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DIFFERENTIATION THERAPY OF MYELODYSPLASTIC SYNDROMES: FACT OR FICTION?

Few therapies for haematological diseases are as unsatisfactory and frustrating as those for the myelodysplastic syndromes (MDS), whose elusive clinical behaviour and biological characteristics hamper many attempts at cure. Current knowledge of maturation induction in the myelodysplastic syndromes has derived from data developed in vitro using acute myeloid leukaemia models. The most recent opinion considers acute myeloid leukaemia and the myelodysplastic syndromes, especially high-risk ones, as identical and unique diseases, whose clinical treatment has therefore to be the same (Mufti, 1992; De Witte et al, 1995). Although this concept was probably based on final outcome of the disease, the biology and pathogenesis of myelodysplasia differs from that of acute leukaemia, especially in its susceptibility to therapies which do not aim at aggressively attacking the dysplastic clone. The transformed clone is not usually endowed with high proliferative potential, and shows a block in maturation, without giving rise to a threatening neoplastic burden. These observations and perplexities are shared by a large number of investigators, indicated by the regular publication of new studies both in vivo and in vitro, exploring the possibility of treating myelodysplastic syndromes with differentiating agents, in an attempt to overcome the maturation blockade and improve the pancytopenia, instead of eradicating the transformed clone (Sachs, 1987). In this sense, the success of differentiation therapy in MDS is easily judged by increased numbers of platelets, erythrocytes and leucocytes, leading the patient to independence from supportive care. These end-points simplify the clinical evaluation of the therapies, but do not take into account the rate of maturation (if any) induced in bone marrow and peripheral blood blasts of treated patients. Only a few clinical studies have used cytogenetic analysis to assess differentiation of the myelodysplastic clone (Schmetzer et al, 1997). The hypothesis of therapeutic induction of maturation, founded on in vitro data, should be supported by in vivo proof, i.e. by the identification of terminally mature cells with an abnormal karyotype. This concept is important, because what may be considered as a successful maturative effect is, in fact, the recovery of normal haemopoiesis after ablation of the dysplastic clone. The molecules inducing in vivo maturation in MDS can be divided into the following categories: interferons (IFN-alpha and IFN-gamma); polar planar compounds such as HMBA; homoarringtonine; 5-azacytidine; low-dose ara-C; butyrates; amifostine; haem-arginine; vitamins, including retinoids, vitamin D3 and vitamin E; and haemopoietic growth factors such as Epo, G-CSF, GM-CSF and IL-6. Recently combinations of growth factors and differentiation molecules have been introduced.