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794 uRADAR: European Patients Referral Frame to Improve Access to New Drugs and Therapies in Ultra-Rare Anemia Disorders and Severe Hereditary Spherocytosis

Program: Oral and Poster Abstracts
Type: Oral
Session: 905. Outcomes Research: Non-Malignant Conditions Excluding Hemoglobinopathies: Innovative Approaches to Improve Care for Understudied Non-Malignant Hematologic Diseases
Hematology Disease Topics & Pathways:
Research, Adult, Epidemiology, Elderly, Clinical Research, Hemoglobinopathies, Pediatric, Diseases, Treatment Considerations, Registries, Young adult , Study Population, Human
Monday, December 9, 2024: 10:45 AM

Maria A. Rodríguez Sánchez1*, Anna Collado Gimbert, MD1,2*, Sara Reidel, MSc1*, Patricia Aguilar-Martinez, MD, PhD3*, Celeste Bento, PhD4*, Elena Cela, MD, PhD5*, Laurence Dedeken, MD6*, Emma Drasar, MD, PhD7*, Frederic Galacteros, Prof, MD8*, Andreas Glenthoej, MD, PhD9, Monika Horvathova, PhD10, Pavla Koralkova, PhD10*, Andreas E. Kulozik, MD, PhD11, Joachim B. Kunz, Prof., MD12*, Marta Morado-Arias, MD, PhD13*, Ana Ortuno Cabrero, MD14*, Dagmar Pospíšilová, Prof., PhD15*, Minke A.E. Rab, MD, PhD16,17*, Noemi Roy, MD, PhD18*, Eduard J. Van Beers, MD, PhD19, Richard van Wijk, PhD20, Sarah Wambacq, MSc21*, Claire Diot, MEd1*, Victoria Gutiérrez Valle1*, Raquel Mosull del Campo, MSSc1*, Stella Tamana, PhD22*, Raffaella Colombatti, MD, PhD23*, Petros Kountouris, PhD24*, Béatrice Gulbis, MD, PhD25*, Paola Bianchi, PhD, BSc26 and Maria Del Mar Mañú Pereira1*

1Rare Anemia Disorders Research Laboratory, Cancer and Blood Disorders in Children, Vall d'Hebron Research Institute / Vall d'Hebron University Hospital, Barcelona, Spain
2Pediatric Oncology and Hematology, Vall d'Hebron Barcelona Hospital, Barcelona, Spain
3Department of hematology biology, University and CHU de Montpellier, Montpellier, France
4Hematolody Department, University Hospital Coimbra, Coimbra, Portugal
5Pediatric Hematology and Oncology, Hospital Gregorio Marañón. Universidad Complutense de Madrid, Madrid, Spain
6Department of Hematology-Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
7Department of Haematology, Whittington Health NHS Trust, London, United Kingdom
8GHU Henri Mondor, AP-HP, Creteil, France
9Danish Red Blood Cell Center, Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
10Department of Biology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic
11Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University, Heidelberg, Germany
12Department of Pediatric Hematology, Oncology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
13Hematology department, Hospital Universitario La Paz, Madrid, Madrid, Spain
14Haematology, Whittington Hospital, London, United Kingdom
15Department of Pediatrics, Faculty Hospital, Palacky University, Olomouc, Czech Republic
16Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
17Central Diagnostic Laboratory, University Medical center Utrecht, Utrecht, Netherlands
18Haematology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
19Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Centre Utrecht, University of Utrecht, Utrecht, Netherlands
20Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht, Netherlands
21Hôpital Universitaire des Enfants Reine Fabiola, Haemato-oncology, Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium
22Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
23Department for Woman's and Child's Health, University of Padova, Padova, Italy
24Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, CYP
25Centre of Human genetics, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
26Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

Background:

Ultra-rare anemia disorders (uRADs) are commonly neglected from health planning and clinical research hampering its timely diagnosis and leading to sub-optimal clinical management and very few treatment options. The Rare Anemia Disorders European Epidemiological Platform (RADeep) together with the ERN-EuroBloodNet have joint efforts to establish the uRADAR initiative aiming to develop a referral frame for patients affected by uRADs in the European Union. The uRADAR ultimate goal is to enable access to clinical trials (CT), including drug repurposing i.e. ERN-EuroBloodNet SATISFY Phase 2 Trial (NCT05935202).

Methodology:

The uRADAR disease scope includes all ultra-rare hemolytic anemias (pyruvate kinase deficiency (PKD), other rare cell enzyme and membrane defects, congenital dyserytropoietic anemias I-IV (CDAs), unstable hemoglobinopathies, ultra-rare iron metabolism defects, sideroblastic anemias and metheglobinemias. Chronic and severe forms of hereditary spherocytosis (HS) and G6PD deficiency were also considered.

The RADeep uRADAR module for standardized collection of uRADs data was developed in a REDcap web application. We gathered disaggregated data by age ranges (0-11, 12-15, 16-17 and ≥18 yo) on: sex, genetic diagnosis, common CT exclusion criteria, and therapeutic intervention (splenectomy and/or blood transfusion dependence (TD)). Anemia is considered as Hb <11g/dL in NTD patients. Severity based on therapeutic intervention and anemia is analyzed for >12yo.

Results:

Data from 5,623 patients from 82 centers (13 EU countries, Norway and United Kingdom) has been collected, 1,302 (23%) of them with an uRAD. The cohort has a balanced age and sex distribution, except for X-linked diseases. Information about severity is available for 3,465 (62%) patients, 1,015 (78%) for the uRADs. Genetic confirmation is available for 815 (14%) patients, 308 (24%) for the uRADs. Analyzing by age ranges, we noted patients were constantly diagnosed and followed during pediatric care, however about 2/3 are lost during follow-up at adult age.

RBC enzyme defects: 1,600 patients (1,175 G6PD deficiency, 415 PKD and 46 Other). Even G6PD deficiency is a non-severe disease in most cases we detected 38.4% anemic patients. In PKD 48% required therapeutic intervention. 26.7% were anemic and 10.3% remained TD after splenectomy, twice as reported for other ultra-rare enzyme defects.

Membranopathies: 3,468 patients (3,146 HS, 162 Hereditary elliptocytosis-HE, 122 dehydrated hereditary stomatocytosis-DHS and 38 Other). In the HS group 46% required therapeutic intervention and 26.4% were anemic. Only 3 patients (0.27%) remained TD after splenectomy. HE is usually not severe, nevertheless 9% required therapeutic intervention and 21.6% were anemic. In DHS 11.3% were anemic.

CDAs: 154 patients. 45% required therapeutic intervention. 18% were anemic. 6.4% remained TD after splenectomy.

Ultra-rare iron defects: 46 patients. 6% required therapeutic intervention. 6.3% were anemic. 2.9% remained TD after splenectomy.

Sideroblastic anemias: 84 patients. 24% required therapeutic intervention. 5.3% were anemic. 6% remained TD after splenectomy.

Interestingly we also collected 21 patients with sitosterolemia, 175 unstable hemoglobinopathies and 60 with congenital methemoglobinemia. These numbers are higher than expected suggesting an under-representation of these diseases in available literature.

Conclusions

Only 24% of uRADs patients had confirmed molecular diagnosis thus precluding the inclusion in clinical trials for about 2/3 of patients.

Although splenectomy is the main therapeutic option for most uRADs, we detected 47 patients over 12yo who are non-splenectomized despite being TD.

About 2/3 of adult patients are lost in follow-up which is concerning due to the majority of serious complications appearing in this period and the cutoff age for inclusion in clinical trials is usually 18yo. Overall only 128 (2%) patients presented with the usual exclusion criteria from clinical trials.

There is a need for national health policies that support the concentration of patients affected by uRADs in expert centers for both diagnosis and follow-up. Currently, patients with uRADs are spread across EU, hampering enrollment in clinical trials. The uRADAR approach represents a valid approach to retrieve information on patient’s severity and distribution.

Disclosures: Rodríguez Sánchez: Agios: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Collado Gimbert: Agios: Research Funding; Bristol myers squibb: Research Funding; Novonordisk: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Reidel: Bristol Myers Squibb: Research Funding; Agios: Research Funding; Novartis: Research Funding. Bento: Arkray: Consultancy. Cela: Pfizer: Consultancy; Vertex: Consultancy, Speakers Bureau. Drasar: VERTEX therapeutics: Consultancy, Speakers Bureau; Pfizer: Consultancy. Galacteros: Agios: Consultancy; Vertex: Consultancy. Glenthoej: Agios: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pharmacosmos: Consultancy; Vertex: Consultancy; Sanofi: Research Funding. Kulozik: Vertex: Honoraria. Morado-Arias: sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Honoraria; Novonordisk: Honoraria. Rab: RR Mechatronics: Research Funding; Agios Pharmaceuticals: Research Funding. Van Beers: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. van Wijk: Agios Pharmaceuticals: Research Funding; Pfizer: Research Funding; RR Mechatronics: Consultancy. Wambacq: Vertex: Consultancy. Diot: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Gutiérrez Valle: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Mosull del Campo: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Colombatti: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Vertex/Addmedica: Membership on an entity's Board of Directors or advisory committees. Kountouris: Agios: Research Funding. Gulbis: Novartis: Research Funding; Agios Pharmaceutical: Research Funding; Bristol-Myers Squibb SA: Research Funding. Bianchi: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Mañú Pereira: Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Agios: Other: Advisory board, Research Funding.

*signifies non-member of ASH