical practice, particularly when the tests are not covered by insurance. This affects the completeness of the dataset as well as the cost associated with the conduct of a large-scale study like INHERENT.
- need for a more detailed standardization and simplification of the INHERENT CRF to ensure uniform and consistent collection of data across participating centers.
- unavailability, limited access, or high costs for molecular diagnostic services.
- storage, quality, and shipping of biological material.
Summary/Conclusion
The INHERENT pilot study tested common standards developed within INHERENT and enabled early identification of key challenges associated with the execution of a large, multi-ethnic study for hemoglobinopathies. The pilot is pivotal for scaling up the INHERENT GWAS across the entire network membership, enabling the study of a hemoglobinopathy population of unprecedented size and diversity which will facilitate novel discoveries and pave the way for advanced personalized treatments and diagnosis.
Disclosures: Archer: Haemonetics: Other: My spouse receives equity as part of his salary; Quilt Health: Current holder of stock options in a privately-held company. Tshilolo: Novo Nordisk: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Waziri: Pfizer: Consultancy, Research Funding. Christou: MIDA Biotech-Orgenesis: Ended employment in the past 24 months. Diamantidis: Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacosmos: Research Funding; WinMedica: Consultancy, Other: Travel Grant; AstraZeneca: Honoraria; Forma Therapeutics: Research Funding; Abbvie: Other: Travel Grant; Demo: Other: Travel Grant. Glenthoej: Novo Nordisk: Consultancy, Research Funding; Pharmacosmos: Consultancy; Vertex: Consultancy; Sanofi: Research Funding; Agios: Consultancy, Research Funding. Delicou: ELPEN: Honoraria; DEMO: Honoraria; ISIS: Research Funding; Vifor: Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Hippokrateio General Hospital: Current Employment. Giannuzzi: Agios: Research Funding; Celgene: Research Funding; Novo Nordisk: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Pharmacosmos: Research Funding; Pfizer: Honoraria. Chatzimatthaiou: MIDA Biotech-Orgenesis: Ended employment in the past 24 months. Lederer: Devyser: Other: Travel Funding; Agios Pharmaceuticals: Research Funding. Kountouris: Agios: Research Funding.