Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
Primary Purpose
Myelodysplastic Syndromes
Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Epoetin Zeta
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring myelodysplastic syndromes, erythropoiesis stimulating agents, factors of response
Eligibility Criteria
Inclusion Criteria:
> 18y patients
with MDS subtypes :
- refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB) with <10 % blasts (according to FAB classification) CMML with white blood cell (WBC) <13.000/mm3
- RA, RARS, RCMD, RAEB-1, CMML-1 with WBC <13.000/mm3 (according to OMS classification), 5q- syndrome
- Low int-1 IPSS score
- With hemoglobin (Hb)<10 g/dL or red blood cell transfusion (RBC) transfusion dependent
- treated by ESA according to national French recommendations
- without renal insufficiency
- with ECOG PERFORMANCE STATUS <2
Exclusion Criteria:
- higher risk MDS (IPSS intermediate-2 or high)
- CMML with >10 % of BM blasts or WBC>13.000/mm3
- Non-controlled hypertension
- Cardio-vascular disease :uncontrolled, angina pectoris, cardiac insufficiency,
- Renal insufficiency : Creatinine clearance<40ml/min
- EPO level>500UI/l
- Systemic infection or inflammatory chronic disease
- Serum folates<2 ng/mL or vitamin B12 <200 pg/mL
- Other causes of anemia (eg hemolysis, hemorrhage, iron deficiency)
- Pregnancy (positive betaHCG) or nursing
- Women of childbearing age without effective contraception why?
- Hypersensitivity to Darbepoietin alfa or other ESA
- Patient unable to understand the protocol or to follow adequately
- History of epilepsy
- History of thrombosis
- Concomitant thalidomide or lenalidomide treatment
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
epoetin zeta
Arm Description
Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.
Outcomes
Primary Outcome Measures
Determination of the Red score on the prediction of response to ESA
The flow cytometry (FCM) "Red score" described by Mathis et al, Leukemia 2013, ranges from 0 to 7 and includes CD36 and CD71 CV and Hb levels.
Determination of Ogata FCM score on the prediction of response to ESA
The "Ogata FCM score" described by Ogata et al, Haematologica 2009, ranges from 0 to 4 and includes parameters of dysgranulopoiesis and excess of CD34+ blasts
Determination of the number of molecular gene mutations on the prediction of response to ESA
Gene mutations numbers, assessed by next generation sequencing on a 39 gene panel
Determination of GDF-15 levels on the prediction of response to ESA
Mean and median values of GDF15 (pg/ml) levels
Determination of hepcidin levels on the prediction of response to ESA
Mean and median values of hepcidin (ng/ml)
Secondary Outcome Measures
Response rate to ESA
Response rate will be evaluated by IWG 2006 criteria of erythroid response.
Full Information
NCT ID
NCT03598582
First Posted
May 26, 2018
Last Updated
July 23, 2018
Sponsor
Association pour la recherche sur les Affections Malignes en Immunologie Sanguine
1. Study Identification
Unique Protocol Identification Number
NCT03598582
Brief Title
Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
Official Title
Biological Predictive Factors of Response to Erythropoiesis Stimulating Agent (ESA) in Low Risk Myelodysplastic Syndromes (MDS) Patients
Study Type
Interventional
2. Study Status
Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
January 1, 2013 (Actual)
Primary Completion Date
May 1, 2017 (Actual)
Study Completion Date
May 1, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Association pour la recherche sur les Affections Malignes en Immunologie Sanguine
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes
Keywords
myelodysplastic syndromes, erythropoiesis stimulating agents, factors of response
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
70 (Actual)
8. Arms, Groups, and Interventions
Arm Title
epoetin zeta
Arm Type
Other
Arm Description
Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Epoetin Zeta
Other Intervention Name(s)
Retacrit
Intervention Description
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.
Primary Outcome Measure Information:
Title
Determination of the Red score on the prediction of response to ESA
Description
The flow cytometry (FCM) "Red score" described by Mathis et al, Leukemia 2013, ranges from 0 to 7 and includes CD36 and CD71 CV and Hb levels.
Time Frame
5 years
Title
Determination of Ogata FCM score on the prediction of response to ESA
Description
The "Ogata FCM score" described by Ogata et al, Haematologica 2009, ranges from 0 to 4 and includes parameters of dysgranulopoiesis and excess of CD34+ blasts
Time Frame
5 years
Title
Determination of the number of molecular gene mutations on the prediction of response to ESA
Description
Gene mutations numbers, assessed by next generation sequencing on a 39 gene panel
Time Frame
5 years
Title
Determination of GDF-15 levels on the prediction of response to ESA
Description
Mean and median values of GDF15 (pg/ml) levels
Time Frame
5 years
Title
Determination of hepcidin levels on the prediction of response to ESA
Description
Mean and median values of hepcidin (ng/ml)
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Response rate to ESA
Description
Response rate will be evaluated by IWG 2006 criteria of erythroid response.
Time Frame
5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
> 18y patients
with MDS subtypes :
refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB) with <10 % blasts (according to FAB classification) CMML with white blood cell (WBC) <13.000/mm3
RA, RARS, RCMD, RAEB-1, CMML-1 with WBC <13.000/mm3 (according to OMS classification), 5q- syndrome
Low int-1 IPSS score
With hemoglobin (Hb)<10 g/dL or red blood cell transfusion (RBC) transfusion dependent
treated by ESA according to national French recommendations
without renal insufficiency
with ECOG PERFORMANCE STATUS <2
Exclusion Criteria:
higher risk MDS (IPSS intermediate-2 or high)
CMML with >10 % of BM blasts or WBC>13.000/mm3
Non-controlled hypertension
Cardio-vascular disease :uncontrolled, angina pectoris, cardiac insufficiency,
Renal insufficiency : Creatinine clearance<40ml/min
EPO level>500UI/l
Systemic infection or inflammatory chronic disease
Serum folates<2 ng/mL or vitamin B12 <200 pg/mL
Other causes of anemia (eg hemolysis, hemorrhage, iron deficiency)
Pregnancy (positive betaHCG) or nursing
Women of childbearing age without effective contraception why?
Hypersensitivity to Darbepoietin alfa or other ESA
Patient unable to understand the protocol or to follow adequately
History of epilepsy
History of thrombosis
Concomitant thalidomide or lenalidomide treatment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sophie PARK, MD, PHD
Organizational Affiliation
CHU Grenoble Alpes
Official's Role
Principal Investigator
12. IPD Sharing Statement
Learn more about this trial
Biological Predictive Factors of Response to ESA in Low Risk MDS Patients
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