Improving Treatment for Myelodysplastic Syndromes Patients.

Abstract

Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the microenvironment or the soil of the bone marrow (BM) as well as in the cell or the seed provide a growth advantage for clonal myeloid cells. Slowly accumulating senescent cells which can no longer divide because they have reached the end of their proliferative life cycle, but which continue to produce metabolic debris, overwhelm the natural autophagy mechanisms resulting in pro-inflammatory changes in the BM soil. In addition, the seed or stem cells acquire passenger mutations with each round of proliferation resulting from DNA copying errors. Some mutations commonly associated with MDS can be found in older, otherwise healthy individuals; however, when combined with other passenger mutations or in the setting of a noxious soil, the result could be a proliferative advantage for one stem cell over others, leading to its clonal expansion and development of the clinical syndrome. When considering therapeutic options for MDS patients, the important considerations are related to both the common co-morbidities of an elderly population along with the heterogeneous passenger mutations and the inflammatory changes in the soil. At present, allogeneic stem cell transplant is the only potentially curative option in MDS. Palliative strategies are directed at improving the quality of life and prolonging survival. Only three drugs are FDA approved, two being the hypomethylating agents azacytidine and decitabine while the third is lenalidomide which is restricted to lower risk MDS patients with deletion 5q. Promising future therapies are directed at reversing the pro-inflammatory changes in the microenvironment (luspatercept) or targeting specific mutations isocitrate dehydrogenase (IDH)1, IDH2, p53, EZH2. More durable responses are to be expected when the seed and soil are targeted simultaneously through a combination of drugs.