Pretransplant Risk Factors for Calcineurin Inhibitor-Induced Encephalopathy and Limbic Encephalitis Following Allogeneic Hematopoietic Cell Transplantation

Background:

Central nervous system (CNS) complications after allogeneic hematopoietic cell transplantation (allo-HCT) can be fatal. Although numerous studies have reported risk factors for CNS complications after allo-HCT, most defined CNS complication events as a composite endpoint, for example, composed of cerebrovascular disease, infection, posterior reversible encephalopathy syndrome (PRES), and metabolic encephalopathy. For a more precise and targeted approach, risk factor analyses for each individual CNS event are needed.

Few studies have reported risk factor analyses for individual CNS complications. They have included analyses for cerebrovascular disease, viral encephalitis, HHV6 encephalitis, and noninfectious neurologic complications. To our knowledge, no pretransplant risk factor analysis for calcineurin inhibitor-induced encephalopathy (CNIE) and limbic encephalitis (LE) has yet been reported.

Method:

We retrospectively examined consecutive patients who underwent allo-HCT at our institute between January 2005 and November 2017. CNIE was defined as a patient who exhibited clinical symptoms of PRES or neurological manifestations of thrombotic microangiopathy during cyclosporin A (CSA) or tacrolimus (TAC) administration. LE was defined as a patient who displayed selective medial temporal lobe involvement in brain MRIs. As a rule, HHV-6 DNA polymerase chain reaction was performed on cerebrospinal fluid (CSF) for LE cases.

Results:

A total of 485 patients between 16- and 69-years-old (median, 46 years) were eligible for this study. They received myeloablative (n = 292) or reduced-intensity conditioning (n = 193) for allo-HCT. Diagnoses included AML/ALL (n = 292), MDS (n = 59), NHL (n = 93), and others (n = 41). HLA allele typing was performed at HLA-A, -B, -C, and -DRB1. Donor sources consisted of HLA-matched or -one allele mismatched sibling peripheral blood (PB) or bone marrow (BM) (n = 98)/HLA matched unrelated donors (n = 93) (hereafter referred to as HLA-matched donors), HLA-mismatched unrelated BM (uBM; n = 36), umbilical cord blood (uCB; n = 110), haploidentical PB (n = 118), and allele unknown uBM (n = 30). A total of 33 CNS events were identified: 11 CNIE (33 %), 14 LE (42 %), 3 transverse myelitis (9.0 %), 2 drug encephalopathy (6.0 %), 1 aseptic meningitis (3.0 %), 1 fungal brain abscess (3.0 %), and 1 acute epidural hematoma (3.0 %). The median follow-up time among the survivors was 1836 days (range, 45-4860 days) after allo-HCT. By landmark time analysis, the prognosis of those with any CNS complications within 30 days was significantly worse than those who did not (1-year OS, 37.5 % vs. 55.4 %, Log-rank p = 0.011). A multivariable time-dependent Cox model revealed that CNS complications were an independent prognostic factor for overall survival (Hazard ratio (HR) 4.49, 95 % CI, 2.30-8.76, p < 0.001), adjusted for age and disease risk index. CNIE cases included 6 CSA-induced and 3 TAC-induced cases, of which 4 patients (44 %) were alive. In the multivariable Cox models, MDS (HR 9.4 (vs. AML/ALL), 95 % CI, 2.2-40, p = 0.002) and HLA-mismatched uBM (HR 16 (vs. HLA-matched donors), 95 % CI, 3.0-81, p = 0.001) were significantly associated with CNIE development. LE included 7 HHV6-negative (2 alive), 5 HHV6-positve (1 alive), and 2 unknown cases (1 alive). Eleven of these patients were treated by methylprednisolone pulse therapy; all patients responded partially or effectively and four patients (36 %) achieved complete remission. In the multivariable Cox models, HLA-mismatched uBM (HR 7.5 (vs. HLA-matched donors), 95 % CI, 1.2-45, p = 0.028) was significantly associated with LE development.

Conclusion:

CNS complications were found to be an independent risk factor for OS after allo-HCT, as reported previously. MDS and HLA-mismatched uBM were risk factors for CNIE; the former may be partly explained by the fact that a subset of MDS may be predisposed to vascular endothelial damage (e.g. vasculitis), since CNIE may be triggered by endothelial dysfunction caused by CNI. Moreover, HLA-mismatched uBM was a risk factor for LE. Experimental data revealed that major histocompatibility complex class 1 protein was expressed in hippocampal neurons; thus, the limbic system may be targeted by alloimmune reactions more frequently in HLA-mismatched uBM settings, regardless of whether HHV-6 reactivation occurs.