PREDİCTİON OF THE RİSK OF LEUKEMİA DEVELOPMENT İN AGED HEALTHY POPULATİON: IMPLEMENTATİON İN THE PUBLİC HEALTH SYSTEM

Abstract

In the last 10-years, several scientific reports have provided evidence of the accumulation of somatic mutations in Hematopoietic Stem and Progenitor Cells (HSPC) in subjects aged > 50yrs. This phenomenon is defined as Clonal Hematopoiesis of Indeterminate Potential (CHIP). As discovered and developed by Abelson et.al. (Nature. 2018) these mutations are detectable many years before the clinical onset of Acute Myeloid Leukemia (AML) and are potentially linked to its subsequent evolution. It is important to underline that the correlation between mutations and the development of AML does not represent an early diagnosis but only an increased risk of developing AML. The risk depends on many factors: type of mutations, how many cells carry the mutation, and combination of mutations. A risk score has been established (NEJM 2023); according to this study few subjects with CHIP are going to develop AML. Of note: the studies that document these correlations were retrospective. It might be relevant to emphasize that “early diagnosis of AML” does not seem to have, given the dynamics of cellular proliferation, concrete advantages. The identification early in advances of a constellation of mutations and their combinations possibly associated with the risk of developing AML could instead be very effective, if there were drugs targeting specific mutations. From a precision, personalized and participatory medicine perspective, these studies have led us to launch a prospective project on a healthy population of individuals between 50 and 80-years old. We reasoned that this type of screenings based on complex landscapes of genetic mutations will become more and more present in the evolving scenario of predictive medicine. Thus, the company Dedalus Italia S.p.A. designed the model and the software for implementing these screening studies in the Health Services. The project’ name is “SInISA”*. The experimentation is carried out in the territory of the Regional-Health-Service (ASL5) of Eastern Liguria (Italy), with the aim of verifying and evaluating both the organizational model and the technological infrastructure to support it, with the ambition of initially sequencing the DNA with a panel of about 90 genes. The first step was to identify subjects with higher probability of bearing mutations. The first screening element will be the RDW parameter. Subjects with RDW > 15 have higher probability of bearing mutations in blood cells. It was calculated that to identify individuals with RDW > 15 it is necessary start from a population of approx. 12000 subjects This study is based on the free and voluntary participation of citizens. Therefore, this approach opens the doors to the so-called “participatory medicine” which is, and will be, an essential element for the development of these new paths for the management of citizens' health. The objectives are therefore: 1) To verify the correlation of RDW > 15 and presence of mutation in a prospective study; 2) To define an organizational model that can be the basis of future screening processes, in the adult/elderly population; 3) To design and implement an integrated technological platform capable of supporting the screening campaign, managing the information and process peculiarities of genetic studies, automating the identification of the target, the sequence of controls and the interactions with the sequencing structures, activating in a logic of continuity of care and follow-up pathways. * “SInISA” is funded under the POR-FESR Liguria 2021‒2027 Action 1.1.1 and is carried out by Dedalus Italia S.p.A., lead company, Leonardo S.p.A, Genartis S.r.l., Rulex Innovation Labs S.r.l., CherryChain S.r.l., VIS S.r.l., University of Genoa with Department of Experimental Medicine and the SRV Center”.