Central Nervous System Complications after Allogeneic Hematopoietic Stem Cell Transplantation: The Role of Calcineurin Inhibitors
Authors: Sala Elisa , von Harsdorf Stephanie , Wais Verena , Nguyen Thanh Mai Anne , Beck Raphael , Döhner Hartmut , Bunjes Donald , Kuchenbauer Florian 
Published: October 2019

Abstract
Introduction
Despite its curative potential, the outcome after allogeneic hematopoietic stem cell transplantation (SCT) strongly depends on transplant-related mortality. Neurological complications, especially those affecting the central nervous system (CNS), are often associated with a significant rate of morbidity. Commonly used immunosuppressive drugs are calcineurin inhibitors (CNI) such as cyclosporinA (CsA) and tacrolimus (TAC) which are associated with an increased risk of neurotoxicity. So far no direct comparison between CsA and TAC has been performed to identify the better option in terms of "neurologic tolerability" in the setting of SCT.
Patients and Methods
We performed a retrospective analysis of consecutive patients (pts) who underwent SCT for different hematological malignancies and developed one or more CNS complications between 1999 and 2018 at the University Hospital of Ulm (Germany) and received CsA or TAC as Graft versus Host Disease (GvHD) prophylaxis/therapy. During post transplant follow up, in case of neurological manifestations, neurological evaluation, brain imaging (CT-scan or MRI), electroencephalography and, if necessary, a lumbar puncture (including microbiological analysis) were performed.
Results
We identified 60 out of 1256 pts who experienced a total of 79 CNS complications. Pts' characteristics are listed in Table 1. Seventy-four of 79 (94%) complications occurred in pts receiving CNI (n=58/60 pts): 51/74 (69%) were detected during or after TAC administration, while in 23/74 cases (31%) CsA was used. No statistically significant differences were observed in the two subgroups with regard to conditioning regimen (myeloablative vs reduced intensity), donor type (matched related vs matched unrelated vs mismatched related), and incidence of severe GvHD (both acute and chronic). In both cohorts early complications (within 1 month after SCT) were mostly represented by vascular events and metabolic encephalopathy (sepsis or chemotherapy-related). As intermediate complications (2-6 months after SCT) we observed a trend towards increased infections of herpes encephalitis in the TAC cohort (p=0.08), CNI-neurotoxicity and CNS symptoms due to severe transplant-associated microangiopathy (TMA). As late effects (>1 year (y) after SCT) we detected secondary CNS neoplasms, CNS relapse or neurologic effects of chronic GvHD. Comparing the time of onset of all complications, we observed a median time of 6 months after SCT in the TAC-cohort (range: day -1 - 13y) and of 11 months in the CsA-cohort (range: day 0 - 4y). The frequency of the different types of CNS complications was similar in the two cohorts with exception for the occurrence of neurological manifestations related to TMA (Figure 1), which was statistically significant higher (p=0.01) in pts receiving TAC. These changes were reversible in 33% of cases (4/12) after discontinuation of TAC (which, at the time of TMA onset, was within or below the therapeutic ranges in 91% of cases) or after specific treatment (e.g. Eculizumab, plasma exchange).
Conclusions
Our data suggest a possible increment of neurologic complications in pts undergoing GvHD prophylaxis/therapy with TAC, especially related to the development of severe TMA, which is known to promote mental status changes. Although these findings need to be further explored and validated in larger prospective cohorts, they could have clinical relevance, such as avoiding TAC in pts at high risk of developing TMA as well as a stricter TMA monitoring in pts undergoing GvHD prophylaxis with TAC to minimize the development of severe TMA forms with neurological involvement.

Disclosures
Döhner: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding.