Continuing Education Activity

Refractory anemia with ring sideroblasts (RARS) is a type of myelodysplastic syndrome (MDS) that is characterized by anemia and the presence of at least 15 percent ring sideroblasts in the marrow. Generally, patients will have normochromic, normocytic anemia and erythroid hyperplasia. This activity examines when RARS should be considered on differential diagnosis and how to properly evaluate for it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Summarize the etiology of refractory anemia with ring sideroblasts.
• Review the common presentation of refractory anemia with ring sideroblasts.
• Describe the management of refractory anemia with ring sideroblasts.
• Explain a well-coordinated interprofessional team approach to provide effective care to patients affected by refractory anemia with ring sideroblasts.

Introduction

Anemia is defined by a deficiency in hemoglobin, causing decreased oxygen capacity within the blood. Many of these causes are iatrogenic, but some can be genetic, secondary to malignancy or chronic inflammation, impairment of globin chain synthesis or acquired forms. Genes that are involved in iron metabolism may also be responsible, causing severe congenital deficiencies in iron and sequestration of iron.  Iron is then trapped within the mitochondria, forming a "ring" around the early red blood cell. It was not until the 1960s in which this became a known variant of anemia.  These congenital diseases include sideroblastic anemia which can be either monosyndromic or polysyndromic (systemic expressivity).[1] 

Refractory anemia with ringed sideroblasts is a version of myelodysplastic syndrome (MDS) which is characterized by anemia and the presence of >/= to 15% ring sideroblasts in the marrow. Generally, the patient presents with normochromic, normocytic anemia with overall erythroid hyperplasia.[1][2]  Often, the level of hemoglobin is generally in the range of 9 to 12 g/dL, though lower levels may be present.  The red blood cells may show dimorphism and populations can also show hypochromia.  The platelets and neutrophils are hyperplastic with variable degrees of dyserythropoiesis and occasional megaloblastoid features.  Granulopoiesis and megakaryocytopoiesis are normal findings and present within a majority of the cases. 

Etiology

Sideroblastic anemia has been known to be caused by several genetic mutations mostly due to a defect in hemoglobin synthesis.  Congenital sideroblastic anemia (CSAs) are inherited conditions due to mitochondrial dysfunction due to defects in heme biosynthesis, iron biogenesis, or even generalized mitochondrial protein synthesis.[1][3] Like most of the pathway to heme biosynthesis, this is an evolutionarily conserved mitochondrial pathway that involves multiple enzymes that reduce organic sulfur to sulfide, complexes it with iron and then delivers it to the mitochondria and cytosol. One of the best-characterized forms of CSA is the X-linked sideroblastic anemia, XLSA which is typically due to missense mutations in ALA synthase or ALAS2 which is the first step in heme biosynthesis.   

However, most of the refractory anemia with ringed sideroblasts will have an evolution in two forms: MDS with a normal lifespan or MDS with development to a higher grade MDS or AML. The majority of cases belonging to the first category and will develop in only 7-10% of all RARs patients.  Morphology at the time of diagnosis is crucial as it will drive the evolution of the disease.

Epidemiology

The variation of sideroblastic anemia stretches from the very young (congenital) to much older (>40 years old) individuals.[4]

Histopathology

Morphologic evaluation of this condition centers on the entire clinical picture.[5]  Clinically, a patient may present with progressive neutropenia, normal vitamin B12 and folate levels, and normal iron levels.  If bone marrow assay is ordered for progressively low counts, it often shows a hypocellular picture with serious degenerative changes or even erythroid hyperplasia which may be reflective on smears.  Granulopoiesis is often left shifted, but full maturation still occurs. Bone marrow is often stained for iron and will show numerous iron-laden macrophages present but not as well appreciated on the smear.  What is critical is to stain the peripheral blood smear, looking for ringed sideroblasts in early forms, which are reliable forms of evaluation. 

History and Physical

This condition requires a physical examination of the patient, including a head to toe examination of mucous membranes, conjunctiva for pallor, heart and lung exam, evaluation of fingers for changes in nail beds secondary to anemia, and evaluation for alternative causes of anemia. The clinician may want to review all potential social exposures, smoking, drinking, and work-related exposures and previous surgical procedures.  It is also essential to evaluate all systems for any past medical history of cancer, familial hematologic malignancies, and other idiopathic causes. 

Evaluation

Often in addition to a full history and physical examination, other laboratory tests are required. A complete blood panel, with differential, chemistries, and evaluation of vitamin deficiencies (vitamin B12 and folate, copper) are necessary.  If warranted, evaluation of the patient's gastrointestinal history is an essential review as many causes of anemia have links to absorption problems of the gut.  If persistent anemia, then a peripheral smear should be reviewed as well as the potential for a bone marrow biopsy.

Treatment / Management

Often, the underlying causes of sideroblastic anemia requires therapeutic action before any improvement of the condition ensues.[6]  Though some patients may be successful on the watch and wait regimen; azacytidine (AZA) is a new option for these patients.  Administration of 75 mg/m^2 for seven consecutive days with a 28-day cycle subcutaneously or intravenously is an option for these patients.  If the patient is > 20 years of age, who meet criteria for RARS and whose neutrophil count is less than 1x10^9/L, would qualify for the therapy.

Alternatively, if a verifiable cause is unable to be linked to the sideroblastic anemia, watching and waiting is always another option for patients and their clinicians.

Differential Diagnosis

Morphologic scrutiny is essential for patients with a potential diagnosis for this condition.  Accurate accounting of dysplasia with approximately 7-10% of the entire population of erythroid cells is adequate for diagnosis. However, if there is more than one lineage with dysplasia, then a multi-lineage nomenclature must be used. 

Prognosis

Rarely a patient with findings of RARs and no increase in blast count in the marrow and a rare blast with an Auer rod may be found.  Depending on the level of blasts encountered, a patient may classify as RARS-2, which would portend a worse prognosis for the patient.  Correlation with the mutational status of SF3B1 is also important and been identified in these cases. The blast count will determine the overall prognosis of the patient in the end, the higher the count, the greater the propensity to develop acute myeloid leukemia (AML).[7]

Complications

Complications of RARs span the gamut from very subtle symptoms to aggressive progression to AML.  The level of blast counts and response to potential treatments will often determine the overall survival of the patients. Additionally, vascular and thrombotic complications are also very prevalent in these patients.[8]

Enhancing Healthcare Team Outcomes

The persistence of this condition is an important communication event in a hematopathologist's diagnostic days.  Patients who develop this condition may be at risk for subsequent progression to AML.  Therefore, communication between the pathologist and hematologist/primary care physician is essential. Once a case of RARs is a consideration as a differential diagnosis, communication that a careful evaluation of the peripheral smear with iron staining performed is in order, as well as ancillary mutational analysis for SF3B. Treatment will often be determined by the clinician shortly after the review of the peripheral blood smear.[5]