Myelodysplastic syndrome patients present with variable cytopenias even though their bone marrows are generally hypercellular. Excessive cytokine-induced apoptosis of hematopoietic cells in the marrows has been proposed as a possible mechanism to explain the paucity of cells in the periphery. Tumor necrosis factor–alpha (TNF-alpha) is a proinflammatory cytokine that has been found in excessive amounts in myelodysplastic syndrome marrows. In addition, recent studies demonstrate excessive neoangiogenesis in myelodysplastic syndrome marrows as well.
TNF-alpha is a potent inducer of neoangiogenesis via upregulation of vascular endothelial growth factor and basic fibroblast growth factor. A strategy for improving ineffective hematopoiesis in myelodysplastic syndrome would be directed at suppressing TNF-alpha and neoangiogenesis. Thalidomide is active at both levels. We have treated 61 myelodysplastic syndrome patients with oral thalidomide at 100 to 400 mg at bedtime for 12 weeks. Of these, 22 had refractory anemia, 13 had refractory anemia with ringed sideroblasts, 19 had refractory anemia with excess blasts, 4 had refractory anemia with excess blasts in transformation, and 3 had chronic myelomonocytic leukemia.
Of the 61 patients, 11 are off study, 25 are too early, and 25 are evaluable for response; of the 25 evaluable patients, 17 are responding while 8 are not. Three have trilineage, 4 bilineage, and 10 monolineage responses. The most dramatic improvements are noted in erythroid series, in that long-term transfusion-dependent patients are becoming transfusion independent. Responses can take up to 12 weeks to become apparent. Most patients tolerated the drug well in low doses (200 mg at bedtime).
CONCLUSION: Thalidomide in low doses given to myelodysplastic syndrome patients for prolonged periods can produce excellent palliation. It deserves to be tested in a larger series of patients either alone or in combination with chemotherapy or anticytokine therapy.