LAUSR

Myeloid sarcoma (MS), or granulocytic sarcoma, is a rare extramedullary tumor of immature myeloid cells. MS may present simultaneously with or during the course of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or any forms of myeloproliferative neoplasms (MPN). Less commonly, it is detected as an isolated form without bone marrow (BM) involvement. Although the prognosis of MS has not been well examined due to the rarity of this disorder, it is known to be refractory to standard therapies of AML and is generally associated with a poor outcome. Furthermore, it has been noted that patients with myeloid sarcoma have a predisposition to extramedullary relapses. Recently, immune checkpoint blockade with ipilimumab was shown to induce complete remission in four patients with extramedullary relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for AML, which lasted for more than 1 year in two of them. This was an intriguing therapeutic breakthrough in that extramedullary myeloid leukemia, which had hitherto been an area of unmet medical need for being unamenable to standard treatment, was highly susceptible to immuno-oncology drugs. In light of this distinct biologic behavior of MS compared to that of conventional AML, namely, homing and clustering outside the hematopoietic system, being responsive to immune checkpoint inhibitors while refractory to conventional chemotherapeutic agents used in AML, we hypothesized that MS could share some of the genetic abnormalities commonly found in solid tumors demonstrating features mimicking them. The aim of this study was to explore this using a more expanded panel of cancer genes, which are not necessarily restricted to known AML-associated genes, to gain insight into the molecular pathogenesis of MS and to identify potential drug targets. We retrospectively identified and collected clinical data of 62 patients with a diagnosis of MS made between March 2003 and May 2016 at Seoul National University Hospital (SNUH). Of these, 13 patients went through planned panel sequencing of 83 genes (Figure S1). The study protocol was reviewed and approved by the Institutional Review Board of SNUH. Genomic DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks using the QIAamp DNA Mini Kit (Qiagen, Mancheester, UK), and the qualified DNA samples were captured and sequenced with SureSelect (Agilent, Inc., USA) following the manufacturer’s instructions. The targeted 83 cancer genes were concentrated more on well-known oncogenes reported in the Catalog of Somatic Mutations in Cancer database than on relatively unknown genes whose functional effects are currently in question and included the coding exons of 72 genes for the detection of single nucleotide variants (SNVs), insertion/deletions (indels), and copy number variations (CNVs), and some introns for 5 genes for the detection of gene fusions. The mean coverage of all the samples was 673 × (range 33–1506). (see Supplementary Methods for details). Sixty-two patients with a clinical and/or pathologic diagnosis of MS were included in our clinical analysis, whose median age at presentation was 46 years old (range 18–83), and the female-to-male ratio was 1.06. These MS cases presented most commonly with a concurrent initial diagnosis of AML (33.9%) followed by a relapse or persistence of marrow disease (22.6%), and so on. Except for de novo MS, all cases were accompanied by AML