Refractory anemia (RA) is a chronic blood disorder that does not respond to standard treatments like iron or vitamin B12 supplementation. This condition is a type of bone marrow failure where the production of healthy red blood cells is impaired. Refractory anemia is now understood to be a low-risk manifestation of Myelodysplastic Syndromes (MDS). MDS are stem cell disorders characterized by the inefficient and disordered production of all blood cell types within the bone marrow.
Defining Refractory Anemia and MDS
Refractory anemia (RA) originated from the older French-American-British (FAB) classification system. While still used conversationally, the term has been largely replaced by the World Health Organization (WHO) classification of Myelodysplastic Syndromes. RA generally corresponds to low-risk MDS subtypes, such as Myelodysplastic Syndrome with single lineage dysplasia (MDS-SLD) or Myelodysplastic Syndrome with ring sideroblasts (MDS-RS).
MDS is a disorder of hematopoietic stem cells, the precursor cells for all mature blood cells. A defect in these stem cells causes the resulting blood cells to be defective and fail to mature properly, a process called ineffective hematopoiesis. The bone marrow in MDS patients is typically hypercellular, but this cellularity is ineffective because the abnormal cells die prematurely.
In Refractory Anemia, the primary defect is concentrated in the erythroid lineage, leading to a low red blood cell count in the peripheral blood. MDS-RS is a specific subtype where at least 15% of red blood cell precursors in the bone marrow are ring sideroblasts, which contain abnormal iron deposits surrounding the cell nucleus. The WHO classification system allows for more accurate categorization based on morphology, cell counts, and genetic features, which impacts treatment and prognosis.
Symptoms That Lead to Diagnosis
Symptoms that lead to a diagnosis of refractory anemia are typically non-specific and result from the sustained low red blood cell count. Anemia reduces the blood’s oxygen-carrying capacity, causing chronic oxygen deprivation. Patients commonly report profound fatigue and weakness that does not improve with rest.
Other common symptoms include shortness of breath (dyspnea), particularly during physical activity. Paleness (pallor) is often noticeable due to the decreased amount of hemoglobin. These symptoms often worsen gradually, leading patients to seek medical attention when the effects become debilitating. Less frequent symptoms may include dizziness, headaches, or a rapid heart rate. Since these symptoms are common to many types of anemia, a diagnosis of refractory anemia is often delayed until standard treatments have failed.
Establishing a Diagnosis
Diagnosing refractory anemia, or low-risk MDS, requires excluding other common causes of anemia and confirming abnormal blood cell production. The process begins with a Complete Blood Count (CBC), which often reveals macrocytic anemia, meaning the red blood cells are larger than normal. The CBC also shows a low reticulocyte count, indicating ineffective production of new red blood cells.
The definitive diagnosis relies on a bone marrow aspiration and biopsy, allowing physicians to examine the cells directly. The biopsy reveals morphological changes (dysplasia) in the blood cell lines, confirming ineffective hematopoiesis. For a diagnosis of low-risk MDS, the percentage of immature white blood cells (blasts) in the bone marrow must be less than 5%.
Cytogenetic analysis is performed on the bone marrow sample to look for specific chromosomal abnormalities characteristic of MDS, such as the deletion of the long arm of chromosome 5 (del[5q]). The diagnosis is one of exclusion, established only after deficiencies like vitamin B12 or folate and other reversible causes of anemia have been ruled out.
Treatment Approaches and Management
Management of low-risk MDS, including refractory anemia, centers on alleviating symptoms caused by low blood counts and improving quality of life. For severe anemia, regular red blood cell transfusions are the cornerstone of supportive care. While transfusions address symptoms, long-term use can cause iron overload, requiring monitoring and iron chelation therapy.
The first-line medical therapy often involves Erythropoiesis-Stimulating Agents (ESAs) to boost red blood cell production. ESAs are most effective in patients who are not heavily dependent on transfusions and have low levels of endogenous erythropoietin. If ESAs fail, specific drug therapies are considered.
Patients with the del(5q) chromosomal abnormality often respond well to the immunomodulatory drug lenalidomide, which can reduce or eliminate the need for transfusions. For those with MDS-RS refractory to ESAs, luspatercept may be used, as it regulates the maturation of red blood cell precursors. Hematopoietic stem cell transplantation is the only potentially curative treatment for MDS, but it is typically reserved for younger, higher-risk patients due to the intensity and risks of the procedure.
Long-Term Outlook and Monitoring
The prognosis for low-risk MDS, which includes refractory anemia, is generally favorable, with many patients living for years with supportive care. Continuous surveillance is necessary to monitor for disease progression. Doctors use risk stratification tools, such as the Revised International Prognostic Scoring System (IPSS-R).
This system assigns a risk score based on five factors: the percentage of blasts in the bone marrow, specific cytogenetic abnormalities, and the levels of hemoglobin, platelets, and neutrophils. This scoring system helps predict the likelihood of the disease transforming into Acute Myeloid Leukemia (AML). Regular blood counts track the stability of cytopenias and patient health. Periodic bone marrow examinations may also be necessary to check for an increase in blast percentage or the development of new chromosomal abnormalities, which signal disease progression.