Myelodysplastic Syndromes (MDS) are acquired clonal bone marrow disorders, characterised by impaired maturation and dysplastic morphology of haematopoietic precursor cells. Patients with MDS suffer from ineffective haematopoesis, causing anaemia, infectious complications, and haemorrhagic diathesis. Leukaemic transformation occurs in about 25% of cases.
In vitro studies suggest that combining two principles of epigenetic treatment, namely reversal of Deoxyribonucleic Acid (DNA) promoter hypermethylation by inhibitors of DNA methyltransferases, and reversal of chromatin condensation by histone acetylase inhibitors, synergize in reversing abnormal gene silencing.
The principal question of this clinical trial is to test whether the in vitro findings can be translated into therapeutic success in vivo.
Approval received from the Ethics Committee of the medical faculty of the Heinrich-Heine-University (leading) and the Ethics Committee of medical faculty of the Johann-Wolfgang-Goethe University on the 22nd June 2006 (ref: MC-LKP-107).
Phase II, open, prospective, single-armed, multicentre trial.
Primary study design
Secondary study design
Patient information sheet
Myelodysplastic syndromes (MDS)
Epigenetic treatment of MDS with demethylating agents has achieved remarkable clinical responses and seems to be superior to supportive care or intensive chemotherapy. Low-dose 5-azacytidine was the first drug shown to alter the natural course of MDS by significantly prolonging the time until leukaemia transformation.
At our institute we tried a different type of epigenetic treatment when we conducted the first clinical trial with Valproic Acid (VPA) in MDS. This drug has been shown to act as an inhibitor of Histone Deacetylase (HDAC). Since HDAC inhibitors and demethylating agents show synergistic effects in vitro, it appears promising to try the combination in vivo.
The differentiation-inducing agent All-Trans Retinoic Acid (ATRA) will be added after four months if 5-Aza plus VPA do not produce a satisfactory treatment response.
The treatment was as follows:
1. From beginning: Valproic acid 1500 - 2000 mg/d over one year, and azacytidine 100 mg/m^2/d applied over five days repeated every 28 days
2. After four months (if no improvement): All-trans retinoic acid 80 mg/m^2/d day one to seven repeated every 14 days
5-Azacytidine (5-Aza), Valproic Acid (VPA), and All-Trans Retinoic Acid (ATRA)
Primary outcome measure
Safety/toxicity, assessed at one year after treatment start.
Secondary outcome measures
All endpoints will be assessed at one year after treatment start:
1. Haematological response
2. Progression-free survival
3. Overall survival
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant inclusion criteria
1. Primary Myelodysplastic Syndromes (pMDS) with unfavourable risk profile (more than 10% blast cells in the bone marrow, unfavourable karyotype)
2. Therapy-related (secondary) Myelodysplastic Syndromes (sMDS)
3. Chronic Myelomonocytic Leukaemia (CMML)
4. De-novo or secondary acute myeloid leukemia in elderly patients who cannot be treated with intensive chemotherapy
Target number of participants
Participant exclusion criteria
1. Impaired liver or kidney function
3. Simultaneous participation in another clinical trial
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
Department of Haematology, Oncology and Clinical Immunology
c/o Professor N Gattermann
Department of Haematology
Oncology and Clinical Immunology
Funding Body Type
Funding Body Subtype
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)