Myelodysplastic Syndromes

Myelodysplastic Syndromes (MDS) are characterized by morphological abnormalities in one or more of the major myeloid cell lineages of hematopoiesis. They are caused by somatic mutations in hematopoietic stem cells. Patients with MDS suffer from cytopenia (i.e., a reduction in the number of mature blood cells) and they have a propensity to develop acute myeloid leukemia (AML).

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MDS shows marked clinical heterogeneity, ~70% of patients suffering from “low risk” MDS with a low risk of AML progression but cytopenias (mainly anemia), and ~30% suffering from “high risk” MDS, with high risk of AML progression and short survival. Fit high-risk patients may potentially be cured with allogeneic hematopoietic stem cell transplantation, but this treatment can be applied in about 15 % of MDS patients.  Other high-risk patients are usually treated with hypomethylating agents, which prolong survival rather than cure the patient. Life expectancy is always reduced in high-risk patients (median survival of 2 years). Usually affecting elderly individuals, the incidence of MDS is expected to increase as a result of the aging of our population and the rising number of cancer survivors (i.e., secondary MDS).

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Key questions

By pooling data from multiple clinical trials and databases, the first work of in MDS HARMONY will be the creation of a dataset of ~4000 high risk MDS patients. A substantial subgroup of these (~1700) have been particularly well-studied, including for instance data on somatic mutations. Examples of key questions that HARMONY will address using this dataset include:

How do molecular data relate to disease course and treatment response?

• As hypomethylating agents such as azacitidine have been introduced to the market relatively recently, there is little insight in the long-term outcome of these treatments. By pooling data of thousands of MDS patients, HARMONY will be able to explore both short-term and long-term outcomes and relate these to prognostic factors such as the presence of certain somatic mutations

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Which rare side-effects can we observe in patients that are treated with hypomethylating agents?

• The most common side-effects of hypomethylating agents are infections and hemorrhages. These complications are already well-studied and can be treated. In HARMONY, we will explore the incidence of more rare complications such as heart problems, lung problems, and neuropathy.

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Can we identify new outcomes to effectively evaluate the efficacy of new treatments after a shorter observation period?

• The current absence of consensus on outcomes other than survival for evaluating new drugs is hampering the assessment of emerging targeted therapies.

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MDS Features

• Type of malignant cells: hematopoietic stem cells.
• Tissue of origin: bone marrow.
• Clinical symptoms: cytopenia (most notably anemia).
• Five-year survival in Europe: For all MDS,  median survival of 3.5 years  and 25 % risk of AML progression at 3 years, 5 year survival 20%
• Incidence in Europe: crude incidence rate is 4 per 100,000 per year (>30,000 new cases per year).
• Age at diagnosis: mainly in the elderly: median age at diagnosis is 70-75.
• Relevant outcomes: event-free survival, prevention of progression to AML.

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HARMONY Leadership: MDS

• Pierre Fenaux, GFM and hôpital St Louis, France
• Andrea Kuendgen, Heinrich-Heine-University, Germany
• Valeria Santini, FisMonlus Fondazione Italiana Sindromi, Italy

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