A Survival Study in Patients With High Risk Myelodysplastic Syndromes Comparing Azacitidine Versus Conventional Care

• Kaplan-Meier Estimates for Median Time to Death From Any Cause [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact.
• Summary of Subgroup Analyses for Kaplan-Meier Estimates for Time to Death From Any Cause [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]

  Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact.

  Subgroups that were analyzed are age, gender, French-American-British (FAB) classification, World Health Organization (WHO) classification and International Prognostic Scoring System (IPSS) classification.

• Number of Participants Who Died [ Time Frame: 42 months ] [ Designated as safety issue: No ]
  Count of participants who died during the study

• Kaplan-Meier Estimate for Median Time to Transformation to Acute Myeloid Leukemia (AML) or Death From Any Cause, Whichever Occurred First [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  The time to transformation to AML or death from any cause (whichever occurred first) was defined as the number of days from the date of randomization until the date of documented AML transformation or death from any cause. Patients who did not transform to AML or die were censored at the date of last follow-up.
• Kaplan-Meier Estimates for Median Time to Transformation to Acute Myeloid Leukemia (AML) [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  The time to transformation to AML was defined as the number of days from the date of randomization until the date of documented AML transformation, defined as a bone marrow blast count ≥ 30% independent of baseline bone marrow count. Patients who did not transform to AML were censored at the date of last follow-up or date of death.
• Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Summary of dependence and independence from red blood cell (RBC) transfusion at baseline and during treatment, for patients who were dependent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.
• Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Summary of dependence and independence from red blood cell (RBC) transfusion at baseline and during treatment, for patients who were independent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.
• Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Summary of dependence and independence from platelet transfusion at baseline and during treatment for patients who were dependent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.
• Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Summary of dependence and independence from platelet transfusion at baseline and during treatment for patients who were independent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.
• Number of Participants Considered Hematologic Responders by Investigator Determinations Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS) [ Time Frame: Day 1 to 42 months ] [ Designated as safety issue: No ]

  Investigator determined responses followed IWG criteria for

  • complete remission(CR): repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia
  • partial remission(PR) is the same as CR for peripheral blood: bone marrow shows blasts decrease by >=50% or a less advanced FAB classification from pretreatment
  • stable disease(SD) is a failure to achieve at least a partial remission, but with no evidence of progression for at least 2 months.
• Number of Participants Showing Hematologic Improvement Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS) Assessed by Independent Review Committee [ Time Frame: Day 1 to 42 months ] [ Designated as safety issue: No ]

  IWG 2000 Criteria: Pretreatment=hemoglobin <100g/L or RBC transfusion-dependent, platelet count <100x10^9/L or platelet transfusion dependent, absolute neutrophil count <1.5x10^9/L.

  Erythroid response: Major->20g/L increase or transfusion independent. Minor- 10-20g/L increase or >=50% decrease in transfusion requirements.

  Platelet response: Major-absolute increase of >=30x10^9/L or platelet transfusion independence. Minor->=50% increase.

  Neutrophil response: Major->=100% increase or an absolute increase of >0.5x10^9/L. Minor->=100% increase and absolute increase of <0.5x10^9/L.

• Time to Disease Progression, Relapse After Complete or Partial Remission, or Death From Any Cause [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  The time to disease progression, relapse after complete or partial remission (CR, PR), or death from any cause was defined as the time from the date of randomization until the first date of documented disease progression, relapse after CR or PR, or death from any cause.
• Duration of Any Hematologic Improvement [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  The duration of improvement was defined as the time from the date of hematologic improvement until the date of first documented progression or relapse after hematologic improvement or death from any cause.
• Number of Infections Per Treatment Year Requiring Intravenous Antibiotics, Antifungals or Antivirals [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  The on-treatment adverse event rate of infection requiring IV antibiotics, antifungals, or antivirals per patient-years. The on-treatment period was considered the period from the date of randomization to the last treatment study visit.
• Number of Participants in Different Categories of Adverse Experiences During Core Study Period [ Time Frame: Day 1 (randomization) to 42 months ] [ Designated as safety issue: No ]
  Patient counts for a variety of subsets of adverse experiences for the core study period (day 1 to 42 months). The individual options for Conventional Care Regimens (Best Supportive Care Only, Low-Dose Cytarabine, and Standard Chemotherapy) are presented as separate treatments.

The purpose of this study is to determine whether patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine have improved survival compared to conventional care treatments. The study will also assess the effect of treatments on response, duration of response, and transformation to acute myeloid leukemia (AML). The study will continue for 12 months following last patient enrolled.

See study AZA PH GL 2003 CL 001 E for information about the extension to this study.

Comparison/Control Interventions offered the physician three options:

• Best supportive care (BSC) alone,
• Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
• Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).

All three options included best supportive care. Neither the experimental group (azacitidine) nor any of the comparison/control options allowed use of erythropoietin.

Duration of Intervention: Patients will be treated until death, withdrawal, unacceptable toxicity or conclusion of the study.

• Drug: Azacitidine
  Azacitidine was injected subcutaneously (SC) at an initial dose of 75mg/m^2/day for 7 days. The 7-day dosing was repeated every 28 days with dose adjustment based on predefined hematology and renal laboratory results. Number of cycles: Azacitidine treatment was to be continued until the end of the study unless treatment was discontinued due to unacceptable toxicity, relapse after complete or partial response, transformation to AML or disease progression.
  Other Name: AZA
• Other: Physician Choice

  Physician Choice was one of three options:

  • Best supportive care (BSC) alone,
  • Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
  • Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).

  All three options included best supportive care

  Other Names:

  • cytarabine
  • anthracycline

• Experimental: Azacitidine
  Study Drug plus best supportive care. Treatment with erythropoietin was not permitted
  Intervention: Drug: Azacitidine
• Active Comparator: Conventional Care
  Physician choice of low dose cytarabine (plus best supportive care), standard chemotherapy (plus best supportive care) or best supportive care (only). Treatment with erythropoietin was not permitted
  Intervention: Other: Physician Choice

• Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21.
• Fenaux P, Gattermann N, Seymour JF, Hellström-Lindberg E, Mufti GJ, Duehrsen U, Gore SD, Ramos F, Beyne-Rauzy O, List A, McKenzie D, Backstrom J, Beach CL. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol. 2010 Apr;149(2):244-9. Epub 2010 Feb 5. Erratum in: Br J Haematol. 2010 Jun;149(6):919.
• Santini V, Fenaux P, Mufti GJ, Hellström-Lindberg E, Silverman LR, List A, Gore SD, Seymour JF, Backstrom J, Beach CL. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Eur J Haematol. 2010 Aug;85(2):130-8. Epub 2010 Apr 12.
• Seymour JF, Fenaux P, Silverman LR, Mufti GJ, Hellström-Lindberg E, Santini V, List AF, Gore SD, Backstrom J, McKenzie D, Beach CL. Effects of azacitidine compared with conventional care regimens in elderly (>/=75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol. 2010 May 5; [Epub ahead of print]
• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. Epub 2009 Feb 21.

Inclusion Criteria:

• Have a diagnosis of refractory anemia with excess blasts or refractory anemia with excess blasts in transformation according to the French-American-British classification system for myelodysplastic syndromes (MDS) and a relatively high risk of acute myeloid leukemia (AML) transformation, with an International Prognostic Scoring System score of INT-2 or High.
• Be 18 years of age or older
• Have a life expectancy of at least 3 months
• Be unlikely to proceed to bone marrow or stem cell transplantation therapy following remission
• Have serum bilirubin levels less than or equal to 1.5 times the upper limit of normal range for the laboratory
• Have serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) or serum glutamic-pyruvic transaminase (alanine aminotransferase) levels less than or equal to 2 times the upper limit of normal (unless these are considered to be related to transfusion-induced secondary hemosiderosis)
• Have serum creatinine levels less than or equal to 1.5 times the upper limit of normal

Exclusion Criteria:

• Secondary myelodysplastic syndromes (MDS)
• Prior treatment with azacitidine;
• Prior history of acute myeloid leukemia (AML);
• Malignant disease diagnosed within prior 12 months;
• Metastatic disease;
• Hepatic tumors;
• Radiation, chemotherapy, cytotoxic therapy for non-MDS conditions within prior 12 months;
• Prior transplantation or cytotoxic therapy to treat MDS;
• Serious medical illness likely to limit survival to 12 months or less;
• Treatment with erythropoietin or myeloid growth factors during prior 21 days or androgenic hormones during prior 13 days;
• Active HIV, viral hepatitis type B or C;
• Treatment with investigational drugs during prior 30 days;
• Within the 28-day screening period, documented red cell folate deficiency, as evidenced by red blood cell folate (not serum folate) or vitamin B12 deficiency