Complete Hematologic and Cytologic Remission in M6A Erythroleukemia Using Decitabine Hypomethylation Monotherapy

Abstract Hypomethylating drugs (e.g. Azacitadine, Decitabine) are becoming increasingly attractive choices for the treatment of acute myelogenous leukemia (AML), particularly in populations deemed inappropriate for standard anthracycline-based induction chemotherapy (i.e., 7+3), such as the elderly. Acute erythroleukemia (French-American- British M6) is a rare, heterogeneous disorder involving increased red cell precursors and myeloblasts, that accounts for 3–5% of de novo AML and 20–30% of secondary AML. Three subsets have been described: M6A (myeloblast-rich erythroleukemia); M6B (proerythroblast-rich erythroleukemia); and M6C (myeloblast- and proerythroblast-rich mixed variant). Little data exists on the efficacy of hypomethylation therapy in this uncommon subtype of AML. We report the rapid induction of a complete hematologic and cytologic remission in a patient with the M6A variant erythroleukemia using decitabine monotherapy. A 75 year-old white male with a history of coronary artery disease, was admitted for elective cardiac catheterization because of recurrent exertional chest pain. A pre-catheterization complete blood count (CBC) revealed pancytopenia with a white blood cell (WBC) count of 1400/mm3, hemoglobin of 6.2 g/dL (mean cell corpuscular volume of 113 fL), and a platelet count of 51,000/mm3. The differential showed neutropenia, but was otherwise normal with no circulating blasts. Blood transfusion completely relieved his chest pain, and his catheterization was uneventful. A bone marrow aspirate and biopsy demonstrated a hypocellular marrow (15–20%) with erythroid hyperplasia (70% of total cellularity) and increased blasts (10% of total cellularity, 30% of non-erythroid cells), most compatible with acute M6A erythroid/myeloid leukemia. Cytogenetic studies revealed a normal male karyotype, but a single cell with a 5q- deletion. Subsequent fluorescent in situ hybridization (FISH) analysis using an LSI DNA probe (Vysis Inc.) for detection of the EGR1 gene on chromosome 5q, failed to confirm the 5q deletion, consistent with normal cytogenetics. Because of the patient's advanced age and co-morbidities, induction with hypomethylation monotherapy was begun with intravenous decitabine (Dacogen®) 20 mg/m2 daily for five consecutive days, repeated every four weeks. Growth factor support (Neupogen® 375 mcg daily) and antibiotic prophylaxis (ciprofloxaxin, acyclovir, fluconazole) were only required after the first cycle of decitabine because neutropenia did not occur with subsequent cycles. WBC and platelet counts normalized shortly after cycle one, while the hemoglobin normalized by cycle five. An interim bone marrow aspirate/biopsy was repeated after cycle three, showing normocellularity (30%), and no evidence of residual leukemia. Other than a localized herpetic reactivation following cycle one, the patient has tolerated hypomethylation therapy extremely well. He has now completed eight cycles of therapy, and remains in complete remission. Epigenetic alterations (such as DNA methylation) may play a role in AML leukemogenesis by inducing the inhibition of tumor suppressor genes. Recent studies have also shown that high estrogen receptor-α and p15INK4B methylation levels in AML patients in clinical remission, were associated with a high risk for leukemia relapse and poor relapse-free survival. However, little data exist for epigenetic dysregulation in the etiology of human erythroleukemia. Cell culture studies using human erythroleukemia cell lines indicate that DNA methylation may have functional consequences for gene activity, including globin gene expression and cellular differentiation. The current case indicates a potential role for DNA methylation in the pathogenesis of human erythroleukemia, and argues for further investigation into this potential mechanism of leukemogenesis. Future studies will include the effect of hypomethylating compounds on the growth and differentiation of human erythroleukemia cells, and the evaluation of DNA methylation levels in bone marrow biopsy samples from M6 patients.