V600E-Mutant Acute Myeloid Leukemia: A Case Series and Literature Review of a Rare Entity.

Although V600E mutations are common in solid tumors and select hematologic neoplasms, they are reported less frequently in myeloid malignancies. Of the cases of V600E-mutant acute myeloid leukemia (AML) that have been described, most display monocytic morphology and concurrent rearrangement. Strikingly, all cases have been associated with poor survival. Here, we report two cases of AML, one diagnosed in an elderly male with metastatic lung adenocarcinoma and hepatocellular carcinoma and the other diagnosed in a young boy previously treated for B-cell acute lymphoblastic leukemia. Peripheral blood NGS revealed oncogenic mutations in p.V600E (VAF = 33%), p.M508Cfs25 (VAF = 48%), p.C211 (VAF = 49%), p.R295* (VAF = 71%), p.N581S (VAF = 6%), and c.118-2A>G, p.? (VAF = 4%) in case 1 and p.V600E (VAF = 1%) and p.G12A (VAF = 28%) in case 2. Cytogenetic workup revealed a complex karyotype in case 1 and an abnormal karyotype with non-clonal aberrations and () rearrangement in case 2. Morphologically, both patients were found to have AML with monocytic features. The post-mortem examination of case 2 also revealed extensive solid organ infiltration, consistent with a monocytic leukemia. Both patients died within days of diagnosis, demonstrating the lethality of this molecular subgroup of AML. Our cases add to the literature, highlighting the poor prognosis of patients diagnosed with -mutant AML. Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of mutations in AML. We further posit whether patients with V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of V600-mutant solid tumors and -mutant histiocytic neoplasms.