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1132 Analysis of the Pilot Study of the International Hemoglobinopathy Research Network (INHERENT)

Program: Oral and Poster Abstracts
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
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Natasha Archer, MD, MPH1, Coralea Stephanou2*, Maria Xenophontos3*, Leon Tshilolo, MD PhD4*, Franck Nzengu Lukusa5*, Sylvain Fazili5*, Obiageli E Nnodu, MD6, Maxwell Nwegbu7*, Ali Dahiru Waziri, MD8*, Sani Awwalu9*, Soteroula Christou10*, Irene Savvidou11*, Ann Rekleiti11*, Anna Minaidou3*, Michail D Diamantidis, MD, PhD, MSc12, Norafiza Mohd Yasin, MD13*, Norasmidar Abdul Aziz14,15*, Veena Selvaratnam, MBBS, FRCPath16*, Ezalia Esa17*, Andreas Glenthoej, MD, PhD18, Sophia Delicou19*, Livingstone Gayus Dogara, FMCPath20*, Maria Dimopoulou, MD21*, Raja Sabudin22*, Norunaluwar Jalil23*, C-Khai Loh24*, Sie-Chong Doris Lau24*, Bin Alwi Zilfalil25*, Norsarwany Mohamad25*, Syahiran Mohammad25*, Ahmad-Zafrullahafham Ahmad-Fakri25*, Halim-Fikri Hashim25*, Morohuntodun O. Oni26*, Antonieta Lukangu27*, Ligia Alves, MD27*, Miguel Brito, PhD28*, Viviana Giannuzzi29*, Fedele Bonifazi29*, Kyriaki Michailidou30*, Sotiroula Chatzimatthaiou31*, Carsten Lederer31* and Petros Kountouris, PhD32*

1Dana-Farber/Boston Children's Cancer and Blood Disorder Ctr., Boston, MA
2The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
3The Cyprus Institute of Neurology & Genetics, Nicosia, CYP
4Centre Hospitalier Monkole, Kinshasa, Congo (The Democratic Republic of the)
5CEFA-Monkole Institut de Recherche Biomédicale, Kinshasa, Congo (The Democratic Republic of the)
6Centre of Excellence for Sickle Cell Disease Research and Training, Department of Haematology and Blood Transfusion, College of Health Sciences, University of Abuja, Abuja, Nigeria
74Centre of Excellence for Sickle Cell Disease Research and Training, University of Abuja, Abuja, Nigeria
8Ahmadu Bello University Teaching Hospital, Kaduna, NGA
95Ahmadu Bello University Teaching Hospital, Kaduna, Nigeria
10Thalassemia Centre, Archbishop Makarios III Hospital, Nicosia, Cyprus
11Thalassemia Centre, Archbishop Makarios III Hospital, Nicosia, Greece
12General Hospital of Larissa, Larissa, GRC
13Haematology Unit, Cancer Research Centre, Selangor, MYS
14Hospital Pulau Pinang, Pulau Pinang, MYS
15Hospital Sultanah Bahiyah, Kedah, Malaysia
16Ampang Hospital, Kuala Lumpur, Malaysia
17Cancer Research Centre, Selangor, Malaysia
18Danish Red Blood Cell Center, Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
19Hippokrateio General Hospital, Athens, Greece
20Kaduna State University, Kaduna, Nigeria
21Laiko General Hospital, Athens, Greece
22Department of Pathology, UKM Medical Centre, Kuala Lampur, Malaysia
23Department of Laboratory Diagnostics Services, UKM Specialist Children's Hospital, Kuala Lumpur, Malaysia
24UKM Specialist Children's Hospital, Kuala Lumpur, Malaysia
25Universiti Sains Malaysia, Kubang Kerian, Malaysia
26Dana-Farber / Boston Children’s Cancer and Blood Disorders Center, Brookline, MA
27Maternidade Lucrécia Paim, Luanda, Angola
28H&TRC, Escola Superior de Tecnologia da Saude de Lisboa, Lisbon, AL, Portugal
29Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Bari, Italy
30The Cyprus Institute of Neurology and Genetics, Nicosia, CYP
31The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
32Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, CYP

Background

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.

*signifies non-member of ASH