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Published on 28 May 2009

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Methyltransferase inhibitors to treat myelodysplastic syndromes

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The methyltransferase inhibitors azacytidine and decitabine are promising new therapeutic agents in the treatment of myelodysplastic syndromes

Stef Meers

Michel Delforge
Haematology Department
University Hospital of Leuven, Belgium

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematologic diseases. Cytopenia is the presenting symptom in most patients diagnosed with MDS and is the consequence of impaired production of mature blood cells in the bone marrow (BM). The BM failure in MDS primarily results from acquired genomic defects in the haematopoietic progenitor cells. But also factors from the marrow microenvironment in which these progenitor cells reside have been described to influence the process.

There is currently no standard treatment for patients with MDS. The only putative curative treatment is allogeneic stem cell transplantation, but only a minority of patients are eligible for this treatment because of concerns over their age and co-morbidities. Hence, the majority of patients receive supportive therapy with frequent transfusions, antibiotics or haematopoietic growth factors.

Recently, several new treatment modalities have emerged with promising results. The immunomodulatory drug lenalidomide (Revlimid) has been shown to induce transfusion independency, especially in patients with an interstitial deletion of the long arm of chromosome five.[1] Another putative target for therapy is the induction of DNA hypomethylation, which is discussed in this review.

DNA methylation in MDS
The pathogenesis of haematopoietic malignancies including MDS is complex. Apart from acquired defects in genes and chromosomes, it is also shown that epigenetic modifications play an important role. Epigenetic modifications are those changes in chromatine structure that do not alter the DNA sequence. The two most important epigenetic modifications are
DNA methylation and histone modifications (acetylation/ deacetylation), which are potentially reversible. In cancer cells many specific genes, including tumour suppressor genes, are abnormally silenced by DNA methylation, while global DNA methylation (specifically methylation of tandem repeat sequences) is decreased.

This process of DNA methylation is a conserved process used for the selective silencing of imprinted alleles and for repression of the inactivated X chromosome in females. Methylation most frequently occurs at the 5-carbon position of cytosine residues at cytosine–guanine (CpG) sites. It occurs during the S phase and is catalysed by the DNA methyltransferase (DNMT) family of genes. Clusters of CpG dinucleotides (CpG islands) are often found in promoter regions of genes, and hypermethylation of these promoter-associatedCpG islands results in gene silencing.

Gene silencing of potential tumour suppressor genes is a critical event in the development of several forms of cancer. Aberrant methylation occurs in a non-random but tumour-specific manner. In several haematological diseases including MDS the promoter region of the p15INK4B gene, an inhibitor of the cyclindependent kinase-4 and a negative regulator of G1/S
progression of the cell cycle, is frequently hypermethylated.
In MDS patients treated with the hypomethylating drug decitabine, this leads to demethylation of the hypermethylated p15INK4B gene and increased p15 protein expression in the myeloid precursors of these patients, which has been observed to coincide with clinical responses.[2]

Hypomethylating drugs
The rationale behind demethylating therapies is to reverse hypermethylation-induced gene silencing. The two most prominent DNA methyltransferase inhibitors used in clinical practice are 5-azacytidine (azacytidine: Vidaza; Pharmion) and 5-aza-2′-deoxycytidine (decitabine: Dacogen; MGI Pharma). Azacytidine and decitabine are cytosine analogues and, after conversion to their active form (5-aza-2′-deoxycytidine-triphosphate), become incorporated into replicating DNA strands in place of cytosine residues.

Once present in DNA, azanucleotides covalently bind to and inactivate DNMT. By decreasing the amount of available DNMT, the methylation modifications are not able to be effectively copied during replication. Subsequently, after each round of replication the DNA becomes progressively hypomethylated. It has been suggested that the demethylating effect of these drugs could be mediated by two distinct mechanisms. The drugs could selectively suppress malignant cells in the BM and thereby facilitate the expansion of normal (and potentially less methylated) BM progenitor cells. Alternatively, the drug could directly demethylate malignant BM cells and thereby allow their epigenetic reprogramming.

Clinical studies
Several years ago, the management of MDS patients who were considered unfit for allogeneic stem cell transplantation encompassed solely vigorous transfusions and best supportive care. The DNMT inhibitors have emerged as therapeutic agents, being the first drugs to be approved for this disease. Early positive trials in the mid-90s resulted in a larger phase II trial comprising 66 patients with MDS. Decitabine was given at
45mg/m² per day for three days intravenously every six weeks, resulting in an overall response rate (ORR) of 49% and a complete remission (CR) in 20%.[3]

These results were confirmed in a large phase III trial encompassing 170 patients comparing decitabine with best supportive care.[4] The ORR was 17% in the treated group vs 0% in the control group, resulting in a longer median interval to progression to acute myeloid leukaemia or to death. This study was the basis for FDA approval of the drug.

Decitabine is well tolerated, but cytopenias are common; however, they are sometimes difficult to discern from the underlying disease. Given the short half-life of the molecule and the fact that it needs to be incorporated into DNA during the S phase (requiring cycling of the target stem cells), new studies with decitabine are using longer treatment schedules (eg, five or 10 consecutive days) with lower doses of the
drug.

Azacytidine is approved in the USA for the treatment of MDS based on the CALGB 9221 trial in 191 patients randomised to receive supportive care or 75mg/m2 azacytidine subcutaneously daily for seven days.[5] Response rate as well as median time to leukaemic transformation or death were superior in the treatment group.

These data have been confirmed in a European phase III trial (AZA-001) showing a complete or partial response rate in 28.5% and a superior two-year survival rate of 50.8%, compared with only 26% for those treated solely with supportive care.[6]

Conclusion
The treatment of MDS has changed markedly, largely through the use of the methyltransferase inhibitors azacytidine and decitabine. Whereas several years ago haematologists could only offer supportive care for most patients with MDS, these new drugs might alter the natural course of the disease. Nevertheless, the best treatment schedule with these drugs has yet to be established. This is because, since these drugs
require cycling cells for their effect, they require a long exposure time. As some responses occur only after six or more cycles, the real benefit of these drugs might therefore currently be underestimated.

References
1. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352(6):549-57.
2. Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Köhler G, Wijermans P, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 2002;100:2957-64.
3. Wijermans P, Lübbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of highrisk
myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000;18(5):956-62.
4. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006;106(8): 1794-803.
5. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20:2429-40.
6. Fenaux P, Mufti GJ, Santini V, et al. Azacitidine treatment
prolongs overall survival in high-risk MDS patients compared with conventional care regimens. Results of the AZA-001 phase III study [abstract]. Blood 2007;110: Abstract 817.



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