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:Vheralia: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: 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.

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2024
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