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MDS: Prognostic factors to hypomethylating agents and intensive chemotherapy in higher risk Myelodysplastic Syndromes

Challenge: Identify prognostic factors to assist in identifying patients with myelodysplastic syndromes who will respond to treatment with hypomethylating agents and intensive chemotherapy (although this latter treatment is less often used).

Not all patients with MyeloDysplastic Syndromes (MDS) respond to treatment with hypomethylating agents and intensive chemotherapy. Moreover, at present time, there are a lack of validated prognostic markers to facilitate the accurate prediction of patient outcomes, and the use of large data sets is required to allow validation to proceed.


Status end 2019

Anonymized data have been collected from 3,000 MDS patients from seven European countries. The team is now contacting other European registries for data sharing. In the course of 2020, a first analysis of all clinical, cytogenetic and molecular parameters will be performed. The data will be analyzed to assess prognostic factors for outcome after treatment with hypomethylating agents (HMAs). In addition, the team plans to study the correlation between response to HMAs and specific parameters such as cytogenetic alterations (e.g., monosomy 7) or gene mutations (e.g., in TP53).


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Project Summary

MDS are among the most frequently observed hematological disorders, and it is anticipated that participation in the HARMONY Alliance will provide a unique opportunity to construct a large patient database and so analyze treatment outcomes in a large cohort of patients with MDS. In addition, we hope that it will be possible to evaluate response predictors and prognostic factors, including somatic mutations, that may impact on the efficacy of treatment with the current standard of care, the hypomethylating agents (or less often intensive chemotherapy).

Certain patients with myelodysplastic syndromes are considered at high risk of progression to acute myeloid leukemia (AML). The optimal treatment pathway for such patients is unclear, and analysis of a large group of these patients may clarify the best therapeutic approach. The database will consist of patients from a total of nine countries within Europe: France, Austria, Belgium, Germany, Italy, the Netherlands, Sweden, Spain, and the UK. This HARMONY MDS project will be run by a network of well-established clinical research groups with the capability to contribute data from several hundred patients each, and who have a relatively long history of collaborative working, for example, participation in the same randomized controlled clinical trials. The project will aim to recruit around 3,000 MDS patients, aiming to add 3,000 datasets to the HARMONY Big Data Platform.

The key objective of this study project is to correlate patient characteristics with overall survival (OS), and in particular to analyze characteristics of MDS patients who exhibit an OS that is greater than the current median of 2 years. OS is the main traditional endpoint in most higher-risk myelodysplastic syndromes clinical trials, and the aim will be to examine whether factors such as somatic mutations, and earlier endpoints such as event-free survival (EFS) may align with OS. The large size of the database will also allow an analysis of prognostic factors in several different patient subgroups. For example, it is hoped that it will be possible to examine the very elderly (≥ 80 years) or younger patients, to identify those patients who may require additional or alternative treatments and analyze the potential for Allo SCT following treatment with hypomethylating agents.

The aim of this project is to be able to identify those patients with myelodysplastic syndromes who are most likely to respond to treatment with hypomethylating agents and experience a prolonged duration of response. Hypomethylating agents were introduced in 2009, and so are a relatively recent treatment innovation. Although we have a good knowledge of their properties, there are still many unanswered questions, and it is hoped that this project may provide clarity around some of the unknowns. For example, whether the use of a hypomethylating agent alone is sufficient to prepare a patient with MDS for Allo SCT.  The same analysis will be performed in higher risk patients who received intensive chemotherapy, a treatment less often used, except in candidates to Allo SCT and more recently with the advent of encapsulated forms of intensive chemotherapy. The number of such patients in the centres participating to this project is however not precisely known.