Disease and Therapy Associated Complications of the Central Nervous System after Allogeneic Hematopoietic Cell Transplantation - a Significant Proportion of Patients Will Suffer from Permanent Damage
Authors: Haen Sebastian P. , Zierhut Manfred , Mirza Nora , Simon Christoph M. , Korn Andreas , Faul Christoph , Vogel Wichard , Rammensee Hans-Georg , Kanz Lothar , Bethge Wolfgang 
Published: October 2019

Abstract
Introduction: Neurological symptoms after allogeneic hematopoietic cell transplantation (HCT) represent diagnostic challenges, since their onset can be rapid and permanent neurological damage is imminent. Little data is available on incidence, morbidity and mortality of central nervous system (CNS) complications after allogeneic HCT.
Methods: We retrospectively analyzed data from 1204 patients undergoing allogeneic HCT at our center within the last 10 years. Out of this cohort, 102 patients (8.6%; 38 women and 64 men, median age 55 years, range 19-75 years) suffered from 107 post-HCT CNS complications. Underlying diagnoses were acute (ALL n=24; AML n=49) or chronic leukemia (CLL n=2; CML n=1; CMML n=2), myelodysplastic (n=8) or myeloproliferative (n=5) syndromes, non-Hodgkin lymphoma (n=10) or severe aplastic anemia (n=1). Conditioning was performed using reduced-intensity (n=61) or myeloablative (n=41) regimens. Grafts were applied from matched related (n=22), mismatched related (n=1), haploidentical (n=4), matched unrelated (n=49) or mismatched unrelated donors (n=26). 41 patients in the cohort suffered from acute (median grade 1; grades 1-4) and 41 patients from chronic GvHD (limited n=20; extensive n=21), respectively.
Results: CNS complications comprised cerebrovascular events (hemorrhagic, n=26; thromboembolic, n=10), infections (n=19; viral infections including CMV and VZV n=11; bacterial n=2; toxoplasmosis n=6), toxic leukoencephalopathy (n=11), inflammatory changes without detection of underlying cause (n=14) including cerebral vasculitis or cerebral graft versus host disease (GvHD), disease relapse (n=13; meningeosis leucaemica n=10; myeloid sarcoma of the dura n=1), secondary intracerebral tumors (n=2), posterior reversible encephalopathy syndrome (PRES; n=4), seizures (n=6), migraine (n=1), or neurological and psychiatric syndromes without detection of a defined etiology (n=2). Median time between HCT and onset of CNS symptoms was 4.6 months (range, 0-155 months). CNS complications occurring early after HCT comprised hemorrhagic events (median 1.4 months after HCT; 0.2-107.9 months), seizures (median 3.0 months after HCT; 0.1-6.9 months), infections (median 4.7 months after HCT; 0.1-70.3 months), leukoencephalopathy (median 3.7 months; 0-33.6 months) and psychiatric disorders (median 1.3 months; 0.8-6.4 months). Other complications occurred later (p=0.006) comprising inflammatory disorders without a definite cause (median 7.1 months; 1.2-97.4 months), ischemia (median 29.9 months; 0.6-95.5 months), and malignant causes (median 10 months; 1.7-156 months).
Treatment was guided by the respective diagnosis and symptoms including transfusion of platelet concentrates, interventional recanalization, antibiotics or virostatic drugs, immunosuppression, or systemic and/or intrathecal chemotherapy. These therapies led to complete resolution of neurological symptoms in 31 (30%) patients. In 43 patients (42%) amelioration with residual symptoms (n=15; 15%) or stabilization (n=28; 27%) was achieved. In 28 cases (27%) no response to therapy was observed resulting in a letal outcome (causes of death: cerebrovascular events n=7 (19%); infections n=10 (53%); leukencephalopathy n=2 (18% ); GvHD n=1 (7% l); CNS malignancy n=6 (40% ); unknown cause n=2).
Risk factors for the development of CNS complications were thrombocytopenia (bleeding, n=18), positivity for toxoplasmosis before HCT (toxoplasma infections, n=6), arterial hypertension (PRES, n=4) and possibly irradiation of the neurocranium (inflammatory diseases; n=4).
Median overall survival was 13.8 and 6.4 months after HCT and onset of CNS complications, respectively. Cumulative incidence of CNS disease related deaths was 11% and 21% at 100 days and 12 months, respectively (1% and 2% for the complete patient cohort of 1,204 patients).
Conclusions: Complications and/or manifestations in the CNS account for a significant number of HCT-related complications resulting in significant mortality and morbidity. 70% of these patients will suffer from irreversible neurological damage. Therefore, precise and timely diagnosis is necessary to guide causal therapy and prevent permanent damage.

Disclosures
No relevant conflicts of interest to declare.