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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Azacitidine; Drug: Erythropoetin

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • Department of Hematology, Aalborg University Hospital
  • Aarhus, Denmark
    • Department of Hematology, Aarhus Univsersity Hospital
  • Copenhagen, Denmark
    • Department of Hematology, Rigshospitalet Univsersity Hospital
  • Herlev, Denmark
    • Department of Hematology, Herlev Hospital
  • Odense, Denmark
    • Department of Hematology, Odense University Hospital
• Norway
  • Bergen, Norway
    • Department of Medcine, Haukeland University Hospital
  • Oslo, Norway
    • Department of Hematology, Rikshospitalet University Hospital
• Sweden
  • Eskilstuna, Sweden
    • Department of Medicine, Mälarsjukhuset Hospital
  • Falun, Sweden
    • Department of medicine, Falun Hospital
  • Göteborg, Sweden
    • Department of Medicine, Sahlgrenska University Hospital / Östra
  • Linköping, Sweden
    • Department of Hematology, Linköping University Hospital
  • Luleå, Sweden
    • Department of Medicine, Sunderbyn Hospital
  • Lund, Sweden
    • Department of Hematology, Lund University Hospital
  • Stockholm, Sweden
    • Department of Hematology, Karolinska University Hospital
  • Stockholm, Sweden
    • Department of Medicine, Södersjukhuset Hospital
  • Umeå, Sweden
    • Department of Medicine, Umeå University Hospital
  • Uppsala, Sweden
    • Department of Medicine, Uppsala University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

  1. Serum creatinine >2.0 mg/dL (177 micromol/L)
  2. 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)
  3. Serum total bilirubin >1.5 mg/dL (26 micromol/L)
• Uncontrolled systemic infection
• Considered not capable of following the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azacitidine +/- erythropoetin	Drug: Azacitidine; 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; Drug: Erythropoetin; For those patients not responding to Azacitidine alone, the combination of Azacitidine and erythropoetin 60 000 U / week for 16 weeks will be given.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Nordic MDS Group
• Investigators: Study Director: Magnus Tobiasson, M.D., Nordic MDS Group

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: January 12, 2010
• First Submitted That Met QC Criteria: January 12, 2010
• First Posted (Estimate): January 13, 2010

Study Record Updates

• Last Update Posted (Estimate): October 29, 2013
• Last Update Submitted That Met QC Criteria: October 28, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Azacitidine; Myelodysplastic syndrome; Chronic myelomonocytic leukemia; Transfusion dependency; Transfusion therapy; Hypomethylating therapy; DNA-methylation; Epigenetic modifications
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Hematinics; Epoetin Alfa; Azacitidine
• Other Study ID Numbers: NMDSG08A; 2009-011483-11 (EudraCT Number)