Contact information
Type
Scientific
Primary contact
Prof B. Löwenberg
ORCID ID
Contact details
Erasmus Medical Centre
Daniel den Hoed Cancer Centre
Department of Hematology
P.O. Box 5201
Rotterdam
3008 AE
Netherlands
+31 (0)10 439 1598
b.lowenberg@erasmusmc.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
NTR212; HO43
Study information
Scientific 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)
Acronym
HOVON 43 AML/SAKK 30/01
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.
Ethics approval
Ethics approval received from the local medical ethics committee
Study design
Prospective randomised, active controlled, parallel group, multicentre trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Acute Myeloid Leukaemia (AML)
Intervention
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).
Intervention type
Drug
Phase
Phase III
Drug names
Cytarabine, daunomycin, gemtuzumab ozogamicin
Primary outcome measure
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 measures
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)
Overall trial start date
09/10/2000
Overall trial end date
01/11/2005
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Senior
Gender
Both
Target number of participants
800
Participant 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
Recruitment start date
09/10/2000
Recruitment end date
01/11/2005
Locations
Countries of recruitment
Netherlands
Trial participating centre
Erasmus Medical Centre
Rotterdam
3008 AE
Netherlands
Sponsor information
Organisation
Dutch Haemato-Oncology Association (Stichting Hemato-Oncologie Volwassenen Nederland) (HOVON) (Netherlands)
Sponsor details
Vrije University Medical Centre (VUMC)
PO Box 7057
Amsterdam
1007 MB
Netherlands
+31 (0)20 444 2693
hdc@hovon.nl
Sponsor type
Research organisation
Website
Funders
Funder type
Research organisation
Funder name
Koningin Wilhelmina Fonds (KWF) (Netherlands)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19776405
2. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20103782
Publication citations
-
Results
Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, Ferrant A, Sonneveld P, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, Breems D, de Muijnck H, Schaafsma R, Verhoef G, Döhner H, Gratwohl A, Pabst T, Ossenkoppele GJ, Maertens J, , , , Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study., Blood, 2010, 115, 13, 2586-2591, doi: 10.1182/blood-2009-10-246470.
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Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G, , , , High-dose daunorubicin in older patients with acute myeloid leukemia., N. Engl. J. Med., 2009, 361, 13, 1235-1248, doi: 10.1056/NEJMoa0901409.