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

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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) 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 have been administered for their "differentiating" potential, and from this experience has emerged drug therapies based on pyrimidine analogues. Azacitidine is directly cytotoxic but also inhibits
DNA methylation, thereby altering gene expression. Azacitidine improves blood counts and modestly improves survival in about 16% of MDS patients, compared to best supportive care. Azacitidine is administered subcutaneously at a dose of 75 mg/m2, daily for 7 days, at 4-week intervals, for at least four cycles, although further cycles may be required to observe a response. Decitabine is closely related to azacitidine and more potent. Similar to azacitidine, about 20% of patients show responses in blood counts, with a duration of response of almost a year. Activity may be higher in more advanced MDS subtypes. Decitabine dose is 15 mg/m2 by continuous intravenous infusion, every eight hours for three days, repeating the cycle every 6 weeks for at least four cycles. The major toxicity of both azacitidine and decitabine is myelosuppression, leading to worsened blood counts. Other symptoms associated with cancer chemotherapy frequently occur. Ironically, it has been difficult to establish that either agent acts in patients by a mechanism of DNA demethylation. Thalidomide, a drug with many activities including antiangiogenesis and immunomodulation, has modest biologic activity in MDS. Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is particularly effective in reversing anemia in MDS patients with 5q– syndrome; not only do a high proportion of these patients become transfusion-independent with normal or near-normal hemoglobin levels, but their cytogenetics also become normal. Lenalidomide is administered orally, 10 mg daily. Most patients will improve
within 3 months of initiating therapy. Toxicities include myelosuppression (worsening thrombocytopenia and neutropenia, necessitating blood count monitoring) and an increased risk of deep vein thrombosis and pulmonary embolism. Other treatments for MDS include amifostine, an organic thiophosphonate that blocks apoptosis; it can improve blood counts but has significant toxicities. ATG and cyclosporine, as employed in aplastic anemia, also may produce sustained independence from transfusion, especially in younger MDS patients with more favorable International Prognostic Scoring System (IPSS) scores. Hematopoietic growth factors can improve blood counts but, as in most other marrow failure states, have been most beneficial to patients with the least severe pancytopenia. G-CSF treatment alone failed to improve survival in a controlled trial. Erythropoietin alone or in combination with G-CSF can improve hemoglobin levels, but mainly in those with low serum erythropoietin levels who have no or only a modest need for transfusions. The same principles of supportive care described for aplastic anemia apply to MDS. Despite improvements in drug therapy, many patients will be anemic for years. RBC transfusion support should be accompanied by iron chelation in order to prevent secondary hemochromatosis. Myelophthisic Anemias
Fibrosis of the bone marrow (see Fig. 103-2), usually accompanied by a characteristic blood smear picture called leukoerythroblastosis, can occur as a primary hematologic disease, called myelofibrosis or myeloid metaplasia (Chap. 103), and as a secondary process, called myelophthisis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis can be a response to invading tumor cells, usually an epithelial cancer of breast, lung, a prostate origin or neuroblastoma. Marrow fibrosis may occur with infection of mycobacteria (both Mycobacterium tuberculosis and M. avium), fungi, or HIV, and in sarcoidosis. Intracellular lipid deposition in Gaucher disease and obliteration of the marrow space related to absence of osteoclast remodeling in congenital osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a late consequence of radiation therapy or treatment with radiomimetic drugs. Usually the infectious or malignant underlying processes are obvious. Marrow fibrosis can also be a feature of a variety of hematologic syndromes, especially chronic myeloid leukemia, multiple myeloma, lymphomas, myeloma, and hairy cell leukemia. The pathophysiology has three distinct features: proliferation of fibroblasts in the marrow space (myelofibrosis); the extension of hematopoiesis into the long bones and into extramedullary sites, usually the spleen, liver, and lymph nodes (myeloid metaplasia); and ineffective erythropoiesis. The etiology of the fibrosis is unknown but most likely involves dysregulated production of growth factors: platelet-derived growth factor and transforming growth factor βhave been
implicated. Abnormal regulation of other hematopoietins would lead to localization of blood-producing cells in nonhematopoietic tissues and uncoupling of the usually balanced processes of stem cell proliferation and differentiation. Myelofibrosis is remarkable for pancytopenia despite very large numbers of circulating hematopoietic progenitor cells. Anemia is dominant in secondary myelofibrosis, usually normocytic and normochromic. The diagnosis is suggested by the characteristic leukoerythroblastic smear (see Fig. 103-1). Erythrocyte morphology is highly abnormal, with circulating nucleated red blood cells, teardrops, and shape distortions. White blood cell numbers are often elevated, sometimes mimicking a leukemoid reaction, with circulating myelocytes, promyelocytes, and myeloblasts. Platelets may be abundant and are often of giant size. Inability to aspirate the bone marrow, the characteristic "dry tap," can allow a presumptive diagnosis in the appropriate setting before the biopsy is decalcified. The course of secondary myelofibrosis is determined by its etiology, usually a metastatic tumor or an advanced hematologic malignancy. Treatable causes must be excluded, especially tuberculosis and fungus. Transfusion support can relieve symptoms. Further Readings
Bagby GC, Alter BP: Fanconi anemia. Semin Hematol 43:147, 2006 [PMID: 16822457] Estey E et al: Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 25:1908, 2007 [PMID: 17488990] Fisch P et al: Pure red cell aplasia. Br J Haematol 111:1010, 2000 [PMID: 11167735] Lipton JM: Diamond Blackfan anemia: New paradigms for a "not so pure" inherited red cell aplasia. Semin Hematol 43:167, 2006 [PMID: 16822459] List A et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549, 2005 [PMID: 15703420] Young NS, Brown KE: Parvovirus B19. N Engl J Med 350:586, 2004 [PMID: 14762186] ——— et al: Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108:2509, 2006
Bibliography Greenberg PL (ed): Myelodysplastic Syndromes: Clinical and Biological Advances. Cambridge, UK, Cambridge University Press, 2006 Horowitz MM: Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol 37:30, 2000 [PMID: 10676909] Molldrem J et al: Treatment of bone marrow failure of myelodysplastic syndrome with antithymocyte globulin. Ann Intern Med 137:156, 2002 [PMID: 12160363] Silverman JR et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol 20:2429, 2002 [PMID: 12011120] Young NS (ed): Bone Marrow Failure Syndromes. Philadelphia, Saunders, 2000 ———, Calado RT: Telomere repair complex gene mutations in bone marrow failure syndromes. Blood. In preparation, 2006
Young NS: Acquired aplastic anemia, in Young NS, Gerson SL, Hish KA (eds): Clinical Hematology. Philadelphia, Mosby, 2006, p. 136–157