Skill Checkup: Woman With Persistent Anemia and Fatigue

Medscape

10-06-2025

A 72-year-old woman presents with persistent anemia and fatigue. Her height is 5 ft 2 in (1.57 m) and weight is 131 lb (59.42 kg; body mass index of 24). She was diagnosed with low- to intermediate-risk myelodysplastic syndrome (MDS) with ring sideroblasts 2 years ago when she presented with unexplained macrocytic anemia. Bone marrow biopsy at the time showed blasts were 5%-7%, and her specimen tested positive for SF3B1 mutation and negative for del(5q) . Her erythropoietin levels were < 400 and she received erythropoiesis-stimulating agent (ESA) therapy, requiring ≥ 2 red blood cell (RBC) units over 8 weeks. However, despite ESA therapy, the patient presents with symptomatic anemia; her hemoglobin is 10.1 g/dL. There are no blasts in the blood; 16% of erythroid precursors with ring sideroblasts are identified.
Because this patient's anemia is not responding to treatment, the likely diagnosis is MDS with ESA-refractory anemia. ESAs are a potential therapy for the treatment of patients with MDS. However, most patients with MDS either do not respond to ESAs or eventually will develop resistance to these agents.
Progression to acute myeloid leukemia (AML) in myelodysplastic syndrome is defined by the presence of ≥ 20% blasts in the peripheral blood or bone marrow (World Health Organization criteria). In this case, the patient has no blasts in the blood and had 5%-7% blasts at diagnosis, which is consistent with MDS but not AML.
Copper deficiency can cause a sideroblastic-like anemia, but it is typically associated with neurologic symptoms (eg, ataxia, paresthesias), leukopenia, and a history of risk factors such as zinc overuse, malabsorption, or gastric surgery. This patient has a known diagnosis of MDS with ring sideroblasts and a pathogenic SF3B1 mutation, strongly supporting a clonal myeloid neoplasm rather than a nutritional deficiency.
Although symptomatic anemia is a major morbidity of MDS, the anemia described in the present case, refractory anemia with ring sideroblasts (MDS-RS), is a subtype often associated with SF3B1 mutations, which lead to defective RNA splicing and secondary mitochondrial iron accumulation. This results in the formation of ring sideroblasts. SF3B1 is the most frequently mutated splicing factor gene in MDS-RS, and it is associated with better outcomes and longer survival. In this case, the presence of this mutation confirms a diagnosis of MDS over secondary causes of ring sideroblasts.
Anemia in MDS might or might not be symptomatic at presentation and varies in degree, from mild to severe. Clinical symptoms of MDS, including fatigue as described by this patient, arise because of low peripheral blood counts, usually from anemia, but also can occur from thrombocytopenia or neutropenia.
Features predictive of ESA response include a lower baseline serum erythropoietin (EPO) level (< 500 IU/mL), a low transfusion burden (< 2 units a month), a fixed-dose regimen, shorter time from diagnosis to starting treatment, and diagnosis of refractory anemia or MDS-RS. Although the patient in the present case is in fact diagnosed with refractory anemia or MDS-RS, response rates to ESA therapy are variable in patients with lower-risk MDS, ranging from 30%-60%.
In this patient population, close monitoring of hemoglobin level is recommended to avoid increases to > 12 g/dL (as it is associated with a risk for systemic hypertension and thrombosis). In addition, the immunomodulatory agent lenalidomide can reduce transfusion requirements in patients with lower-risk MDS and a normal karyotype.
In MDS, anemia is usually anisocytic, with a normal or a hypochromic microcytic population coexisting with the macrocytes. It is also generally macrocytic (mean cell volume, > 100 fL) with RBCs that are oval-shaped (macro-ovalocytes). Punctate basophilia is observed in RBCs. Symptomatic anemia in MDS frequently presents as a hypoproductive macrocytic anemia, often associated with suboptimal elevation of serum EPO levels.
The National Comprehensive Cancer Network (NCCN) guidelines advise that during MDS workup, cytogenetics, bone marrow aspiration with iron stain, biopsy, serum EPO, and other coexisting causes should be ruled out. For MDS to be classified as MDS-RS, as in the present case, anemia should be present but with low blasts in the blood; for bone marrow, either ≥ 15% of erythroid precursors with ring sideroblasts must be identified, or if SF3B1 mutation is present, ≥ 5% ring sideroblasts.
The same guidelines also make recommendations for additional testing of symptomatic anemia with MDS. These include flow cytometry to evaluate for large granular lymphocyte and paroxysmal nocturnal hemoglobinuria clone. Human leukocyte antigen typing offers clinical value if the patient is a hematopoietic cell transplant candidate. Because the patient in the present case is considered lower risk, she probably is not at this juncture.
Recombinant fusion protein, such as luspatercept, is the most appropriate option for this patient, given its approval for the treatment of anemia in patients with lower-risk MDS-RS who have not responded to treatment with ESAs. In patients with lower-risk MDS and symptomatic anemia, treatment is usually guided by cytogenetic findings, serum EPO levels, and the presence of ring sideroblasts or SF3B1 mutations.
For patients with del(5q) , lenalidomide remains the preferred treatment regardless of EPO level. For those with SF3B1 mutations or ring sideroblasts ≥ 15% (or ≥ 5% with a mutation), luspatercept is preferred, with imetelstat recommended if EPO is > 500 mU/mL and the patient is ineligible for ESAs. In patients without these features, ESAs plus granulocyte colony-stimulating factor or imetelstat may be considered on the basis of EPO levels, with follow-up based on response. Escalation to agents like ivosidenib or enasidenib is recommended only in the presence of IDH mutations.
Neither hypomethylating agents or allogeneic transplant are included in this lower-risk anemia-focused treatment pathway. Further, intensive induction chemotherapy is not typically utilized in this setting.