Phase III Randomized Study of Subcutaneous Azacytidine vs Observation in Myelodysplastic Syndrome

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedover 15NCICLB-9221


I.  Determine the response rate of patients with previously untreated 
myelodysplastic syndrome (MDS) to azacytidine (AZA).

II.  Compare red cell transfusion requirements, platelet and neutrophil 
counts, rates of infection and hemorrhage, and percentage of bone marrow 
blasts in patients treated with AZA vs. an untreated observation group.

III.  Assess which MDS types respond optimally to subcutaneous AZA.

IV.  Evaluate the safety and toxicity of AZA in patients with MDS.

V.  Assess whether quality of life is significantly different between the 
treatment and observation groups.

Entry Criteria

Disease Characteristics:

Myelodysplastic syndrome confirmed by peripheral blood and bone marrow
maturation abnormalities of erythrocytic, megakaryocytic, and granulocytic

All FAB classifications are eligible, i.e.:
  Refractory anemia (RA)
  Refractory anemia with ringed sideroblasts (RARS)
  Refractory anemia with excess blasts (RAEB)
  Refractory anemia with excess blasts in transformation (RAEB-T)
  Chronic myelomonocytic leukemia (CMMol)

RA and RARS must be associated with at least one of the following:
  Symptomatic anemia requiring peripheral RBC transfusions for at least 3
  months prior to entry

  Platelets 50,000 or less or thrombocytopenia with significant clinical
  hemorrhage requiring platelet transfusion

  Absolute neutrophil count less than 1,000 with infection requiring
  antibiotic treatment

The following exclude:
  Greater than 30% myeloblasts in bone marrow
  M6 leukemia as defined by FAB criteria
  Prior history of leukemia

Concurrent enrollment on protocols CLB-8961 and CLB-8461 for cytogenetic
studies is strongly encouraged

Prior/Concurrent Therapy:

No prior cytotoxic therapy for MDS

Biologic therapy:
  No prior G-CSF, GM-CSF, IL-3, or other hematopoietic growth factors except
  No interferons within 1 month of entry

  No retinoids within 1 month of entry
  No prior azacytidine
  At least 6 months since chemotherapy for other cancer (no prior chemotherapy
     for leukemia)

Endocrine therapy:
  No corticosteroids within 1 month of entry

  At least 6 months since radiotherapy for other cancer (no prior radiotherapy
  for leukemia)

  Not specified

Patient Characteristics:

  Over 15

Performance status:

Life expectancy:
  At least 2 months

  (within 2 weeks prior to registration)
  Bone marrow differential count of at least 200 cells

  (within 2 weeks prior to registration)
  Bilirubin no greater than 1.5 x ULN unless there is active hemolysis or
     elevation is secondary to ineffective erythropoiesis
  SGOT/SGPT no greater than 2 x ULN

  (within 2 weeks prior to registration)
  Creatinine no greater than 1.5 x ULN
  Bicarbonate at least 19 mEq/liter

  No uncontrolled or severe congestive heart failure (CHF)
     Controllable high-output CHF secondary to anemia permitted

  At least 3 years since any evidence of malignancy
  No serious medical or psychiatric illness that would limit survival to less
    than 6 months or prevent informed consent
  No pregnant women

Expected Enrollment

Approximately 174 patients will be entered over 25 months in order to obtain a 
maximum of 158 evaluable patients.  Accrual will stop early if an interim 
analysis (performed after entry of every 45 patients) indicates rejection of 
the null hypothesis at the p = 0.05 level.


Randomized study.

Arm I:  Observation.

Arm II:  Single-Agent Chemotherapy.  Azacytidine, AZA, NSC-102816.

Published Results

Kornblith AB, Herndon JE 2nd, Silverman LR, et al.: Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 20 (10): 2441-52, 2002.[PUBMED Abstract]

Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002.[PUBMED Abstract]

Related Publications

Santini V, Fenaux P, Mufti GJ, et al.: Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Eur J Haematol 85 (2): 130-8, 2010.[PUBMED Abstract]

Silverman LR, McKenzie DR, Peterson BL, et al.: Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 24 (24): 3895-903, 2006.[PUBMED Abstract]

Silverman LR, Mufti GJ: Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat Clin Pract Oncol 2 (Suppl 1): S12-23, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Lewis Silverman, MD, Protocol chair
Ph: 212-241-5520

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.