Randomised induction and post-induction therapy in adult patients (less than or equal to 60 years of age) with acute myelocytic leukaemia (AML) or refractory anaemia with excess of blasts (RAEB, RAEB-t) with IPSS score greater than or equal to 1.5

ISRCTN ISRCTN38648181
DOI https://doi.org/10.1186/ISRCTN38648181
Secondary identifying numbers Ho42; NTR230
Submission date
20/12/2005
Registration date
20/12/2005
Last edited
18/11/2008
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year

Plain English summary of protocol

Not provided at time of registration

Study website

Contact information

Prof B. Löwenberg
Scientific

Erasmus Medical Centre
Daniel den Hoed Cancer Centre
Department of Hematology
P.O. Box 5201
Rotterdam
3008 AE
Netherlands

Phone +31 (0)10 439 1598
Email b.lowenberg@erasmusmc.nl

Study information

Study designMulticentre, randomised, active controlled, parallel group trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Scientific title
Study acronymHOVON/SAKK 42 AML
Study objectivesThe three hypotheses to be tested are that the outcome in:
1. The high dose arm B is better than in the low dose arm A
2. The granulocyte colony-stimulating factor (G-CSF) arm is better than in the non-G-CSF arm
3. The peripheral-blood stem-cell transplantation (PBSCT) arm 2 is better than the chemotherapy cycle III arm 1
Ethics approval(s)Received from the local medical ethics committee
Health condition(s) or problem(s) studiedAcute myeloid leukaemia (AML)
InterventionPatients will be randomised on entry for induction between:
Arm A: Cycle I: idarubicin and conventional dose cytarabine, Cycle II: amsacrine and intermediate dose cytarabine
Arm B: Cycle I: idarubicin and intermediate dose cytarabine, Cycle II: amsacrine and high dose cytarabine

A second randomisation for induction will involve yes or no priming with G-CSF during chemotherapy of induction cycles I and II. All CR patients will be distinguished according to good risk, intermediate risk, and poor risk features:
1. Good risk patients will receive a third cycle of chemotherapy (cycle III: mitoxantrone plus etoposide) and will not be randomised
2. Intermediate or poor risk patients with age below 55 years and with a HLA matched family donor will proceed to allogeneic stem cell transplantation
3. Poor risk patients with age below 50 yrs without a HLA matched sibling donor, but with a phenotypically matched unrelated donor may proceed to marrow ablative treatment and allogeneic stem cell transplantation as soon as they have entered CR. If patients are already distinguished as poor risk following cycle I and logistically there are no impediments the patient may proceed to Allo SCT as soon as possible after cycle I.
4. All other patients in CR, including patients who refuse stem cell transplantation, will undergo stem cell mobilisation with G-CSF and stem cell collection

Patients with an adequate harvest and meeting the eligibility criteria will be randomised between:
Arm 1: chemotherapy cycle III: mitoxantrone and etoposide
Arm 2: busulfan-cyclophosphamide ablation and autologous PBSCT

Patients who are not eligible for Allo-SCT or who do not meet the eligibilty criteria for randomisation will receive cycle III as consolidation treatment. Poor risk patients in PR after cycle II with a HLA matched family donor (and patient’s age below 55 years) or with a phenotypically matched unrelated donor (and patient’s age below 50 years) may proceed to allogeneic stem cell transplantation.
Intervention typeDrug
Pharmaceutical study type(s)
PhaseNot Specified
Drug / device / biological / vaccine name(s)Idarubicin, cytarabine, amsacrine, mitoxantrone, etoposide, busulfan-cyclophosphamide
Primary outcome measure1. Endpoint for the comparison of induction treatment arm B with arm A and for the comparison yes or no G-CSF priming: 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.
2. Endpoint for the comparison of PBSCT with cycle III: Disease-free survival measured from the date of second randomisation to relapse or death from any cause.
3. Endpoint for the evaluation of Allo-SCT: Disease-free survival measured from the date of Allo-SCT to relapse or death from any cause.
Secondary outcome measures1. Endpoints for the comparison of induction treatment arm B with arm A and for the comparison yes or no G-CSF priming:
1.1. Response and especially CR to chemotherapy cycles I and II
1.2. Overall survival measured from the time of registration
1.3. 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)
1.4. Toxicities and treatment related mortality
1.5. Time to haematopoietic recovery (ANC 0.5 and 1.5 x 10^9/l; platelets 50 and 100 x 10^9/l) after each treatment cycle
1.6. Number of platelet transfusions and last day of platelet transfusion after each cycle

2. Endpoints for the comparison of PBSCT with cycle III:
2.1. Overall survival measured from the date of second randomisation
2.2. Probability of relapse and death in first CR from date of second randomisation calculated as competing risks
2.3. Duration of hospitalisation as well as transfusion requirements (red cell and platelet transfusion)
2.4. Time to haematopoietic recovery

3. Endpoints for the evaluation of Allo-SCT:
3.1. Overall survival measured from the date of Allo-SCT
3.2. Probability of relapse and death in first CR from date of second randomisation calculated as competing risks
3.3. Duration of hospitalisation as well as transfusion requirements (red cell and platelet transfusions)
3.4. Time to haematopoietic recovery
3.5. Incidence and severity of acute and chronic GvHD
Overall study start date02/01/2001
Completion date01/01/2006

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants800
Key inclusion criteria1. Aged 18 - 60 years (inclusive)
2. Subjects with a cytopathologically confirmed diagnosis of:
2.1. AML (M0-M2 and M4-M7, FAB classification), or
2.2. With refractory anaemia with excess of blasts (RAEB) or refractory anaemia with excess of blasts in transformation (RAEB-t) with an IPSS score of greater than or equal to 1.5
3. Patients with therapy-related AML/RAEB/RAEB-t are eligible provided they have not received chemotherapy during the past 6 months. Also patients with biphenotypic leukemia may be included.
4. Subjects with a secondary AML progressing from antecedent myelodysplasia are eligible. Antecedent MDS refers to a condition of at least 4 month duration
5. World Health Organization (WHO) performance status less than or equal to 2
6. Written informed consent
Key exclusion criteria1. Prior chemotherapy within 6 months of study entry
2. Relapse of AML or MDS after induction chemotherapy
3. Prior stem cell transplant
4. Previous polycythemia rubra vera
5. Primary myelofibrosis
6. Blast crisis of chronic myeloid leukemia
7. AML-FAB type M3 or AML with cytogenetic abnormality t(1517) or AML with a PML/RAR alpha or a variant RAR alpha fusion gene
8. Impaired hepatic or renal function as defined by: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 3 x normal value, bilirubin greater than 3 x normal value, serum creatinine greater than 3 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: myocardial infarction within the last 6 months of study entry, or reduced left ventricular function with an ejection fraction less than or equal to 50% as measured by MUGA scan or echocardiogram (another method for measuring cardiac function is acceptable), unstable angina, unstable cardiac arrhythmias
11. Pregnancy
Date of first enrolment02/01/2001
Date of final enrolment01/01/2006

Locations

Countries of recruitment

  • Netherlands

Study participating centre

Erasmus Medical Centre
Rotterdam
3008 AE
Netherlands

Sponsor information

Dutch Haemato-Oncology Association (Stichting Hemato-Oncologie Volwassenen Nederland) (HOVON) (Netherlands)
Research organisation

Vrije University Medical Centre (VUMC)
PO Box 7057
Amsterdam
1007 MB
Netherlands

Phone +31 (0)20 444 2693
Email hdc@hovon.nl
Website http://www.hovon.nl/
ROR logo "ROR" https://ror.org/056kpdx27

Funders

Funder type

Research organisation

Dutch Haemato-Oncology Association (Stichting Hemato-Oncologie Volwassenen Nederland) (HOVON) (The Netherlands)

No information available

The National Cancer Fund (Koningin Wilhelmina Fonds [KWF]) (The Netherlands)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan