High Mortality Associated with Neurological Complications after Allogeneic Stem Cell Transplantation
Authors: Lozano Sara , Zabalza Amaya , Aoiz Intza , Hamdi Djatri Mohamed , Arregui Pedro , Quispe Ivan , Montoya Mari Cruz , Alvarellos Montserrat , Garcia Ramirez Patricia , Gorosquieta Ana , Perez Equiza Katy , Olavarria Eduardo 
Published: October 2019

Abstract

The incidence and outcome of neurological complications of patients undergoing allogeneic stem cell transplantation (alloSCT) remains to be established. We have retrospectively studied all transplants (n = 88) performed over a five year period (2009-2014) in our transplant center with the aim of characterizing all types of neurological events. For the purpose of this study, neurological complications were divided between early (within the first 100 days of alloSCT) and late (from 3 months to 3 years after alloSCT) complications.
The overall incidence of neurological complications was 21% (19 episodes in 19 patients). Median age at alloSCT for patients developing neurological complications was 39 years (range 26-65) with 73% of patients (n=13) being male. Diagnosis included acute leukemia (n=9), plasma cell dyscrasia (n=4) and a variety of other hematologic malignancies (Mantle cell lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, aplastic anemia, myelofibrosis, myelodysplastic syndrome, one each). At time of alloSCT, 11 patients (58%) were in CR, 3 (15%) in PR, 2 (11%) untreated, 2 (11%) with progressive disease and one patient with refractory leukemia. No patient had developed CNS involvement by their disease prior to alloSCT and 3 patients (15%) had a previous history of CNS events (stroke, subarachnoid hemorrhage and intraparenchymal hemorrhage). Conditioning was myeloablative in 8 patients (42%) and reduced intensity in 11 (58%). Over 95% of transplants were performed using peripheral blood stem cells from HLA-identical siblings (n=10, 53%) or matched unrelated donors (n=9, 47%). GvHD prophylaxis included Cyclosporine and Methotrexate in all cases plus in vivo T-cell depletion with Alemtuzumab (n=8) or ATG (n=1) in all unrelated donor transplants.
The median interval between alloSCT and development of a neurological complication was 92 days (range 0-970). A total of 11 (57%) cases were classified as early compared with 8 (43%) neurological events that occurred beyond 3 months of alloSCT. All but one case of peripheral neuropathy were CNS complications. We further classified the neurological complications as: 1) Infectious (n=5; HHV-6 limbic encephalitis, VZV meningo-encephalitis, rhino-cerebral mucormycosis, toxoplasma chorioretinitis and Staph. Aureus invasive rhinosinusitis); 2) Encephalopathic (n=4; one Voriconazole associated; three other metabolic causes); 3) Vascular (n=2; pontine ischemia, intracranial hemorrhage); 4) Epileptic (n=2) and 5) Other (n=6, including one case each of reversible posterior leucoencephalopathy, Cyclosporine associated papilledema, optic neuritis, idiopathic leucoencephalopathy, immune transverse myelitis and drug-related polyneuropathy).
Five patients (26%) died as a direct consequence of their neurological complication. Two more patients died of additional causes resulting in an associated mortality of 37% (8% overall mortality for all transplants). The Kaplan-Mayer estimated overall survival at three years for patients that develop neurological complications was 62% (similar to the overall transplant population) with a median follow up of 37 months.
In summary, the incidence of neurological complications in our series was significant (21%), with a heterogeneous pathogenesis and associated with a high mortality (37% amongst patients that developed any neurological event). These data support the need for efforts directed towards the prevention of neurological complications in patients undergoing alloSCT.TableNeurogical ComplicationDescriptionTimingStatus InfectiousHHV-6 lymbic encephalitisEarlyDead*VZV meningo-encephalitisEarlyDead *Rhino-cerebral mucormycosisLateAliveToxoplasma chorioretinitisLateAliveStaph. Aureus invasive rhinosinusitisLateAlive EncephalopathicVoriconazole-relatedEarlyAliveMetabolicEarlyDeadMetabolicLateAliveMetabolicLateAlive VascularPontine ischemiaEarlyDead *Intracranial hemorrhageEarlyDead * EpilepticTonico-Clonic seizureEarlyAliveTonico-Clonic seizureEarlyAlive OtherReversible posterior leucoencephalopathyEarlyDead*Cyclosporine-associated papilledemaLateAliveOptic neuritisLateAliveIdiopathic leucoencephalopathyLateDeadImmune transverse myelitisLateAliveDrug-related polyneuropathyLateAlive
* Patients that died as a direct consequence of the neurological complication

Disclosures
No relevant conflicts of interest to declare.