Progress in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are the most prevalent haematological malignancies with an incidence of 0.5/100,000 below the age of 50 years, but 45/100,000 above the age of 70 years. The term MDS comprises a heterogeneous group of clonal or oligoclonal disorders, characterised by cytopenias, marrow hyperplasia (although not always) and dysplastic features of all three cell lineages (erythroid, myeloid and megakaryocytic).

The fact that classification schemes are continuously evolving, with the proposal of new risk models, bears witness to the difficulty in predicting the course of the disease in a particular patient and, therefore, the selection of treatment to be administered. The classification of the MDS is still based, to a large extent, on morphology, although karyotypic and molecular markers can already distinguish certain subgroups^1–3.

Progress in treatment is being made slowly and the new drugs described in the paper by Grossi and Liumbruno in this issue⁴ are offering the possibility of remission and in some cases prolongation of life, in addition to decreasing the need for transfusions.

Despite intensive investigations in the last two decades, the pathogenesis of these syndromes remains unclear. MDS are characterised initially by impaired differentiation of haematopoietic cells and increased apoptosis, leading to cytopenias; the fact that they often progress to acute myeloid leukaemia, hence to decreased apoptosis and increased proliferation of immature cells, suggests the need for a “second hit”, namely a multi-step pathogenesis⁵.

In the era of targeted therapies, the identification of molecular markers that could be used as targets, is of major interest. Numerous molecular and cytogenetic abnormalities have been described in MDS but none is characteristic, implying that abnormalities in the bone marrow microenvironment and immunological factors may contribute to the development of MDS. Nevertheless the correlation of the presence of certain chromosomal abnormalities with particular subgroups of patients, and their response to treatment, with one of the new drugs, is promising.

The 5q- syndrome, which occurs predominantly in female patients, is characterised by an isolated cytogenetic abnormality, macrocytic anaemia, normal or increased platelet count and a low incidence of evolution to acute myeloid leukaemia; it has been shown to respond to lenalidomide. Recent evidence suggests that lenalidomide re-establishes the expression of the haplodeficient tumour suppressor gene SPARC included in the 5q deletion, which normally inhibits myeloid proliferation⁶. Patients responding may remain transfusion independent for a median of 2.2 years, and some for up to 6 years⁷. It should, however, be remembered that a deletion within the long arm of chromosome 5 is not always equivalent to the 5q- syndrome, as the areas deleted are not the same in all patients. In the 5q- syndrome the deletion is in q13–31, in other MDS cases it is in 5q22–33.

Another cytogenetic abnormality, the 20q-syndrome, marks a group of patients with a favourable prognosis, although the critical genes deleted from the region remain unidentified so far, as do the genes implicated in the 7q- syndrome which, however, responds to azacitidine⁸.

If the above abnormalities are part of a more complex karyotype, prognosis worsens significantly¹.

The response to imatinib mesylate of a small subgroup of patients with myeloproliferative chronic myelomonocytic leukaemia and constitutively activated PDGF-b receptor tyrosine kinase, again shows the need for cytogenetic and molecular studies in each MDS patient in the effort to find appropriate treatment⁹.

Studies of the combination of transcriptional modulation by agents interfering with histone acetylation and hypomethylation are under way but have not shown spectacular results so far¹⁰. The combination of lenalidomide with erythropoietin is also a possibility in an attempt to minimise transfusions.

Azacitidine appears to be the standard of care for high-risk MDS patients, although it is also active in low-risk patients leading to transfusion independence. Efforts at easing the ways of administration of 5-AZA, either by decreasing the length of treatment, e.g. to four courses as shown in one study¹¹, or by developing an oral formulation¹² are of interest and may allow for wider use of this therapeutic agent.

Although the new drugs are indeed decreasing the need for transfusions, erythropoietin, which is not that new, continues to be used, either alone or in combination with granulocyte colony-stimulating factors, in a significant percentage of MDS patients. The growth factors are easily available and physicians are familiar with their use. A recent review by Jaedersten et al.¹³ demonstrating the safety of the combination, in terms of evolution of the MDS to acute myeloid leukaemia, is reassuring.

Since bone marrow transplantation, the only curative treatment for MDS, is applicable in only a small percentage of patients, efforts to optimise the treatment with combinations of available drugs must continue, in parallel with in depth molecular studies aiming at identifying the pathogenesis of these syndromes.