Evaluation of Azacitidine in Transfusion Dependent Patients With Low-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Study Overview
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Brief Summary
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Azacitidine has proved prolonged overall survival in patients with high-risk MDS. Minor pilot studies have shown that treatment with Azacitidine can induce transfusion independency in previous transfusion dependent patients with low-risk MDS. This study will evaluate the effect of Azacitidine in transfusion dependent patients with low-risk MDS (IPSS low or int-1) or low risk CMML. Included patients should first have failed, or considered not being eligible to, treatment with EPO +/- G-CSF. Our hypothesis is that Azacitidine can lead to transfusion independency in this group of patients. Those patients who do not respond to treatment with Azacitidine alone, will be given treatment with the combination of Azacitidine and EPO where our hypothesis is that Azacitidine can restore sensitivity to EPO.

Official Title
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Clinical and Biological Evaluation of Azacitidine in Transfusion-dependent Patients With Low and Intermediate-1 Risk MDS, and Low-risk CMML, Who Are Either Refractory to or Not Eligible for Treatment With Erythropoietin +/- G-CSF

Conditions
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Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Erythropoetin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be 18 years of age at the time of signing the informed consent form MDS at IPSS Low or Int-1, or mixed MDS/MPD; either CMML with < 10% marrow blasts or RARS-T Patients with high or intermediate probability for response according to the predictive model (see Hellstrom-Lindberg et al, Br J Haematol 99:344-51 1997)should be refractory to EPO / darbepoetin (equivalent to > 60 000 U of EPO / week for > 8 weeks) followed by EPO + G-CSF for > 8 weeks, or biosimilar drugs in equipotent doses, or EPO + G-CSF upfront for 8 weeks. Patients with low probability for response according to the predictive model, could be included without prior EPO/G-CSF treatment Transfusion need >4 units over the last 8 weeks, or >8 units over the last 26 weeks. Subject has signed the informed consent document. Men and women of childbearing potential must use effective contraception during, and for up to 3 months after treatment. Exclusion Criteria: Pregnant or lactating females. Patients who are eligible for curative treatment Expected survival less than 24 weeks. Symptomatic thrombocytopenia / active bleeding Patients with JAK-2 positive RARS-T if eligible for new investigational drugs Serum biochemical values as follows Serum creatinine >2.0 mg/dL (177 micromol/L) Serum aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >3.0 x upper limit of normal (ULN) Serum total bilirubin >1.5 mg/dL (26 micromol/L) Uncontrolled systemic infection Considered not capable of following the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine +/- erythropoetin<br> | Drug: Azacitidine<br>* 100 mg / m(2) subcutaneously day 1-5 every 4 weeks for 6 cycles. Another three cycles will be given together with epo for those not responding to the first 6 cycles of Azacitidine<br>Drug: Erythropoetin<br>* For those patients not responding to Azacitidine alone, the combination of Azacitidine and erythropoetin 60 000 U / week for 16 weeks will be given.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin level |  | Week 28 | 
| Number of patients reaching transfusion independency after treatment with Azacitidine |  | Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on leucocyte, platelet count |  | Week 28 and End of Trial | 
| Effect on bone marrow morphology and cytogenetics |  | Week 28 and End of Trial | 
| Number of patients reaching transfusion independency after treatment with Azacitidine and Epo |  | End of Trial | 
| Effect on genetic and epigenetic profile |  | Week 28 | 
| Hemoglobin level |  | End of Trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic syndrome, Chronic myelomonocytic leukemia, Transfusion therapy, Transfusion dependency, Hypomethylating therapy, Azacitidine, DNA-methylation, Epigenetic modifications