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

Background: Although BRAF V600E mutations are common in solid tumors and select hematologic neoplasms, they are reported less frequently in myeloid malignancies. Of the cases of BRAF V600E-mutant acute myeloid leukemia (AML) that have been described, most display monocytic morphology and concurrent KMT2A rearrangement. Strikingly, all cases have been associated with poor survival. Case Presentation: 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 BRAF p.V600E (VAF = 33%), TET2 p.M508Cfs*25 (VAF = 48%), TET2 p.C211* (VAF = 49%), ZRSR2 p.R295* (VAF = 71%), BRAF p.N581S (VAF = 6%), and EZH2 c.118-2A>G, p.? (VAF = 4%) in case 1 and BRAF p.V600E (VAF = 1%) and KRAS 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 KMT2A (MLL) 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. Conclusions: Our cases add to the literature, highlighting the poor prognosis of patients diagnosed with BRAF-mutant AML. Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A 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 BRAF mutations in AML. We further posit whether patients with BRAF 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 BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms.