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Randomised induction and post induction therapy in older patients (greater than or equal to 61 years of age) with Acute Myelocytic Leukaemia (AML) and Refractory Anaemia with Excess of Blasts (RAEB, RAEB-t)
ISRCTN ISRCTN77039377
DOI 10.1186/ISRCTN77039377
ClinicalTrials.gov identifier
EudraCT number
Public title Randomised induction and post induction therapy in older patients (greater than or equal to 61 years of age) with Acute Myelocytic Leukaemia (AML) and Refractory Anaemia with Excess of Blasts (RAEB, RAEB-t)
Scientific title
Acronym HOVON 43 AML/SAKK 30/01
Serial number at source NTR212; HO43
Study hypothesis 1. The first hypothesis to be tested is that the outcome in arm B is better than in arm A.
2. The second hypothesis to be tested is that the outcome in arm two is better than in arm one.
Lay summary
Ethics approval Ethics approval received from the local medical ethics committee
Study design Prospective randomised, active controlled, parallel group, multicentre trial
Countries of recruitment Netherlands
Disease/condition/study domain Acute Myeloid Leukaemia (AML)
Participants - inclusion criteria 1. Age 61 years or more
2. Subjects with a cytopathologically confirmed diagnosis of AML (M0-M2 and M4-M7, FAB classification), or with Refractory Anaemia with Excess of Blasts (RAEB) or Refractory Anaemia with Excess of Blasts in transformation (RAEB-t) with an International Prognostic Scoring System (IPSS) score of greater than or equal to 1.5
3. Subjects with a secondary AML progressing from antecedent Myelodysplasia (MDS) and biphenotypic leukemia are eligible. Antecedent MDS refers to any antecedent haematological disease of at least four month duration
4. World Health Organisation (WHO) performance status less than or equal to two
5. Written informed consent
Participants - exclusion criteria 1. Previous induction treatment for AML/MDS
2. Prior chemotherapy within six months of study entry
3. Previous polycythemia rubra vera
4. Primary myelofibrosis
5. Blast crisis of chronic myeloid leukemia
6. AML-FAB type M3 or AML with cytogenetic abnormality t(1517) translocation
7. Impaired hepatic or renal function as defined by:
a. Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) greater than 25 x normal value
b. Bilirubin greater than 2 x normal value
8. Serum creatinine greater than 2 x normal value (after adequate hydration), unless these are most likely caused by AML organ infiltration
9. Concurrent severe and/or uncontrolled medical condition (e.g., uncontrolled diabetes, infection, hypertension, etc.,)
10. Cardiac dysfunction as defined by:
10.1. myocardial infarction within the last six months of study entry, or
10.2. reduced left ventricular function with an ejection fraction less than or equal to 50% as measured by Multiple Gated Acquisition (MUGA) scan or echocardiogram (another method for measuring cardiac function is acceptable)
11. Unstable angina
12. Unstable cardiac arrhythmias
Anticipated start date 09/10/2000
Anticipated end date 01/11/2005
Status of trial Completed
Patient information material
Target number of participants 800
Interventions Patients will be randomised on entry for induction between:

Arm A:
Cycle I: conventional type daunomycin-cytarabine schedule
Cycle II: intermediate dose cytarabine

Arm B:
Cycle I: daunomycin at escalated dose with standard dose cytarabine
Cycle II: intermediate dose cytarabine

Patients attaining Complete Response (CR) and remaining in CR after cycle II will be randomised between:

Arm one: no further treatment
Arm two: three dosages of Gemtuzumab Ozogamicin (GO, Mylotarg) at four week intervals

For patients with an Human Leukocyte Antigen (HLA) identical sibling donor, an allograft with non-myeloablative conditioning, will be available depending on the active involvement in allotransplantation per centre (optional per centre).
Primary outcome measure(s) Endpoint for the comparison of induction treatment arm B with arm A:
Event-free survival (i.e. time from registration to induction failure, death or relapse whichever occurs first); the time to failure of patients with induction failure is set at one day.

Endpoint for the comparison of post induction maintenance treatment with GO with no further treatment: disease-free survival measured from the date of second randomisation to relapse or death from any cause.
Secondary outcome measure(s) Endpoints for the comparison of induction treatment arm B with arm A:
1. Response and especially CR to chemotherapy cycles I and II
2. Overall survival measured form the time of registration
3. Disease-free interval (duration of the first CR) measured from the time of achievement of CR to day of relapse or death from any cause (whichever occurs first)
4. Probability of complete response, relapse, death in CR1, event-free survival, disease-free survival and overall survival will also be assessed in relation to age (61 - 70, 70 - 80, above 80), cytogenetic abnormalities, CD33-positivity of AML (phenotype), P-glycoprotein (PgP) positivity
5. Toxicities and treatment related mortality
6. Time to haematopoietic recovery (Absolute Neutrophil Count [ANC] 0.5 and 1.5 x 10^9/l; platelets 50 and 100 x 10^9/l) after each treatment cycle
7. Number of platelet transfusions and last day of platelet transfusion after each cycle

Endpoints for the comparison of post induction maintenance treatment with GO with no further treatment:
1. Overall survival measured from the date of second randomisation.
2. Probability of relapse and death in first CR from date of second randomisation calculated as competing risks
3. Number and duration of hospitalisation as well as transfusion requirements (red cell and platelet transfusion)
Sources of funding Koningin Wilhelmina Fonds (KWF) (Netherlands)
Trial website http://www.hovon.nl
Publications 1. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19776405
2. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20103782
Contact name Prof  B.  Löwenberg
  Address Erasmus Medical Centre
Daniel den Hoed Cancer Centre
Department of Hematology
P.O. Box 5201
  City/town Rotterdam
  Zip/Postcode 3008 AE
  Country Netherlands
  Tel +31 (0)10 439 1598
  Fax +31 (0)10 439 1004
  Email b.lowenberg@erasmusmc.nl
Sponsor Dutch Haemato-Oncology Association (Stichting Hemato-Oncologie Volwassenen Nederland) (HOVON) (Netherlands)
  Address Vrije University Medical Centre (VUMC)
P.O. Box 7057
  City/town Amsterdam
  Zip/Postcode 1007 MB
  Country Netherlands
  Tel +31 (0)20 444 2693
  Fax +31 (0)20 444 3670
  Email hdc@hovon.nl
  Sponsor website: http://www.hovon.nl/
Date applied 20/12/2005
Last edited 04/05/2010
Date ISRCTN assigned 20/12/2005
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