Clonal (Refractory) Sideroblastic Anemia

Clonal (Refractory) Sideroblastic Anemia


The term refractory anemia has been used for nearly a century to define erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency and, thus, are unresponsive to the known hematinics.1 At the time, the knowledge base was insufficient to determine the disorder was a neoplasm behaving in a relatively benign fashion. One sage observer likened the disorder to an adenoma in relationship to a carcinoma.1 In 1956, Bjorkman231 defined a subset of refractory anemias by the presence of ringed sideroblasts in the marrow. The intramitochondrial location of the iron in the ringed sideroblasts was described 1 year later.232 Because the finding of ringed sideroblasts was a constant feature of marrow stained with Prussian blue in this situation, the designation refractory anemia with ringed sideroblasts was coined.


The disorder is a clonal multipotential hemopoietic stem cell defect in which ineffective erythropoiesis with normal or slightly shortened red cell survival and only slight impairment of the maturation of other cell lineages occur. Plasma iron turnover is increased, but incorporation of radioactive iron into heme and its delivery to blood as newly synthesized hemoglobin are depressed. These early ferrokinetic studies presaged the evidence that erythroid precursors were subject to aberrant maturation and pathologic apoptosis.78,79 Low levels of the iron transporter gene, ABCB7, have been found in clonal sideroblastic anemia, and this gene is also associated with X-linked sideroblastic anemia with ataxia.233 The genes somatically mutated to initiate this disorder have not been identified, but the frequency of deleted chromosome arms suggests a tumor suppressor gene on the affected chromosome is involved.185

Clinical Features

The disease is very uncommon in individuals younger than age 50 years,24,26,234 except in patients in whom the disease occurs as a result of radiotherapy or chemotherapy of a malignant tumor. The rare concurrence of familial sideroblastic anemia has been reported.235 Males and females are affected almost equally. The signs and symptoms are those of anemia: pallor, easy fatigue, weakness, dyspnea, and palpitations on exertion.232,234 In most patients the anemia is detected as a result of blood cell analysis for other medical reasons. The liver may be slightly enlarged. The spleen is slightly increased in size in approximately 5 percent of patients. Splenic and hepatic enlargement do not necessarily occur together, and more than slight enlargement is unusual.

Laboratory Features

Most patients have mild to severe macrocytic anemia.232,234 The blood film often contains a population of hypochromic cells (dimorphic red cell changes) and, hence, a widened red cell distribution width.232,234–236 Red cell anisocytosis, basophilic stippling, and slight poikilocytosis may be present. The total white cell count and platelet count usually are normal, but mild abnormalities may be seen, including a decreased white cell count and an increased or decreased platelet count. Occasionally, the white cell count or platelet count is increased markedly, or nucleated red cells are present in the blood film. The reticulocyte percentage usually is between 0.5 and 2.0. Hemoglobin F concentration may be increased slightly. The disease may express a subtle phenotype: either mild macrocytic anemia in older patients with few other features of clonal anemia,237,238 or in patients with clonal cytogenetic abnormalities with cytopenia but no unequivocal morphologic evidence of clonal dysmorphic hematopoiesis.239

Marrow cellularity usually is increased as a result of erythroid hyperplasia. Evidence of dyserythropoiesis in the form of vacuolated, small, large, or binucleate erythroblasts may be present. Prussian blue stain of the marrow invariably shows pathologic sideroblasts. The latter may have Prussian blue-positive cytoplasmic granules in a partial or complete circumnuclear pattern (ringed sideroblasts) in 15 or more percent of cells or an increased number (more than five) of Prussian blue-positive granules in their cytoplasm. If the disease progresses to oligoblastic leukemia, sideroblasts may become less prominent.240 Granulopoiesis and thrombopoiesis are not altered significantly in two-thirds of patients.236,241 In the other third of patients, dysgranulopoiesis (hypogranulation, acquired Pelger-Huët anomaly, hypersegmented nuclei, granule abnormalities) or dysmegakaryocytopoiesis (micromegakaryocytes, large lobulated cells) may be present. Marrow iron stores often are increased.

Cytogenetic abnormalities in marrow cells of patients with acquired refractory sideroblastic anemia provide evidence for the clonal character of the disease. Approximately half of the reported patients with sideroblastic anemia in whom cytogenetic studies have been performed have a chromosomal abnormality.235 Involvement of chromosomes 8, 11, and 20 has been notable.184,242,243 The Philadelphia chromosome has been reported.244 Involvement of chromosome 3 has been associated with thrombocytosis.245 The absence of the Y chromosome, only in the pathologic sideroblasts in one report (45;X/46;XY mosaic), substantiates the dimorphic nature of the erythroid lineage involvement and parallels the hypochromic and normochromic red cell populations.246 Involvement of the X chromosome (a breakpoint at Xq13) of female patients with sideroblastic anemia247 is noteworthy because a type of hereditary sideroblastic anemia is X chromosome linked (see Chap. 58).

Serum iron levels and saturation of transferrin are increased. Serum ferritin concentration is increased, reflecting an increase in body iron stores. Bilirubin-proteinate levels (indirect-reacting fraction) may be increased as a result of ineffective erythropoiesis and intramedullary hemolysis.

Special Clinical Feature: Thrombocytosis

A proportion of patients with clonal sideroblastic anemia have thrombocytosis, generally considered a platelet count greater than 450 x 109/L (450,000/µL). This syndrome is referred to as refractory anemia with ringed sideroblasts with thrombocytosis (RARS-T) in the WHO classification. A proportion (approximately 40%) of these patients have a mutation in the JAK2 (Janus kinase 2) gene. The presence of the JAK2 mutation confers a better prognosis on these patients.248–250

Differential Diagnosis

The principal considerations are the anemias with an inadequate reticulocyte response in which erythrocytes are hypochromic. Iron-deficiency anemia in contradistinction to sideroblastic anemia is associated with low serum iron levels, saturation of transferrin of less than 16 percent, low serum ferritin concentration, elevated serum transferrin receptors, and absent marrow sideroblasts and macrophage iron. The anemia of chronic disease can simulate some features of clonal anemia, although the low serum iron in the former and the presence of an overt chronic inflammatory disease, such as rheumatoid arthritis, are important distinctions. -Thalassemia minor is characterized by normal to elevated serum iron and ferritin, low mean red cell volume, elevated hemoglobin A2 concentration, and evidence of the disease in a parent, siblings, or offspring. -Thalassemia trait is common among Americans of African descent. It can be distinguished from MDS by several features. It is microcytic, and often the red cell count is normal or elevated in relationship to the hemoglobin concentration. Target cells are more prominent than in MDS. Similar red cell changes may be present in a parent, sibling, or child supporting its hereditary nature. Molecular techniques are available to detect the loci deletions in the usual -/-,–3.7 kbdel type. Confusion may be engendered because the individual also may have a “low” white cell count based on laboratory normal values not corrected for the lower white cell counts in persons of African descent. Copper deficiency following gastric bypass surgery can also simulate myelodysplasia.51,52 Detection of secondary forms of sideroblastic anemia requires evaluation for exposure to lead or other agents or diseases listed in Chap. 58, as do the hereditary sideroblastic anemias.


Some patients do not require treatment because the moderate decrease in hemoglobin concentration is tolerated without limitation of usual activities.

Folic Acid, Pyridoxal, and Danazol

Occasional patients who have low serum and red cell folate concentrations may have partial improvement in blood hemoglobin concentration after administration of folic acid (1 mg/day orally). Rare patients benefit temporarily from pharmacologic doses of pyridoxine (200 mg/day orally for at least 3 months) or danazol.251 A therapeutic trial with folic acid and pyridoxine is worthwhile if the anemia is symptomatic, even though only a small percentage of patients are responsive. The attenuated androgen danazol has increased the platelet count and decreased the frequency of platelet transfusions in patients with all categories of MDS.252 Danazol also has been combined with retinoic acid and low-dose prednisone.253

Transfusion of Red Cells

If anemia is severe or symptoms of heart failure or coronary insufficiency are present, periodic transfusion of red cells is required.

Iron Chelation

Iron overload is an important therapeutic consideration in transfusion-dependent patients who have a life expectancy measured in years. Cardiac, liver, and other organ dysfunction secondary to iron-overload from transfusion can result. Circumstantial evidence indicates that iron-overload may shorten survival in chronically transfused patients with clonal anemia. Guidelines for initiation of iron chelating agents are not definitive; if a patient has received 20 or more transfusions, has a ferritin level greater than 1000 mcg/L, and has a prognosis for at least 1-year survival, administration of an iron chelating agent should be strongly considered.254–257 Deferasirox, an available oral iron chelator that can be administered once per day (20 mg/kg), has been approved by the FDA for use in transfusion-dependent patients.258 The most common adverse events associated with deferasirox treatment include nausea, vomiting, abdominal pain, constipation or diarrhea, and skin rash. Elevated serum creatinine and, less frequently, elevated liver enzymes may develop. Thus, renal and hepatic function should be evaluated prior to use. Visual and auditory dysfunction has been reported. Careful monitoring of the drug is important since its toxicity profile in older patients is still being assessed.

Erythropoietin and G-CSF

Recombinant human erythropoietin generally is not useful unless the pretreatment serum erythropoietin level is low for the blood hemoglobin concentration (less than 500 U/L) and the transfusion requirement is less than 2 U per month, an infrequent finding in these patients. In eligible patients, the combination of G-CSF with erythropoietin increases the response rate.259–262 Response rates in various studies range widely. On average approximately 40 percent of eligible patients get some benefit from therapy. Duration of response is also variable but averages about 2 years. Improvement in quality of life has been variable among studies. Darbepoetin (long-acting erythropoietin) is probably equally effective as erythropoietin. Serum iron should be maintained at a normal level by oral or intravenous supplementation, if needed, to ensure an optimal erythropoietic response from erythropoietin administration.

Demethylating Agents

Azacitidine, 75 mg/m2 per day, subcutaneously (or intravenously), for 7 days every 28 days, can be useful in the patient with significant anemia and a transfusion requirement, unresponsive to erythropoietin and G-CSF. Approximately 40 percent of patients have a complete or partial response with improvement in hemoglobin level and either a cessation of transfusion requirements or a significant decrease in transfusion frequency. Patients who respond to the drug have an increase in survival and a longer period before progression to AML or death.263–266 These differences are proportionally great (approximately 80%) but are measured only in months. Decreased blood counts are a common initial response and, thus, transfusion requirements may increase temporarily in the first weeks of treatment, even in good responders. The response to the drug may be evident by the end of two treatment cycles, but it may require four or five cycles to obtain a response, and maximal responses may not occur for eight or nine cycles. Thus, the drug should be continued until disease progression or a serious adverse response requires cessation and until improvement is maximized. Nausea and vomiting may be adverse events but they can be treated with antiemetics and usually do not require stopping therapy. If patient tolerance is good, the dose can be increased to 100 mg/m2, if a response is not evident by the second or third cycle. Phase 1 trials are under way to examine the efficacy of an oral preparation of 5-azacytadine. Early results have been promising with decreased side effects. Decitabine has also been approved as a demethylating agent in this situation (see “Therapy for Patients with High-Intermediate (INT-2) Prognostic Scores: Demethylating Agent and Histone Deacetylation Inhibitor Therapy” below).

Course and Prognosis

In many patients, the disorder lasts for years without progression of the anemia or symptoms and without need for specific therapy. A small proportion of patients may have progressive marrow failure, severe cytopenias, and morbidity from infections or hemorrhage. Iron overload is a function of increased absorption related to chronic anemia and, more importantly, repeated red cell transfusions over prolonged periods. Improvement of the anemia and the adverse effects of iron overload in parenchymal tissues can result from iron-chelation therapy.254–258,267

Over a 10- to 15-year period, approximately 10 percent of patients with clonal (sideroblastic) anemia develop AML.268–272 Progression to leukemia is correlated with the degree of abnormal hematopoiesis and trilineage abnormalities.205,240 Transformation to acute lymphocytic leukemia (ALL) also has occurred.273 In one series of 37 patients, 25 had abnormalities confined to the erythroid series, transfusion dependence occurred in 26, and iron overload was common. Five patients progressed to marrow failure and five to AML. Median survival was 72 months.274 Survival in other series has ranged from 85 to more than 100 months.205,274,275 The presence of thrombocytosis (and the JAK2 gene mutation) may confer a better prognosis.248 Survival is better in patients without significant abnormalities in lineages other than the erythroid series and with favorable cytogenetic findings.274,275 This latter prognostic indicator also applies to clonal nonsideroblastic anemias and oligoblastic leukemia.275