CLINICAL AND BIOLOGICAL STUDIES IN MYELODYSPLATIC SYNDROMES

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The myelodysplastic syndromes (MDS) are a highly complex, heterogeneous group of clonal hemopoietic stem cell disorders in which the rapid cell-birth of immature precursors is cancelled by excessive intramedullary apoptosis of their progeny. This combination of rapid proliferation and cell death may account for the clinical syndrome of pancytopenia despite hypercellular marrows and may be a result of the dual actions of cytokines such as tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin 1beta (IL1beta) and IL1beta converting enzyme (ICE). These cytokines (source unknown) may simultaneously stimulate proliferation in the immature cells and apoptosis in mature cells. By interfering with the generation of specific phospholipid second messengers, the signalling pathway for a cascade of cytokines (TNF- alpha, TGF-beta, IL1beta) can be interrupted. A combination of drugs using pentoxifylline/ciprofloxacin/dexamethasone (PCD) were used in a pilot study and resulted in encouraging hematologic and/or cytogenetic responses with resumption of polyclonal hemopoiesis, accompanied by the disappearance of apoptosis from bone marrow (BM) biopsies. A variety of clinical responses were noted following PCD suggesting that this anti-cytokine therapy produces different biological effects in different patients. Non-responsiveness may indicate that either the predominant clinical syndrome was not cytokine-driven or that cytokines other than those suppressed by PCD were involved. A similar case for differences in cytogenetic responses could be made since in the responding patients, the cytogenetically marked clone may have been dependent on cytokines suppressed by PCD. We propose a unique clinical program with correlative biologic studies, unique especially in terms of using clinical response as a way of dissecting the different mechanisms underlying the differences in the manifestations of disease among MDS patients. A series of clinical trials are proposed which attempt to further optimize this new and unique anti-cytokine approach by combining PCD with other conventional and/or novel agents. Parallel biological studies are proposed which are designed to investigate the nature of the stem cell abnormality, the biochemical/molecular/cellular basis for the excessive proliferation/excessive apoptosis leading to ineffective hemopoiesis and the role of cytokines in producing or perpetuating the disease process. A strong clinical program has been organized with 40-50 new MDS patients/year eligible for accrual onto the clinical protocols and for the companion biological studies. With better understanding of the biology and reasons for clinical response versus non-response, we expect to develop critical leads for novel therapeutic and preventive studies in MDS.