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Test project

Which patients with higher risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) benefit from Hypomethylating agents (HMAs)?

MDS are marrow stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias and, in 30-40% of the cases, to acute myeloid leukemia (AML). CMML share those features with MDS, but have in addition a variable “proliferative” myelomonocytic component in the blood , marrow and sometimes other organs. HMAs including azacitidine (AZA) and decitabine (DAC) are the only treatments with a demonstrated impact on survival in higher risk MDS and advanced CMML, if one excepts allogeneic stem cell tranplantation (allo SCT, however possible in only about 20% of the patients). HMAs have therefore become the reference treatment of higher risk MDS and CMML. However, only 50 to 60% of the patients benefit from HMAs

Prognostic factors of treatment with HMAs remain uncertain, especially because predictors of response may differ from prognostic factors of  survival, and as published studies were based on relatively small patient numbers. They include clinical features (performance status) and classical haematological features including WHO classification, karyotype, IPSS and revised IPSS. Prognostic scores have been designed with those parameters, and they can predict to some extent survival. The prognostic value of somatic mutations or epigenetic cell profiles is however unclear. That of additional tests, including flow cytometry orRNA-seq is unknown.

Prognosis has also been generally assessed overall, but the proportion of patients with prolonged response, and prognostic factors of those prolonged responses, have not been precisely analysed.

We will include in the study  about 3000 patients

In addition to conventional clinical and haematological parameters (including karyotype at treatment onset and, when available, at response), the study will focus on the prognostic role of somatic mutations (at least 1000 patients tested are available), of flow cytometry (200 to 250 patients available) and on patients tested for epigenetic profiles (numbers currently unknown). RNA-Seq data or samples suitable for RNA-seq will be listed.

We hope that better prediction of prognostic factors, based on a very large patient cohort, will  help define groups that particularly benefit from HMAs, and on the contrary delineate patient groups that requireaddition of drugs to HMAs, or different treatments. Of note, we will take advantage of this study to also try to define prognostic factors of outcome of higher risk MDS and CMML with intensive chemotherapy, a treatment particularly used before allo SCT in MDS