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Published on 15 September 2009

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Treating myelodysplastic syndromes

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Experts described how azacytidine and lenalidomide offer major advances in treating myelodysplastic syndromes at a Celgene symposium at the European Haematology Association Congress held in Berlin in June

Laurence A
Goldberg
FRPharmS
Editorial Consultant
HPE

For many years the treatment of myelodysplastic syndrome was not a great success, but recent advances in our understanding of the condition and the development of new drugs have given us the opportunity to provide effective treatment for this condition, said Wolf-Karsten Hofmann (head of department of haematology and oncology, University Hospital, Mannheim, Germany).

MDS has been a problem to diagnose and treat, especially in the elderly who are not candidates for stem cell transplant (SCT). Professor Hofmann identifiedseveral key factors that are now driving forward MDS treatment. The International Prognostic Scoring System (IPS) provides scores that correlate well with treatment response and overall survival. During the next  5-10 years cytogenetic profiling is likely to become the routine way of distinguishing MDS patients who are at high and low risk of progression to AML. The distinction is critical because elderly high-risk patients are usually not fit for full-dose AML treatment.

Gene transcription is regulated by DNA methylation, and if specific regions are methylated then there is no corresponding gene expression, which is a problem if a tumour suppressor gene is involved. Agents that can reverse or remove methylation leave transcription factors free to act and restore normal gene expression. Such mechanisms are known to play a part in leukaemia and MDS, and for this reason hypomethylating agents are important treatments.

One group of patients-those with the chromosomal abnormality del(5q)-is known to respond particularly well to treatment, although the reason for this is not clear.

Cancer is a disease of abnormal gene expression, and one mechanism that appears to be important in MDS is epigenetic modification, according to Valeria Santini (associate professor, University of Florence Medical School, Italy). Epigenetic changes typically involve changes in gene expression without changes in DNA sequences (switching genes on or off). Methylation of gene promoter regions can modulate expression of some genes, for example turning off tumour suppressor genes, leading to oncogenic transformation. DNA methylation has an important physiological role in, for example, embryogenesis and differentiation. However, ‘The most important abnormalities in MDS are aberrant DNA methylation and cytogenetic instability. Mutation instability is much less important,’ said Professor Santini. These changes mean that there is silencing of the tumour suppressor genes, and this leads to MDS progression and eventually the onset of leukaemia, she explained.

Azacytidine is a first-in-class hypomethylating agent. Although azacytidine is structurally related to cytosine arabinoside, the two drugs have different actions – cytosine arabinoside does not have hypomethylating activity at all. Azacytidine is taken up by DNA in replicating cells in lieu of cytidine. The enzyme DNA methyl transferase (DMT) would normally methylate cytidine molecules in DNA, but it becomes covalently bonded to azacytidine and is effectively trapped where it is then degraded. As a result, daughter cells are depleted of DMT and there is reduced methylation.

Azacytidine is taken up into RNA and DNA. Its incorporation into RNA leads to disordered protein synthesis (and cytotoxicity), while its inclusion in DNA leads to hypomethylation and gene de-repression. In MDS there is extensive methylation of DNA, and this leads to silencing of tumour suppressor genes. The net effect of azacytidine treatment is restored expression of tumour suppressor genes and a small amount of direct cytotoxic activity. “Another very important concept in the use of hypomethylating agents is that the drug has to be present during cell replication because this ensures that the daughter cells continue to have hypomethylated DNA in the areas that were previously abnormally hypermethylated – so it takes some time and continuous exposure to the drug to see the full effect of gene re-expression,” said Professor Santini.

Recent research has shown that many patients with MDS have high levels of DNA methylation-to a greater extent in high-risk MDS. “This really emphasises the point that hypomethylating drugs are effective because this phenomenon is strictly correlated with the pathophysiology of the disease,” she added.

Azacytidine was licensed in the USA in 2004 following a trial which showed that the drug was associated with an overall response rate of 60%, compared with 5% for best supportive care, said Pierre Fenaux (head of haematology department, Avicenne Hospital, Paris, and professor of haematology at Paris 13 University, France). Other important findings were that the
time to progression was prolonged and there were major improvements in quality of life. Moreover, there was no increased risk of infection or bleeding with azacytidine. “The drug is myelosuppressive but far less so than conventional chemotherapy,” said Professor Fenaux. The time to response was slow -many patients required at least four cycles and some needed six-but once patients started to respond there were further improvements with continued treatment, he noted. The study showed no overall survival difference, but this may have been in part due to the crossover design.

A subsequent study comparing azacytidine with conventional care regimens showed that there was a significant survival advantage with azacytidine treatment in high-risk patients, and this held for all subgroups. Importantly it was markedly better than treatment with low-dose cytosine arabinoside. Overall
responses were better with azacytidine and there were significant haemaotological improvements.

It looks as if azacytidine works not by eradicating the clone but by converting the disease to an earlier or lower-risk stage. A benefit of azacytidine is that it is well tolerated by very old patients – in whom a clear survival advantage has been shown – and this is important especially because this drug is less myelosuppressive then conventional chemotherapy.

Azacytidine is approved in the EU for adults who are not eligible for haematopoietic stem cell transplantation who have intermediate-2 or high-risk MDS. It is also indicated for the treatment of AML with 20-30% blasts and multilineage dysplasia, and for chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder.

The recommended dosing regimen is 75 mg/m2 for seven days every 28 days, and patients should be treated for a minimum of six cycles.

Most patients with MDS become transfusion dependent, said Aristoteles Giagounidis (head of haematology/oncology clinical research unit, St John’s Hospital, Duisburg, Germany). In addition to the serious consequences of iron overload and  he negative impact of anaemia on quality of life, transfusion dependence is associated with increased risk of progression to AML and reduced overall survival compared with patients who are not transfusion dependent. Dr Giagounidis said that a number of therapeutic option sexist for tackling transfusion dependence in low-risk MDS, including erythropoietin in combination with granulocyte colony-stimulating factor (GCSF) and valproic acid, but only one-iron chelation-is approved in the EU. Clinical experience suggests that the vast majority of patients with a chromosome 5q deletion (del(5q)) abnormality will become transfusion dependent during the course of their disease. Lenalidomide has shown promising results in reducing transfusion dependence in patients with and without the chromosome 5q deletion. Two-thirds will achieve transfusion independence, a mean haemoglobin rise of 5.4 g/dl and a median time to response of 4.4 weeks.

The major side-effects are thrombocytopenia or neutropenia (more pronounced in the del(5q) patients). These tend to develop in the first six to eight weeks of treatment but can occur at any time. Close weekly monitoring is advised, and dose modification will be necessary if thrombocytopenia or neutropenia develops, said Dr Giagounidis.



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