- The overall survival (OS) of older AML patients has not been improved during the last
decades with intensive chemotherapy based on cytarabine combined with an anthracycline
("3+7").
- Next generation sequencing technology reveals that mutations in genes involved in
epigenetics are frequently mutated in AML (e.g. DNMT3a), suggesting an important role of
epigenetics in the pathophysiology of AML. Decitabine (given in a 5-day schedule) has
been shown to be superior to low-dose Ara-C.
- A retrospective analysis revealed that epigenetic therapy (either azacitidine or
decitabine) is associated with similar survival rates as intensive chemotherapy in older
patients (n=671) with newly diagnosed AML.
- The recently published encouraging phase 2 data with the 10-day decitabine schedule
suggests that decitabine results in similar CR rates compared with intensive
chemotherapy. Allogeneic transplantation (alloHCT) also offers the opportunity for cure
among older AML patients, therefore treatment strategies should aim to allograft older
AML patients.
- Decitabine treatment can lead to very interesting cure rates when used as "bridging" to
allografting.
Based on the data summarized above, we hypothesize that decitabine at a daily dose of 20
mg/m² starting with the 10-day schedule followed by an alloHCT or by continuation of 5-days
decitabine cycles is superior to conventional intensive chemotherapy in older AML patients.
Inclusion criteria:
1. Age ≥ 60 years
2. WHO Performance status ≤ 2
3. Eligible for standard intensive chemotherapy
4. Newly diagnosed AML cytopathologically confirmed to the WHO classification (up to 2
months prior to randomization)
5. De novo or secondary AML is allowed
6. White blood cell (WBC) count is ≤ 30x10E9/L (measured within 72 hours prior to
randomization).
7. Laboratory assessments (measured prior to randomization):
1. serum glutamate oxaloacetate transaminase (SGOT / ASAT) and serum glutamate
pyruvate transaminase (SGPT / ALAT) < 2.5 x the upper limit of normal range
unless considered AML-related
2. Total serum bilirubin < 2.5 x the upper limit of normal range unless considered
AML-related or due to Gilbert's syndrome
3. Serum creatinine < 2.5 x the upper limit of normal range unless considered
AML-related
8. Patients of reproductive potential should use adequate birth control measures, as
defined by investigator, during the study treatment period and for at least 3 months
after the last study treatment.
9. Before patient registration/randomization, written informed consent must be given
according to the International Conference of Harmonization good clinical practice (ICH
GCP) and national/local regulations
Exclusion criteria:
1. Presence of acute promyelocytic leukemia (APL, i.e. AML-M3 with t(15;17)(q22;q12);
promyelocytic leukemia - retinoic acid receptor-alpha (PML-RARA) fusion gene and
cytogenetic variants)
2. Presence of blast crisis of chronic myeloid leukemia
3. Presence of active central nervous system (CNS) leukemia
4. Patients did not receive any prior treatment for AML (relapsed AML is not allowed),
such as any antileukemic therapy including investigational agents and hypomethylating
agents (decitabine, 5-azacytidine). Treatment with hydroxyurea (HU) is allowed to
control the leukocytosis if given preferably for less than 5 days and is stopped at
least two days prior to the start of any of the protocol regimens
5. Patients received any prior treatment for myelodysplastic syndrome (MDS) or
myeloproliferative neoplasms (MPN) with:
1. hypomethylating agents (decitabine, 5-azacytidine), OR
2. with intensive chemotherapy or transplantation within the last three years
3. NOTE: The following treatments for previous MDS or MPN are allowed (up to one
month before inclusion):
- Growth factors, thrombomimetics, immunosuppression (cyclosporin A, steroids,
antithymocyte globulin etc.), chelation, interferons, anagrelide
- Lenalidomide, low-dose chemotherapy (low-dose melphalan, HU, low-dose
cytarabine etc.), tyrosine-kinase inhibitors, histone deacetylase inhibitors
(e.g. valproic acid, panobinostat etc.), mammalian target of rapamycin
(mTOR) inhibitors, other experimental treatment that is not based on
inhibition of deoxyribonucleic acid (DNA) methyltransferase
6. Presence of concomitant severe cardiovascular disease which would make intensive
chemotherapy impossible, i.e. uncontrolled arrhythmias requiring chronic treatment,
congestive heart failure or symptomatic ischemic heart disease, reduced left
ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram
7. Presence of any malignancy (except basal and squamous cell carcinoma of the skin) for
which the patient received systemic anticancer treatment within 6 months prior to
randomization NOTE: Diagnosis of any previous or concomitant malignancy is thus not an
exclusion criterion.
8. Presence of active uncontrolled infection
9. Presence of any psychological, familial, sociological or geographical condition in the
opinion of the investigator potentially hampering compliance with the study protocol
and follow-up schedule; those conditions should be discussed with the patient before
registration in the trial
