Abstract
Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare hematologic neoplasms characterized by leukocytosis and a hypercellular bone marrow. Although recurrent mutations in the colony-stimulating factor 3 receptor (CSF3R) are frequently observed in patients with (CNL), the mutational landscape in (aCML) is less well-defined. In this report, we describe an 81-year-old male who was diagnosed with aCML. He presented with leukocytosis and anemia but no significant clinical symptoms. Standard laboratory studies revealed the absence of the Philadelphia chromosome. Massively parallel sequencing demonstrated no mutations in CSF3R, but the presence of a heterozygous NRAS-G12D variant (47% allele frequency). The patient was started on treatment with trametinib, an MEK1/2 inhibitor with Food and Drug Administration approval for malignant melanoma. Therapy with trametinib resulted in exceptional improvements in his blood counts and continued disease control with 14 months of follow-up. This case highlights the need for clinical trials evaluating the safety and efficacy of MEK1/2 as a therapeutic target for the treatment of patients with NRAS-mutated aCML/CNL.
Highlights
Atypical chronic myeloid leukemia and chronic neutrophilic leukemia (CNL) are rare myeloid malignancies that exhibit overlapping clinical characteristics, including leukocytosis, anemia, thrombocytopenia, splenomegaly, and constitutional symptoms
Transplantation of Nras-G12D-positive acute myeloid leukemia (AML) cells into mice induces a lethal leukemia and treatment of these mice with trametinib significantly prolongs survival as compared to untreated control mice [7]. These studies indicate that targeting MEK with trametinib may represent a promising therapeutic strategy for the subset of patients with Atypical chronic myeloid leukemia (aCML) whose leukemia harbors RAS mutations
We describe a patient with NRAS-G12D-positive aCML who experienced an exceptional response to MEK1/2 inhibition with trametinib
Summary
Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid malignancies that exhibit overlapping clinical characteristics, including leukocytosis, anemia, thrombocytopenia, splenomegaly, and constitutional symptoms. Transplantation of Nras-G12D-positive AML cells into mice induces a lethal leukemia and treatment of these mice with trametinib significantly prolongs survival as compared to untreated control mice [7]. These studies indicate that targeting MEK with trametinib may represent a promising therapeutic strategy for the subset of patients with aCML whose leukemia harbors RAS mutations. The patient began experiencing progressive fatigue, increasing lower extremity edema, and loss of appetite His laboratory studies demonstrated a steady increase in the WBC count (256 x 103/μl), with a Hgb of 9.9 g/dL, and a platelet count of 66 x 103/μl. At the time of this report, the patient has been on 2 mg of trametinib daily for over 14 months, with his most recent bloodwork from early November 2015 revealing a WBC count of 10 x 103/μl, Hgb of 10.5 g/dL, and a platelet count of 168 x 10 3/μl
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