Translationale Implementation of genetic evidence in the management of MDS (TRIAGE-MDS)

Myelodysplastic syndromes (MDS) constitute a complex group of hematological malignancies. The prognosis for these patients varies considerably, ranging from a stable and indolent course to much more aggressive forms, displaying transformation into acute myeloid leukemia early. Actually it is very difficult to predict prognosis in a given patient. The increasing number of elderly in the western populations will cause a relevant increase in MDS, underlying the clinical relevance of MDS. To better diagnose, prognosticate and stratify patients for targeted forms of therapy, a comprehensive analysis of all possible mutations in MDS would be of great help. This is now possible with the advent of novel, high throughput methodology, known as next generation sequencing (NGS). In this project NGS, detecting all known genetic mutations in MDS in one single experiment, is applied and validated. Cellular material of 1000 well-documented lower-risk MDS patients from the ongoing MDS-registry EU-MDS will be analyzed by NGS. The EU-MDS represents a European-wide registry, which has been recruiting patients since several years and thus represents the largest MDS-registry worldwide. Within the EU-MDS registry clinical status and demographic data are well documented with follow-up visits every six months. Moreover quality of life (QoL), performance status and age-related co-morbidities are registered. Cellular material is available in the majority of patients at initial diagnosis and at different time points of follow-up. The results from NGS will be summarized in a mutation-report. Results from the mutation report will be compared with clinical data. Initial analyses of the clinical data will be followed by quality control, update and review of completeness, plausibility and validity of data in cooperation with the data center of the EU-MDS Registry in Leeds, UK and the Institute of Medical Informatics, University of Münster, Germany. A validated clinical database will be generated by extraction of relevant data. Moreover, an analysis plan and a communication interface between clinical and molecular data will be generated. Subsequently a statistical modeling of associations between molecular data and demographic and clinical parameters including survival, transfusion frequency, QoL and response following different treatment options will be performed by an integrated data analysis. Aspects of elderly including functional activities, comorbidities and QoL will be included. A modeling of data under clinical aspects will be performed addressing possible different aggregations of molecular data as well as involved pathways. It is expected that this analyses will have important implications for disease management in MDS by the molecular definition of progression and clonal evolution, thus forming the basis for individualized treatment algorithms.

Myelodysplastic syndromes (MDS) constitute a group of diverse, haematological malignancies. The prognosis for these patients varies considerably, ranging from a stable, slowly developing disease, to much more aggressive forms. About 30% of the patients progress to aggressive acute myeloid leukemia. So far, it is very hard to predict the clinical course for individual patients. As a consequence, it is unclear which patients would benefit from early therapeutic intervention, and which patients would benefit more from a wait-and- see policy. To better diagnose, prognosticate and stratify MDS patients for wait-and-see policy, intensive or targeted forms of therapy, a comprehensive analysis of genetic mutations has been generated in a large, clinically well annotated cohort of patients. This will help to bring the right therapy to the right patients at the right moment. The Austrian subproject focused on health related quality of life (HRQoL), specifically the linkage of MDS specific health impairments with MDS sub-types. 1690 patients with MDS and quality of life data from the EUMDS registry have been analysed. To distinguish MDS specific characteristics, patients with MDS have been compared to an age and sex matched European cohort. A significant proportion of MDS-patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort and self-assessed health status (EQ-VAS) were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin-levels, or red blood cells transfusion-need. In comparison to age- and sex-matched peers, the proportion of problems in usual activities and anxiety/depression was significantly higher in MDS-patients. MDS-related restrictions in the dimension mobility were most prominent in males, and in older people; in anxiety/depression in female and in younger people. In summary, patients newly diagnosed with IPSS lower-risk MDS experience a pronounced reduction in HRQoL and a clustering of restrictions in distinct dimensions of HRQoL as compared with reference populations. The results of this substudy highlight the need for early intervention in order to relieve quality of life restrictions and to address HRQoL impairments individually. This concept is currently implemented in new treatment guidelines.