Ignite Creation Date:
2024-05-06 @ 4:08 PM
Last Modification Date:
2024-10-26 @ 2:04 PM
Study NCT ID:
NCT04889729
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2022-09-09
First Post:
2021-05-05
Brief Title:
GENOMED4ALL Improving MDS Classification and Prognosis by AI
Sponsor:
Istituto Clinico Humanitas
Organization:
Istituto Clinico Humanitas
Study Overview
Official Title:
Genomic and Personalized Medicine for All GENOMED4ALL Application of Artificial Intelligence to Improve Disease Classification and Prognosis in Myelodysplastic Syndrome
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2022-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Myelodysplastic syndromes MDS typically occur in elderly people Current disese classifcation system and prognostic scores International Prognostic Scoring System IPSS present limitations and in most cases fail to capture reliable prognostic information at individual level Study of MDS has been rapidly transformed by genome characterization and there is increasing evidence that mutation screening may add significant information to currently available prognostic scores The project will aim to develop artificial intelligence AI-based solutions to improve MDS classification and prognostication through the implementation of a personalized medicine approach In close collaboration with the European Reference Network on Rare Hematological Diseases ERN-EuroBloodNet FPA 739541 GENOMED4ALL involves multiple clinical partners from the network while leveraging on healthcare information and repositories that will be gathered incorporating interoperability standards as promoted by ERN-EuroBloodNet central registry the European Rare Blood Disorders Platform ENROL GA 947670
Detailed Description:
Myelodysplastic syndromes MDS typically occur in elderly people Patients present peripheral blood cytopenia and with time a portion of these subjects evolve into acute myeloid leukaemia AML The natural history of MDS is heterogeneous ranging from conditions with a near-normal life expectancy to forms close to AML and therefore a risk-adapted treatment strategy is mandatory Current prognostic scores Revised International Prognostic Scoring System IPSS-R present limitations and in most cases fail to capture reliable prognostic information at individual level
Study of MDS has been rapidly transformed by genome characterization Somatic mutations occur in the genomes of hematopoietic stem cells at a low but detectable frequency during normal DNA replication Any genetic alteration that causes a selective advantage relative to other self-renewing cells will lead to clonal dominance clonal haematopoiesis CH The consequence of CH is genomic instability leading to increased risk of acquiring additional mutations and to develop MDS solid cancer and other illnesses The time and place of individual mutations and their clonal emergence during the course of the disease are central issues for a better comprehension of MDS pathogenesis and phenotype and for the development of cancer preventive strategies
Important steps forward have been made in defining the molecular architecture of MDS The MDS associated with 5q deletion derives from the haploinsufficiency of RPS14 gene Genes encoding for spliceosome components were identified in a high proportion of subjects with MDS There is a close relationship between ring sideroblasts and SF3B1 mutations which is consistent with a causal relationship In addition an increasing number of genes have been found to carry recurrent mutations in MDS involved in DNA methylation DNMT3A TET2 IDH12 chromatin modification EZH2 ASXL1 transcriptional regulation RUNX1 signal transduction KRAS CBL
Gene mutations have been reported to influence survival and risk of disease progression in MDS and the evaluation of the mutation status may add significant information to currently used prognostic scores For instance we found that SF3B1 mutations were independent predictors of favorable prognosis while driver mutations of ASXL1 SRSF2 RUNX1 TP53 and EZH2 genes were associated with a reduced probability of survival MDS with ring sideroblasts provide the best evidence that the identification of the mutant gene responsible for the initial clone is relevant to clinical outcome In fact ring sideroblasts may be found not only in patients with a founding mutation in SF3B1 but also in those with an initiating oncogenic lesion in SRSF2 However the median leukemia-free survival is 10 years in the former vs 2 years in the latter
Moreover mutation screening may affect clinical decision making a in MDS with 5q- subjects carrying TP53 mutations have a higher risk of leukemic progression and a lower probability of response to lenalidomide b in patients receiving HSCT TP53 mutations predict high probability of relapse c SF3B1 mutations are associated with increased probability of erythroid response to TGFb inhibitors luspatercept and d TET2 mutations might be associated with response to HMA
Despite these findings caution is needed against immediately adopting such mutational testing in clinical practice First the presence of mutations in a given individual has only limited predictive power as conversion to MDS is rare regardless of mutation status In addition in patients with overt MDS genetic abnormalities explain only a proportion of the total hazard for survival associated with specific treatments meaning that a large percentage is still associated with clinical and non-mutational factors Comprehensive analyses of large patient population and new methods to study gene-gene interactions and genoptype-phenotype correlations are warranted to correctly estimate the independent effect of each genomic abnormality on clinical outcome and response to treatment
By combining an already available large amount of sequenced genomic data and clinical information the authors hypothesize that AI will allow to understand better MDS biology and classification enhance prognosticpredictive capacity of currently available tools and apply treatments in a more targeted way thus facilitating the implementation of personalized medicine program across EU
Study of MDS has been rapidly transformed by genome characterization Somatic mutations occur in the genomes of hematopoietic stem cells at a low but detectable frequency during normal DNA replication Any genetic alteration that causes a selective advantage relative to other self-renewing cells will lead to clonal dominance clonal haematopoiesis CH The consequence of CH is genomic instability leading to increased risk of acquiring additional mutations and to develop MDS solid cancer and other illnesses The time and place of individual mutations and their clonal emergence during the course of the disease are central issues for a better comprehension of MDS pathogenesis and phenotype and for the development of cancer preventive strategies
Important steps forward have been made in defining the molecular architecture of MDS The MDS associated with 5q deletion derives from the haploinsufficiency of RPS14 gene Genes encoding for spliceosome components were identified in a high proportion of subjects with MDS There is a close relationship between ring sideroblasts and SF3B1 mutations which is consistent with a causal relationship In addition an increasing number of genes have been found to carry recurrent mutations in MDS involved in DNA methylation DNMT3A TET2 IDH12 chromatin modification EZH2 ASXL1 transcriptional regulation RUNX1 signal transduction KRAS CBL
Gene mutations have been reported to influence survival and risk of disease progression in MDS and the evaluation of the mutation status may add significant information to currently used prognostic scores For instance we found that SF3B1 mutations were independent predictors of favorable prognosis while driver mutations of ASXL1 SRSF2 RUNX1 TP53 and EZH2 genes were associated with a reduced probability of survival MDS with ring sideroblasts provide the best evidence that the identification of the mutant gene responsible for the initial clone is relevant to clinical outcome In fact ring sideroblasts may be found not only in patients with a founding mutation in SF3B1 but also in those with an initiating oncogenic lesion in SRSF2 However the median leukemia-free survival is 10 years in the former vs 2 years in the latter
Moreover mutation screening may affect clinical decision making a in MDS with 5q- subjects carrying TP53 mutations have a higher risk of leukemic progression and a lower probability of response to lenalidomide b in patients receiving HSCT TP53 mutations predict high probability of relapse c SF3B1 mutations are associated with increased probability of erythroid response to TGFb inhibitors luspatercept and d TET2 mutations might be associated with response to HMA
Despite these findings caution is needed against immediately adopting such mutational testing in clinical practice First the presence of mutations in a given individual has only limited predictive power as conversion to MDS is rare regardless of mutation status In addition in patients with overt MDS genetic abnormalities explain only a proportion of the total hazard for survival associated with specific treatments meaning that a large percentage is still associated with clinical and non-mutational factors Comprehensive analyses of large patient population and new methods to study gene-gene interactions and genoptype-phenotype correlations are warranted to correctly estimate the independent effect of each genomic abnormality on clinical outcome and response to treatment
By combining an already available large amount of sequenced genomic data and clinical information the authors hypothesize that AI will allow to understand better MDS biology and classification enhance prognosticpredictive capacity of currently available tools and apply treatments in a more targeted way thus facilitating the implementation of personalized medicine program across EU
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None