Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
Condition: Myelodysplastic Syndromes
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      In this trial, the investigators would like to understand why a small percentage of patients
      will be refractory to ESA (independently of International prognostic scoring system (IPSS)
      and % of blasts). In a retrospective study of the "Groupe Francophone des Myélodysplasies
      (GFM)" , the investigators showed that about 43% of patients are refractory or will relapse
      after initial response to ESA and it has been shown that these patients have a poorer
      survival. The investigators plan to give a 12-week treatment of Epoetin alfa or zeta in low
      risk MDS patients and measure different biological factors to predict response to ESA:

        -  evaluation by flow cytometry before and after treatment of the degree of
           dyserythropoiesis and dysgranulopoiesis which could explain the primary resistance or
           loss of response of a subset of patients,

        -  screening by molecular biology of predictive factors of response to ESA,

        -  Iron homeostasis will be measured via hepcidin, GDF-15 and ferritin levels.
    

Detailed description: 
      Lower risk MDS patients, with LOW and INT-1 IPSS score, with anemia Hb<10g/dl, requiring or
      not Red blood cel (RBC) transfusions, treated by erythropoiesis stimulating agent (ESA)
      according to national French recommendations ( epoetin zeta 40000 UI/week in lower risk MDS,
      <10% blasts, with Hb<10g/dl and sEPO<500UI/l, for 12 weeks).

      BM aspirates are collected prospectively at T0 and at W12 of ESA treatment.

      BM aspirates will be collected prospectively at inclusion in all 70 patients, after 12 weeks,
      in 70 patients.

      Fresh bone marrow samples will be centralized at Cochin hospital for flow cytometry analysis
      of dyserythropoiesis and gene sequencing (Hematology laboratory, Cochin, Paris). "Ogata flow
      cytometry score" will be assessed locally in Mulhouse, Creteil, Tours, Grenoble or Cochin.
      Patients have been reevaluated at week 12 by flow cytometry "Ogata score".

      Blood plasma will be been collected for analysis of GDF-15 and hepcidin, and sent to Cochin
      (Institut Cochin, Paris). Hepcidin level was measured by LC-MS/MS method in Louis Mourier
      Hospital.

      Red score analysis was done in a centralized manner in Cochin, according to the methods
      described previously. Basically, it was evaluated on CD36, CD71 CV and Hb level according to
      the gender.

      Genomic studies and Bioinformatic analysis Mutations in a selected panel of 39 genes will be
      screened in the 70 samples by a Next-Generation Sequencing (NGS) assay.

      Sample size justification and Statistical analysis Sample size computation was based on the
      secondary endpoint which was the response rate. The investigators expected a response rate of
      50-60%, therefore about 30 patients will be responders and 30 patients non responders. With
      10%-15% of non evaluable biological data, n=70 patients should be included.
    

Intervention name(s): Epoetin Zeta
Intervention type(s): Drug
Intervention description(s): Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.
Response has been evaluated at 12 weeks according to IWG 2006 criteria. Patients with response continued on epoetin zeta. In non-responders, the patients have been excluded from the protocol.
Other intervention name(s): Retacrit
Intervention MeSH terms: Epoetin Alfa
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: myelodysplastic syndromes; erythropoiesis stimulating agents; factors of response