PTEN-Mutated Histiocytic Sarcoma Treated with Frontline Sirolimus and Prednisone

Introduction:
Histiocytic sarcoma (HS) is an extremely rare non-Langerhans histiocytic neoplasm that can present as unifocal or multifocal disease. Multifocal disease carries an exceedingly poor prognosis and given the rarity, and lack of prospective trials, there are no standardized therapies. Herein, we present a case of HS complicated by severe cytopenias achieving disease response and prolonged survival with frontline sirolimus and prednisone.
Methods:
Case Presentation-A 63-year-old female presented with bilateral leg edema, fatigue, weight loss, grade 2 anemia and thrombocytopenia. Upon further workup, positron emission tomography / computed tomography (PET/CT) revealed multiple intraabdominal fluorodeoxyglucose (FDG)-avid lymph nodes, an enlarged spleen, and diffuse FDG-avidity throughout the axial and appendicular skeleton. She underwent splenectomy, liver and bone marrow (BM) biopsy, all of which revealed involvement with HS. Tissue-based next-generation sequencing demonstrated loss of function (LOF) mutations in the and genes. The patient was not a candidate for combination chemotherapy due to underlying cardiac comorbidities and severe transfusion-dependent cytopenias, but given LOF, she was initiated on sirolimus 2mg with a goal trough of 8-12 and prednisone 1mg/kg with a tapering dose over 3 months. During therapy, she had a clinical and radiological response. There was a decrease in transfusion requirements, and at one year of therapy, repeat PET/CT revealed no evidence of FDG-avid disease, while the BM showed stable involvement of HS. Unfortunately, despite the initial clinical improvement, she developed grade 3 cytopenias after one year, requiring weekly platelets and red blood cells transfusion. Out of concern for BM suppression, sirolimus was stopped after 14 months of therapy. Shortly after, the patient presented to hospital with septic shock, severe thrombocytopenia, and anemia unresponsive to transfusion. She ultimately chose to pursue comfort care measures and died 17 months after diagnosis.
Results:
Discussion-The clinical course of multifocal HS is typically highly aggressive with an estimated overall survival of 6 months or less. Due to the rarity of the disease, there is a lack of efficacious treatments, and multiple chemotherapeutic agents have been utilized in case reports with variable efficacy. The administration of combination chemotherapy can however be challenging when significant cytopenias and comorbidities are present. In patients with targetable driver mutations, some reports have demonstrated the efficacy of agents such as thalidomide, alemtuzumab, and PD-1 inhibitors. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) signaling, with antiproliferative and immunosuppressive properties. In combination with prednisone, it led to objective responses in Erdheim-Chester disease, another rare non-Langerhans cell histiocytosis. acts as a tumor suppressor by negatively regulating the PI3K/Akt/mTOR pathway. LOF indicated a potential benefit from mTOR inhibition which likely underlies the clinical response and prolonged survival observed in this case.
Discussion:
Conclusion-HS is an exceedingly rare histiocytic neoplasm with a paucity of literature on optimal therapeutic management. In patients with severe cytopenias, options are further limited. We report a case of a patient with PTEN-mutated HS with over 1-yr response to the mTOR inhibitor sirolimus in combination with prednisone. Further investigation is certainly needed to assess the role of these agents in HS.