Neurological Adverse Events Determine Morbidity and Mortality Post Allogeneic Hematopoietic Cell Transplantation
Authors: Sakellari Ioanna , Gavriilaki Eleni , Papagiannopoulos Sotirios , Gavriilaki Maria , Batsis Ioannis , Mallouri Despina , Vardi Anna , Constantinou Varnavas , Iskas Michalis , Masmanidou Marianna , Yannaki Evangelia , Geroukis Triantafyllos , Kazis Dimitrios , Kimiskidis Vasilis , Anagnostopoulos Achilles 
Published: October 2019

Abstract
Introduction: Despite advances in the field, diagnosis and management of the wide spectrum of neurological events as sequelae of allogeneic hematopoietic cell transplantation (alloHCT) remain challenging. Therefore, we investigated the incidence, diagnosis, management and long-term prognosis of neurological complications in alloHCT recipients.
Methods: We enrolled consecutive allogeneic HCT recipients transplanted in our center (7/1990-9/2017). We performed a retrospective review of data in our prospectively acquired database.
Results: Among 758 alloHCT recipients, 127 (16.8%) patients presented with neurological complications. Interestingly, neurological complications were more common in unrelated or alternative donors (p<0.001), ALL diagnosis (p<0.001) reduced intensity or toxicity regimens (p=0.037). In the multivariate model, these variables remained independent predictors of neurological complications.
Neurological adverse events presented late post-transplant (median +140day, interquartile range/IR 232). Timing of neurological complications was associated only with acute and chronic graft-versus-host-disease/GVHD (p=0.001 and p<0.001, respectively). The majority of patients developed central nervous system/CNS complications (89.7%). 11 patients (8.7%) presented with >1 episodes (median 10.4 months, IR 25.1). Based on symptoms, timing and additional testing, neurological complications were classified into: CNS relapse (24), thrombotic microangiopathy (12), CNS hemorrhage (7), posterior reversible encephalopathy (6), drug-associated polyneuropathy (7) and seizure (6), other leukoencephalopathy (8), thromboembolic events (5), neuralgia (4), myopathy (3), sinusoidal obstruction syndrome (1), Guillain-Barre syndrome (1), Wernicke encephalopathy (1), myelitis (1) and multiple sclerosis (1). Opportunistic CNS infections were attributed to aspergillosis (12), mucormycosis (3), Cytomegalovirus (9), Epstein-Barr encephalitis (3) or lymphoproliferative disease (4), Human herpesvirus 6 (5), Human herpesvirus 7 (2), toxoplasmosis (3); while others could not be otherwise specified (10). Resolution of neurological complications was achieved in only 37 (29%) patients.
With a median follow-up of 11.4 months (IR 30.3) in patients with neurological complications, incidence of chronic GVHD was 52.8%, relapse mortality 48.6%, treatment-related mortality 39.1% and 5-year overall survival (OS) 25.8% in patients with neurological complications. In the multivariate analysis, favorable OS was independently associated with resolution of neurological syndromes, absence of chronic GVHD and sibling transplantation.
In the whole cohort, acute, chronic GVHD and relapse rates did not differ between patients with or without neurological complications. However, bacterial, viral and fungal infections were significantly increased in patients with neurological complications (p<0.001), possibly reflecting the immunosuppression status of these patients. Patients with neurological complications exhibited significantly decreased 10-year disease-free survival (21.7% versus 41.1%, p<0.001) in our cohort. 10-year OS was also significantly lower in patients with neurological complications (24.9% versus 46%, p<0.001), as shown in Figure. The same was true for 10-year OS when analysis was limited to non-relapsed patients with or without neurological complications (30.2% versus 57.9%, p<0.001). In the multivariate survival analysis of the whole cohort, unfavorable independent predictors of OS were: acute and chronic GVHD (beta=0.566, p<0.001 and beta=1.541, p<0.001, respectively), relapse (beta=0.566, p<0.001), fungal and bacterial infections (beta=0.705, p=0.013 and beta=0.784, p=0.039, respectively) and neurological complications (beta=0.685, p=0.008).
Conclusions: Our large retrospective study highlights the wide spectrum of manifestations and etiologies of neurological complications in alloHCT recipients. Prompt diagnosis is required for adequate management, a major of determinant of survival. Thus, long-term increased awareness and collaboration between expert physicians is warranted to improve patient outcomes.
Figure. Figure.

Disclosures
Gavriilaki: European Hematology Association: Research Funding. Vardi:Janssen: Honoraria; Gilead: Research Funding.