A Survival Study in Patients With High Risk Myelodysplastic Syndromes Comparing Azacitidine Versus Conventional Care
- Conditions
- Myelodysplastic Syndromes
- Interventions
- Other: Physician Choice
- Registration Number
- NCT00071799
- Lead Sponsor
- Celgene
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 358
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Conventional Care Physician Choice 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 Azacitidine Azacitidine Study Drug plus best supportive care. Treatment with erythropoietin was not permitted
- Primary Outcome Measures
Name Time Method Kaplan-Meier Estimates for Median Time to Death From Any Cause Day 1 (randomization) to 42 months 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.
Number of Participants Who Died 42 months Count of participants who died during the study
Summary of Subgroup Analyses for Kaplan-Meier Estimates for Time to Death From Any Cause Day 1 (randomization) to 42 months 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.
- Secondary Outcome Measures
Name Time Method Kaplan-Meier Estimate for Median Time to Transformation to Acute Myeloid Leukemia (AML) or Death From Any Cause, Whichever Occurred First Day 1 (randomization) to 42 months 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.
Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline Day 1 (randomization) to 42 months 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 Day 1 (randomization) to 42 months 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.
Number of Participants in Different Categories of Adverse Experiences During Core Study Period Day 1 (randomization) to 42 months 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.
Kaplan-Meier Estimates for Median Time to Transformation to Acute Myeloid Leukemia (AML) Day 1 (randomization) to 42 months 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 Day 1 (randomization) to 42 months 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.
Number of Participants Considered Hematologic Responders by Investigator Determinations Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS) Day 1 to 42 months 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 Day 1 to 42 months 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 Day 1 (randomization) to 42 months 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.
Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline Day 1 (randomization) to 42 months 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.
Duration of Any Hematologic Improvement Day 1 (randomization) to 42 months 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 Day 1 (randomization) to 42 months 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.
Trial Locations
- Locations (106)
Hospital de Leon
🇪🇸Leon, Spain
Samodzielny Publiczny Szpital Kliniczny
🇵🇱Lublin, Poland
The Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
General Hospital of Chest Disease
🇬🇷Athens, Greece
University Multiprofile Hospital for Active Treatment "Sveta Marina"
🇧🇬Varna, Bulgaria
First Clinical Base - Clinic of Hematology, MHAT - Pleven
🇧🇬Pleven, Bulgaria
MHAT "St George" Clinic of Hematology, Plovdiv
🇧🇬Plovdiv, Bulgaria
District General Hospital of Athens
🇬🇷Athens, Greece
VU University Medical Center Amsterdam
🇳🇱Amsterdam, Netherlands
Samodzielny Publiczny Szpital Kliniczny Nr 1
🇵🇱Wroclaw, Poland
Universitatsklinikum Benjamin Franklin
🇩🇪Hindenburgdamm, Berlin, Germany
University of Pecs, 1st Dept of Internal Medicine
🇭🇺Pecs, Hungary
City Hospital #31
🇷🇺St. Petersburg, Russian Federation
III-rd Internal Department, District Dispensary for Oncology diseases with stationary(DDOncDIU)
🇧🇬Plovdiv, Bulgaria
National Centre of Hematology and Transfusiology, Sofia
🇧🇬Sofia, Bulgaria
University General Hospital of Ioannina
🇬🇷Ioannina, Greece
Univ Hospital St. Radboud
🇳🇱Nijmejen, Netherlands
Institute of Haematology & Blood Transfusion
🇷🇺St. Petersburg, Russian Federation
Burdenko Central Military Clinical Hospital
🇷🇺Moscow, Russian Federation
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Orszagos Gyogyintezeti Kozpont
🇭🇺Budapest, Hungary
Multiprofile Hospital for Active Treatment (MHAT), "St. Marina" Clinic of Hematology
🇧🇬Varna, Bulgaria
Wojskowy Instytut Medyczny
🇵🇱Warszawa, Poland
Pavlov State Medical University
🇷🇺St. Petersburg, Russian Federation
Scientific Haematology Center, Moscow
🇷🇺Moscow, Russian Federation
Indiana University Cancer Center
🇺🇸Indianapolis, Indiana, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Western Pennsylvania Cancer Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Instituto Nazionale Tumori "Regina Elena"
🇮🇹Roma, Italy
Blokhin Cancer Research Center
🇷🇺Moscow, Russian Federation
Mount Sinai Medical Center
🇺🇸New York, New York, United States
University of Alabama School of Medicine
🇺🇸Birmingham, Alabama, United States
Oregon Cancer Center
🇺🇸Portland, Oregon, United States
Froedtert Memorial Lutheran Hospital
🇺🇸Milwaukee, Wisconsin, United States
Royal North Shore Hospital
🇦🇺St. Leonards, New South Wales, Australia
Hopital Beaujon
🇫🇷Clichy, France
The Newcastle Mater Miseriecordiae Hospital
🇦🇺Warratah, New South Wales, Australia
Royal Brisbane Hospital
🇦🇺Hersten, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Hospital Edouard Herriot
🇫🇷Lyon, France
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Fakultni nemocnice Brno
🇨🇿Jihlavska, Brno, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Sokolska, Hradec Kralove, Czechia
Vseobecna Fakultni Nemocnice
🇨🇿Praha, Czechia
Fakultni Nemocnice Olomouc
🇨🇿Olomouc, Czechia
Universitatsklinikum Hambur-Eppendorf
🇩🇪Hamburg, Germany
Uslav Hematologie a Krevni Transfuze
🇨🇿Praha, Czechia
Chu D'Angers
🇫🇷Angers, France
Che De Lille
🇫🇷Lille, France
Institute Paoli Calmettes
🇫🇷Marseille, France
Hospital Saint Louis
🇫🇷Paris, France
Hopital Cochin
🇫🇷Paris, France
Chu De Nantes
🇫🇷Nantes, France
Centre Henri Becquerel
🇫🇷Rouen, France
Chu Purpan
🇫🇷Toulouse, France
Universitatsklinikum Bonn
🇩🇪Bonn, Germany
Klinikum Chemnitz gGmbH
🇩🇪Chemnitz, Germany
St Johannes Hospital
🇩🇪Duisburg, Germany
Universitatsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
Heinrich-Heine University Dusseldorf
🇩🇪Dusseldorf, Germany
Gerorg-August-Universitat Gottingen
🇩🇪Gottingen, Germany
Allgemeines Krankenhaus St. Georg
🇩🇪Hamburg, Germany
University Essen
🇩🇪Essen, Germany
University Hospital-Attikon
🇬🇷Haidari, Athens, Greece
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
Universitatsklinikum Kiel II
🇩🇪Kiel, Germany
University General Hospital of Heraklio Voutes
🇬🇷Heraklio, Crete, Greece
University General Hospital of Patra Rio
🇬🇷Patra, Greece
University of Szeged, 2nd Department of Internal Medicine
🇭🇺Szeged, Hungary
Universita di Firenze
🇮🇹Firenze, Italy
Policlinico S. Orsola-Malpighi
🇮🇹Bologna, Italy
Ospedale San Martino
🇮🇹Genova, Italy
Instituto Nazionale Dei Tumori
🇮🇹Milano, Italy
Centro Oncologico Modenese
🇮🇹Modena, Italy
Policlinico Gemelli
🇮🇹Roma, Italy
Ospedale Casa Sollievo Della Sofferenza - Irrc
🇮🇹San Giovanni Rotondo, Italy
Ospedale San Eugenio
🇮🇹Roma, Italy
Universita Degli Studi Di Sassari
🇮🇹Sassari, Italy
Wojewodzki Szpital Specjalistyczny
🇵🇱Lodz, Poland
Samodzelny Publiczny Centralny Szpital Kliniczny
🇵🇱Warszawa, Poland
John Radcliffe Hospital
🇬🇧Oxford, United Kingdom
Hospital Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hospital Clinic
🇪🇸Barcelona, Spain
Hospital Universitario Germans Trias I Pujol
🇪🇸Barcelona, Spain
Hospital Universitario De La Princesa
🇪🇸Madrid, Spain
Hospital Ramon Y Cajal
🇪🇸Madrid, Spain
Sahlgrenska University Hospital
🇸🇪Goteborg, Sweden
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Hospital Son Llatzer
🇪🇸Palma de Mallorca, Spain
Huddinge University Hospital
🇸🇪Stockholm, Sweden
Hospital Universitario Del Salamanca
🇪🇸Salamanca, Spain
Uppsala University Hospital
🇸🇪Uppsala, Sweden
Lund Universtiy Hospital
🇸🇪Lund, Sweden
University Hospital MAS
🇸🇪Malmo, Sweden
St. Bartholomew's Hospital
🇬🇧London, United Kingdom
Royal Bournemouth General Hospital
🇬🇧Bournemouth, United Kingdom
Norfolk and Norwich University Hospital
🇬🇧Norwich, United Kingdom
Christie Hospital
🇬🇧Manchester, United Kingdom
Kings College Hospital NHS Trust
🇬🇧London, United Kingdom
Royal Cornwall Hospital
🇬🇧Truro, United Kingdom
Hospital La Paz, Madrid
🇪🇸Madrid, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Peter MacCallum Cancer Institute
🇦🇺East Melbourne, Victoria, Australia