JAK1/2 Inhibition in Severe TAFRO Syndrome: A Case Report

Abstract

Background: Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a rare inflammatory disorder of unknown cause (1). It is primarily regarded as a severe subtype of idiopathic multicentric Castleman disease (iMCD), referred to as iMCD-TAFRO. Others believe that TAFRO could be either a clinical entity overlapping with iMCD or a unique autoimmune or inflammatory disease that can be accompanied by an iMCD-like lymph node histopathology (2). Patients with iMCD-TAFRO have a different cytokine spectrum and unusual clinical manifestations (including thrombocytopenia, anasarca, and renal dysfunction) compared with patients with iMCD without TAFRO, referred to as iMCD not otherwise specified (iMCD-NOS) (1,3). Patients with iMCDTAFRO also have lower 5-year survival and higher treatment failure and relapse rates than those with iMCD-NOS (3). In patients with severe iMCD-TAFRO, the recommended first-line therapy is anti–interleukin (IL)-6/IL-6-R therapy with high-dose corticosteroids, although the response rate is as low as one third (1). Cyclosporin and anticalcineurin are recommended by the Japanese TAFRO research group (2), and multiagent chemotherapy should be considered in patients with severe disease (1). Also, abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has been identified in the disease, with therapeutic perspectives (NCT03933904) and recent publications (4, 5) highlighting its possible reliance on Janus kinase (JAK)1/2 signaling. Objective: To present original clinical data supporting JAK1/2 inhibition as a promising therapeutic strategy in severe TAFRO, in line with recent mechanistic studies (4, 5). Case Report:We report a case of TAFRO syndrome in a 55year-old man who originally presented with abdominal discomfort, fatigue, weight loss, fever, and elevated C-reactive protein level. The diagnostic work-up (including human herpesvirus-8 testing) found no sign of infection but revealed anemia (115 g/ L), low platelet count (109 10 cells/L), high alkaline phosphatase level, lymphadenopathies, pleural effusion, ascites, hepatomegaly, and splenomegaly (Figure, left). Multiple surgical biopsies (pleura, thoracic lymph node and inflamed tissues, bone marrow) ruled out lymphoma but revealed inflammatory cell infiltrates (mostly lymphocytes without any morphologic abnormalities) in all resected tissues, pleural plasmacytosis, and World Health Organization grade 2 reticulin myelofibrosis (with slightly atypical and hyperplastic megakaryocytes but not plasmocytosis). Histomorphologic features of the lymph node were not consistent with Castleman disease, but the tissues were congestive (due to the anasarca) and had been damaged during the surgical procedure. Despite intravenous methylprednisolone (1 mg/kg of body weight per day) for 2 weeks, the patient s condition worsened (Eastern Cooperative Oncology Group Performance Status grade 2; hemoglobin level, 73 g/L; platelet count, 33 10 cells/L). As indicated for the treatment of myelofibrosis, ruxolitinib was started at a low dose (10 mg/d [Table, week 4]) and significantly alleviated the constitutional symptoms in a few days, allowing the patient to be discharged. During the following weeks, he had multiple hemorrhages due to gastric ulcer and persistent thrombocytopenia. In the meantime, deep sequencing for myelofibrosis did not find any