Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 15)

Myelodysplasia: Treatment The therapy of MDS has been unsatisfactory. Only stem cell transplantation offers cure: survival rates of 50% at 3 years have been reported, but older patients are particularly prone to develop treatment-related mortality and morbidity. Results of transplant using matched unrelated donors are comparable, although most series contain younger and more highly selected cases.MDS has been regarded as particularly refractory to cytotoxic chemotherapy regimens but is probably no more resistant to effective treatment than acute myeloid leukemia in the elderly, in whom drug toxicity is often fatal and remissions, if achieved, are brief.Low doses of cytotoxic drugs...
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Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 15) Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 15) Myelodysplasia: Treatment The therapy of MDS has been unsatisfactory. Only stem cell transplantationoffers cure: survival rates of 50% at 3 years have been reported, but older patientsare particularly prone to develop treatment-related mortality and morbidity.Results of transplant using matched unrelated donors are comparable, althoughmost series contain younger and more highly selected cases. MDS has been regarded as particularly refractory to cytotoxicchemotherapy regimens but is probably no more resistant to effective treatmentthan acute myeloid leukemia in the elderly, in whom drug toxicity is often fataland remissions, if achieved, are brief. Low doses of cytotoxic drugs have been administered for theirdifferentiating potential, and from this experience has emerged drug therapiesbased on pyrimidine analogues. Azacitidine is directly cytotoxic but also inhibitsDNA methylation, thereby altering gene expression. Azacitidine improves bloodcounts and modestly improves survival in about 16% of MDS patients, comparedto best supportive care. Azacitidine is administered subcutaneously at a dose of 75mg/m2, daily for 7 days, at 4-week intervals, for at least four cycles, althoughfurther cycles may be required to observe a response. Decitabine is closely relatedto azacitidine and more potent. Similar to azacitidine, about 20% of patients showresponses in blood counts, with a duration of response of almost a year. Activitymay be higher in more advanced MDS subtypes. Decitabine dose is 15 mg/m2 bycontinuous intravenous infusion, every eight hours for three days, repeating thecycle every 6 weeks for at least four cycles. The major toxicity of both azacitidineand decitabine is myelosuppression, leading to worsened blood counts. Othersymptoms associated with cancer chemotherapy frequently occur. Ironically, it hasbeen difficult to establish that either agent acts in patients by a mechanism ofDNA demethylation. Thalidomide, a drug with many activities including antiangiogenesis andimmunomodulation, has modest biologic activity in MDS. Lenalidomide, athalidomide derivative with a more favorable toxicity profile, is particularlyeffective in reversing anemia in MDS patients with 5q– syndrome; not only do ahigh proportion of these patients become transfusion-independent with normal ornear-normal hemoglobin levels, but their cytogenetics also become normal.Lenalidomide is administered orally, 10 mg daily. Most patients will improvewithin 3 months of initiating therapy. Toxicities include myelosuppression(worsening thrombocytopenia and neutropenia, necessitating blood countmonitoring) and an increased risk of deep vein thrombosis and pulmonaryembolism. Other treatments for MDS include amifostine, an organic thiophosphonatethat blocks apoptosis; it can improve blood counts but has significant toxicities.ATG and cyclosporine, as employed in aplastic anemia, also may producesustained independence from transfusion, especially in younger MDS patients withmore favorable International Prognostic Scoring System (IPSS) scores. Hematopoietic growth factors can improve blood counts but, as in mostother marrow failure states, have been most beneficial to patients with the leastsevere pancytopenia. G-CSF treatment alone failed to improve survival in acontrolled trial. Erythropoietin alone or in combination with G-CSF can improvehemoglobin levels, but mainly in those with low serum erythropoietin levels whohave no or only a modest need for transfusions. The same principles of supportive care described for aplastic anemia applyto MDS. Despite improvements in drug therapy, many patients will be anemic foryears. RBC transfusion support should be accompanied by iron chelation in orderto prevent secondary hemochromatosis. Myelophthisic Anemias Fibrosis of the bone marrow (see Fig. 103-2), usually accompanied by acharacteristic blood smear picture called leukoerythroblastosis, can occur as aprimary hematologic disease, called myelofibrosis or myeloid metaplasia (Chap.103), and as a secondary process, called myelophthisis. Myelophthisis, orsecondary myelofibrosis, is reactive. Fibrosis can be a response to invading tumorcells, usually an epithelial cancer of breast, lung, a prostate origin orneuroblastoma. Marrow fibrosis may occur with infection of mycobacteria (bothMycobacterium tuberculosis and M. avium), fungi, or HIV, and in sarcoidosis.Intracellular lipid deposition in Gaucher disease and obliteration of the marrowspace related to absence of osteoclast remodeling in congenital osteopetrosis alsocan produce fibrosis. Secondary myelofibrosis is a late consequence of radiationtherapy or treatment with radiomimetic drugs. Usually the infectious or malignantunderlying processes are obvious. Marrow fibrosis can also be a feature of avariety of hematologic syndromes, especially chronic myeloid leukemia, multiplemyeloma, lymphomas, myeloma, and hairy cell leukemia. The pathophysiology has three distinct features: proliferation of fibroblastsin the marrow space (myelofibrosis); the extension of hematopoiesis into the longbones and into extramedullary sites, usually the spleen, liver, and lymph nodes(myeloid metaplasia); and ineffective erythropoiesis. The etiology of the fibrosis isunknown but most likely involves dysregulated production of growth factors:platelet-derived growth factor and transforming growth factor βhave beenimplicated. Abnormal regulation of other hematopoietins would lead tolocalization of bloo ...