Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 13)

Epidemiology Idiopathic MDS is a disease of the elderly; the mean age at onset is 68 years. There is a slight male preponderance. MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to 100 per million persons in the general population and 120 to 500 per million in the elderly. MDS is rare in children, but monocytic leukemia can be seen.Therapy-related MDS is not age-related and may occur in as many as 15% of patients within a decade following intensive combined modality treatment for cancer. Rates of MDS have increased over time,...
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Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 13) Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 13) Epidemiology Idiopathic MDS is a disease of the elderly; the mean age at onset is 68years. There is a slight male preponderance. MDS is a relatively common form ofbone marrow failure, with reported incidence rates of 35 to >100 per millionpersons in the general population and 120 to >500 per million in the elderly. MDSis rare in children, but monocytic leukemia can be seen. Therapy-related MDS is not age-related and may occur in as many as 15%of patients within a decade following intensive combined modality treatment forcancer. Rates of MDS have increased over time, due to the recognition of thesyndrome by physicians and the aging of the population. Etiology and Pathophysiology MDS is caused by environmental exposures such as radiation and benzene;other risk factors have been reported inconsistently. Secondary MDS occurs as alate toxicity of cancer treatment, usually with a combination of radiation and theradiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine(with a latent period of 5–7 years) or the DNA topoisomerase inhibitors (2 years).Both acquired aplastic anemia following immunosuppressive treatment andFanconis anemia can evolve into MDS. MDS is a clonal hematopoietic stem cell disorder leading to impaired cellproliferation and differentiation. Cytogenetic abnormalities are found in about halfof patients, and some of the same specific lesions are also seen in frank leukemia;aneuploidy is more frequent than translocations. Both presenting and evolvinghematologic manifestations result from the accumulation of multiple geneticlesions: loss of tumor suppressor genes, activating oncogene mutations, or otherharmful alterations. Cytogenetic abnormalities are not random (loss of all or partof 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 followingtopoisomerase II inhibitors); chronic myelomonocytic leukemia is often associatedwith t(5;12) that creates a chimeric tel-PDGFβ gene. The type and number ofcytogenetic abnormalities strongly correlate with the probability of leukemictransformation and survival. Mutations of N-ras (an oncogene), p53 and IRF-1(tumor suppressor genes), Bcl-2 (an antiapoptotic gene), and others have beenreported in some patients but likely occur late in the sequence leading to leukemictransformation. Apoptosis of marrow cells is increased in MDS, presumably dueto these acquired genetic alterations or possibly to an overlaid immune response.An immune pathophysiology has been suggested for trisomy 8 MDS, which oftenresponds clinically to immunosuppressive therapy. Such patients have T cellactivity directed to the cytogenetically aberrant clone. Sideroblastic anemia maybe related to mutations in mitochondrial genes; ineffective erythropoiesis anddisordered iron metabolism are the functional consequences of the geneticalterations. Clinical Features Anemia dominates the early course. Most symptomatic patients complainof the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least halfthe patients are asymptomatic and their MDS is discovered only incidentally onroutine blood counts. Previous chemotherapy or radiation exposure is an important historic fact.Fever and weight loss should point to a myeloproliferative rather thanmyelodysplastic process. Children with Down syndrome are susceptible to MDS,and a family history may indicate a hereditary form of sideroblastic anemia orFanconis anemia. The physical examination is remarkable for signs of anemia; about 20% ofpatients have splenomegaly. Some unusual skin lesions, including Sweetssyndrome (febrile neutrophilic dermatosis), occur with MDS. Autoimmunesyndromes are not infrequent. Laboratory Studies Blood Anemia is present in the majority of cases, either alone or as part of bi- orpancytopenia; isolated neutropenia or thrombocytopenia is more unusual.Macrocytosis is common, and the smear may be dimorphic with a distinctivepopulation of large red blood cells. Platelets are also large and lack granules. Infunctional studies, they may show marked abnormalities, and patients may havebleeding symptoms despite seemingly adequate numbers. Neutrophils are hypogranulated; have hyposegmented, ringed, orabnormally segmented nuclei; contain Dohle bodies; and may be functionallydeficient. Circulating myeloblasts usually correlate with marrow blast numbers,and their quantitation is important for classification and prognosis. The total whiteblood cell count is usually normal or low, except in chronic myelomonocyticleukemia. As in aplastic anemia, MDS can be associated with a clonal populationof PNH cells.