Page 595 - Hematology_ Basic Principles and Practice ( PDFDrive )

510 Part V Red Blood Cells

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variable-copy-number tandem repeat sequence. The results show Differential Diagnosis
uniform monoclonality of hematopoiesis in acquired sideroblastic
anemia with or without associated myelodysplastic features. Some Ring sideroblasts are not limited to acquired sideroblastic anemia;
indirect evidence exists for a primary mitochondrial lesion, perhaps they also occur in other myelodysplastic conditions, such as refractory
in the mitochondrial respiratory chain, which impairs the reduction anemia with excess blasts, in which the blast count is higher than
2+
3+
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of Fe because Fe is essential for heme synthesis. 205–208 Recurrent 5%. Careful examination of peripheral blood and bone marrow
mutations in the SF3B1 gene have recently been described in acquired can distinguish acquired idiopathic sideroblastic anemia from these
sideroblastic anemia and are found in up to 85% of patients with related myelodysplastic conditions. Family surveys are very useful in
RARS, RARS-T, and RCMD-RS. 209,210 The product of SF3B1 is distinguishing acquired from hereditary forms of sideroblastic anemia,
associated with mRNA splicing, and mutations in this gene may because the latter may present in late adult life.
influence a number of mitochondrial gene networks, including
changes in the expression of the iron transporter ABCB7, resulting
in iron-laden mitochondria during erythroid development. 211 Prognosis
Acquired idiopathic sideroblastic anemia and the related entity of
Etiology refractory anemia have the most favorable outlook among the myelo-
dysplastic syndromes, with a median survival of 42 to 76 months
Clonal chromosomal changes are found in bone marrow cells in and 3% to 12% incidence of leukemic progression in different
approximately 60% of patients with acquired sideroblastic anemia. series. 212,226,227 The prognosis can be correlated with three factors. First
Characteristic changes are monosomy 7; trisomy 8; deletions is the severity of the anemia, because repeated transfusions markedly
involving chromosomes 5, 7, 11, or 20; and a number of balanced increase iron overload and invariably lead to the organ dysfunction
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translocations. When sideroblastic anemia is acquired after che- characteristic of secondary hemosiderosis (e.g., heart and liver failure,
motherapy or irradiation, chromosomal changes are usually found diabetes), and whether neutropenia and thrombocytopenia are associ-
212
and tend to be multiple. Among these changes, the loss of an ated with the anemia. These cytopenias form the basis of a simple
entire chromosome (5 or 7, or both), deletion of a long arm [del(5), prognostic scoring system in which two or more of the following
del(7), or del(13)], and an unbalanced translocation are typical. 213,214 place the patient in a poor prognostic category: hemoglobin level less
9
When karyotype shows loss of material from chromosomes 5 or than 10 g/dL, neutrophil count less than 1.8 × 10 /L, platelet count
9
7, or both, a detailed occupational history may show exposure to less than 100 × 10 /L. 226,227 Secondly, marrow blasts more than 5%
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potentially mutagenic chemical agents in a proportion of patients. of total nucleated cells predict a poor outcome. Thirdly, karyotypic
However, the development of visible chromosomal changes is analysis of marrow aspirates provides valuable information, because
probably a late event in acquired sideroblastic anemia and may be a normal karyotype carries a more favorable prognosis. Conversely,
preceded by the expansion of a clone of genetically unstable stem chromosome 7 abnormalities impart a high probability of transfor-
cells. This concept is in accord with the view that multiple genetic mation to acute myeloid leukemia. Multiple chromosomal abnor-
events underlie the pathogenesis of other myelodysplastic syndromes malities and del(20q) are also associated with an increased risk for
and acute myeloid leukemia 203,216 (see box on Clinical and Laboratory progression to leukemia; in contrast, trisomy 8 has no adverse prog-
212
Evaluation of Sideroblastic Anemia). nostic significance. The bone marrow blast percentage, karyotypic
analysis, and the presence of peripheral blood cytopenias can be used
to group newly diagnosed cases into one of five prognostic groups,
which range in median survival from more than 8 years to less than
Clinical and Laboratory Evaluation of Sideroblastic Anemia 1 year. Evolution of acquired idiopathic sideroblastic anemia to
228
other myelodysplastic conditions, such as refractory anemia with
Typically, sideroblastic anemia develops insidiously in a middle-aged 229
or elderly patient with normal or increased mean corpuscular volume excess blasts, has been described (see box on Therapy for Acquired
(MCV) and a blood smear showing a population of hypochromic red Sideroblastic Anemia).
cells. Hepatosplenomegaly may be present. Leukocyte and platelet
counts are usually normal, and the presence of a thrombocytosis
should prompt investigating for the presence of the JAK2 V617F muta- SIDEROBLASTIC ANEMIA AND PORPHYRINURIA
tion and RARS-T. 202 If leukopenia or thrombocytopenia is present, a CAUSED BY DRUGS
careful search should be made for myelodysplastic features, which lead
to the more descriptive term of refractory cytopenia with multilineage Alcohol
dysplasia for the condition. 217,218 An iron stain of the bone marrow
aspirate shows ring sideroblasts, which should total more than 15%
of all erythroblasts to make the diagnosis of acquired sideroblastic Ring sideroblasts may be found in the bone marrow of malnourished
anemia. 198,219–221 Iron cannot be assessed in the marrow trephine anemic alcoholics, usually in the presence of associated folate
biopsy core because it may leach out during decalcification.
The bone marrow also shows erythroid hyperplasia. Although mild
dyserythropoiesis (e.g., multinuclearity, nuclear budding) and megalo- Therapy for Acquired Sideroblastic Anemia
blastoid changes are present, myelopoiesis and megakaryopoiesis are
usually normal. When changes are confined to dyserythropoiesis, the Transfusions are indicated for relief of symptomatic anemia. A trial of
condition has been called refractory anemia with ring sideroblasts. 220,222 pyridoxine at 100–200 mg/day for 3 months is worthwhile in patients
However, dysplasia of myelopoietic and megakaryopoietic elements who have anemia but who do not display neutropenia or thrombocy-
may be present (i.e., refractory cytopenia with multilineage dysplasia) topenia. However, few patients with acquired idiopathic sideroblastic
with the following features: Pelger-Huët–like anomaly, hypersegmen- anemia respond to this vitamin. If any response is achieved, mainte-
tation or hypogranularity of neutrophils, micromegakaryocytes, large nance therapy with pyridoxine at lower dosage is indicated. Cyclosporin
mononuclear megakaryocytes, and megakaryocytes with multiple (5–6 mg/kg/day) has been reported to benefit the anemia of the closely
small nuclei (see Chapter 60). 218 Dysmegakaryopoiesis is more easily related myelodysplastic condition of refractory anemia, although the
230
detected in trephine biopsies than in marrow smears, although the response appeared limited to those with hypoplastic bone marrows.
trephine may also show unsuspected islands of myeloblasts charac- A number of agents, including erythropoietin, 5-azacytidine, decitabine,
teristic of myelodysplasia. 223 The overall blast count in marrow smears and lenalidomide, have been studied in therapeutic trials for myelodys-
is, by definition, less than 5%, and the peripheral blood monocyte plastic syndrome, which have included acquired sideroblastic anemia
9
count is less than 1.0 × 10 /L. Cytogenetic analysis of marrow aspirates cases; however, overall outcomes have been poor. 231 It is unclear if iron
provides important information, because a normal karyotype predicts chelation therapy with the oral iron-chelator, deferasirox is of benefit;
long survival in any type of acquired sideroblastic anemia. 224 however, this question may be answered by ongoing clinical trials. 232,233