A 68-year-old woman presents with progressive fatigue and dyspnea on exertion. Laboratory investigations reveal hemoglobin 7.2 g/dL (macrocytic), platelet count 450,000/μL, and neutrophil count 2,800/μL. Bone marrow examination shows erythroid hypoplasia with monolobated megakaryocytes and <5% blasts. Cytogenetic analysis demonstrates the abnormality marked **C** in the diagram. Which of the following is the most appropriate first-line treatment for this patient?
A. Erythropoiesis-stimulating agents (EPO) as monotherapy
B. Decitabine 20 mg/m² intravenously daily for 5 days every 28 days
C. Azacitidine 75 mg/m² intravenously daily for 7 days every 28 days
D. Lenalidomide 10 mg orally once daily for 21 of 28 days
Explanation
Why Lenalidomide 10 mg orally once daily for 21 of 28 days is right
The cytogenetic abnormality marked C — isolated del(5q) — defines 5q- syndrome, a distinct WHO-defined low-grade MDS subtype. Lenalidomide is the first-line treatment for this specific cytogenetic entity. It selectively eliminates del(5q) clones by targeting CSNK1A1 (haploinsufficient on the deleted chromosome) via cereblon-mediated degradation. Response rates exceed 65–75%, with transfusion independence achieved in most patients and cytogenetic responses in ~50%. The clinical presentation (elderly woman, macrocytic anemia, thrombocytosis, hypolobated megakaryocytes, isolated del(5q)) is pathognomonic for 5q- syndrome and mandates lenalidomide as first-line therapy per Harrison's and WHO guidelines.
Why each distractor is wrong
Azacitidine 75 mg/m² intravenously daily for 7 days every 28 days: Azacitidine is reserved for higher-grade MDS (IPSS-R intermediate or higher risk) and MDS-EB2. 5q- syndrome is typically LOW or VERY LOW risk and responds preferentially to lenalidomide. Azacitidine is not first-line for isolated del(5q).
Erythropoiesis-stimulating agents (EPO) as monotherapy: EPO may be used in select patients with 5q- syndrome, but only as adjunctive therapy or in those with lower transfusion burden and lower serum erythropoietin levels. It is not first-line monotherapy for this cytogenetic entity.
Decitabine 20 mg/m² intravenously daily for 5 days every 28 days: Like azacitidine, decitabine is a hypomethylating agent used in higher-grade MDS. It is not indicated as first-line therapy for low-risk 5q- syndrome.
