A Phase II Study of Intravenous Azacitidine Alone in Patients With Myelodysplastic Syndromes

The primary endpoint of this study is to estimate morphologic complete remission rate. Estimation of response rate is also a secondary objection.

Myelodysplastic syndrome (MDS) is a hematological disorder characterized by ineffective hematopoiesis. The only known curative treatment for patients with MDS is allogeneic stem cell transplantation. However, only a minority of patients are candidates for this aggressive therapy. DNA hypomethylation agents have been shown to have activity in this disorder and are postulated to work by reversing this epigenetic mechanism of gene-silencing. Recently, 5-azacitidine, administered subcutaneously for seven days, received approval by the FDA for the therapy of MDS based on a randomized trial which demonstrated a diminished risk of leukemic transformation and improved survival when compared to best supportive care.

The subcutaneous route of administration can present challenges to implementing this therapy. In the CALGB studies 8921 and 9221, approximately 23% of patients had significant injection site pain. Moreover, 35 % of patients had injection site bruising which can be extensive in thrombocytopenic patients. Due to limitations on drug concentration and administration volumes for subcutaneous dosing, patients often need to have two or three injections at separate sites each day to meet target dosing. In addition, the schedule of administration is inconvenient in an outpatient setting secondary to the need to schedule administrations over weekends. Therefore, there is great interest in pursuing an abbreviated intravenous route for administration of the drug.

Eligibility Criteria:
Inclusion Criteria:

1. Pathological MDS either de novo or secondary, fitting any of the FAB classifications, confirmed by institutional pathologist within 2 weeks prior to start of treatment. Patients with 5% bone marrow blasts must also meet one of the following criteria:

   * Symptomatic anemia with either hemoglobin less than 10.0 g/dL or requiring RBC transfusion
   * Thrombocytopenia with a history of two or more platelet counts \< 50,000 / µL or a significant hemorrhage requiring platelet transfusions, or
   * Neutropenia with two or more absolute neutrophil counts less than 1,000 /µL.
2. ECOG performance status of 0-2.
3. Must give written informed consent indicating their awareness of the investigational nature of this study and its potential hazards.
4. Adequate renal and hepatic function (creatinine ≤ 150% of institutional upper limit of normal, total bilirubin ≤ 150% institutional upper limit of normal, AST ≤ 200% institutional upper limit of normal).
5. Life expectancy of at least 12 weeks.
6. Have not received any chemotherapy within 4 weeks of study enrollment and must have recovered from any treatment-related toxicities.
7. Women of childbearing age must have a negative serum pregnancy test prior to initiating therapy.
8. Sexually active women of childbearing potential must use effective birth control during the trial and for an appropriate period after the trial.
9. Men must be willing to avoid fathering a new child while receiving therapy with azacitidine.
10. ≥18 years, no upper age limit
11. Individuals who are candidates for hematopoietic stem cell transplantation and who meet all other study criteria may participate in the study and receive intravenous azacitidine alone as a treatment prior to transplantation.

Exclusion Criteria:

1. Known CNS leukemia.
2. Previously received Azacitidine (Vidaza®, Pharmion Corp., Boulder CO) or decitabine (Dacogen®, MGI Pharma Inc. Bloomington, MN).
3. Known or suspected hypersensitivity to azacitidine or mannitol.
4. Receiving any other investigational agents within 30 days of first dose of study drug.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure of NYHA class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
6. Known positive serology for HIV.
7. Had radiotherapy within 14 days prior to study enrollment.
8. Known presence of hepatic tumors.
9. \<18 years of age
10. Exclude women who are pregnant or breast feeding.