Successful management of central nervous system manifestations of chronic graft-vs-host disease: a case report

Chronic graft-vs-host disease (cGVhd) is an immune-mediated complication that manifests in roughly 40% of patients post allogeneic hematopoietic cell transplantation (allohCt) [1]. cGVhd primarily affects the skin, eyes, mouth, and liver, and is the leading cause of non-relapse mortality two years post-allohCt [2]. Central nervous system (CNS) manifestations of cGVhd are rare but can lead to clinical complications with poor prognosis [3,4]. Although the biological mechanism underlying cGVhd is complex and heterogeneous, it is initially driven by thymic injury and loss of immune tolerance. this imbalance upregulates cytotoxic Cd4+ t-cells and diminishes t-cell and/or B-cell function [5]. in a recent CNS-cGVhd murine model, interferon-γ (iNF-γ) upregulation was identified as a driver of neuroinflammation by triggering overexpression of major histocompatibility (MhC) class ii on donor-derived macrophages [6]. Cerebrovascular complications associated with CNS– cGVhd are exceedingly rare. in a postmortem brain analysis of 109 allohCt patients, 29 cases demonstrated hematomas, necrosis, or ischemia, but only 2 cases of vasculitis were found [7]. Chronic GVhd-induced cerebrovascular complications may present as largeor small-vessel disease, with multifocal inflammatory perivascular lesions consisting of infiltrating Cd3+ and Cd8+ cytotoxic t-cells surrounding arteries in the meninges and parenchyma [8]. Clinically, patients may present with hemiparesis, aphasia, headache, cognitive impairment, and/or seizure [8]. to optimize diagnostic yield beyond an Mri, lesional biopsies including gray and white matter, and leptomeninges, should be taken. Furthermore, electroencephalogram (eeG), angiography, and cerebrospinal fluid (CSF) analysis may be used to detect cerebrovascular complications [4,8]. Certain diagnostic criteria must be met for accurate CNS–cGVhd diagnosis: 1) GVhd involving different organ systems; 2) CNS symptoms with no other explanation; 3) Abnormal brain Mri; 4) positive pathological/ postmortem examination; 5) positive CSF study; and 6) positive response to immunosuppression (iS). All 6 criteria must be met for a definitive CNS-cGVhd diagnosis. A possible diagnosis requires fulfillment of criteria 1 and 2 and two additional criteria [8]. We present the case of a 37-year-old male with CNS–cGVhd manifesting as biopsy-confirmed cerebral vasculitis after allohCt. the treatment course was successfully managed with corticosteroids, anti-epileptic drugs, intravenous immunoglobulin (iViG), and ibrutinib. the patient’s cumulative treatment course is summarized in table 1. the patient was diagnosed in March 2015 with acute myeloid leukemia. his chemotherapy course consisted of 7 + 3 idarubicin plus low-dose cytarabine and re-induction with 3 + 4 idarubicin plus intermediatedose cytarabine to achieve complete remission. Upon completion of consolidation with 2 rounds of high-dose cytarabine measurable residual disease (Mrd) persisted. he was referred for allohCt and received fludarabine 40 mg/m2 x 4 days and busulfan 130 mg/m2 x 4 days (daily target AUC 5300uM*L/min) for conditioning chemotherapy with a peripheral blood human leukocyte antigen (hLA 8/8) match unrelated donor hCt. GVhd prophylaxis consisted of tacrolimus