Early and Late Neurological Complications after Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Conditioning Regimen and GVHD Prophylaxis
  • Evaluation and Classification of Neurologic Complications
  • Statistical Analysis and Endpoints
• Results
  • Patients' Characteristics
  • Incidence, Type of Complications, Etiology, and Risk Factors
    • CNS Complications
    • PNS Complications
  • Clinical Presentation and Time of Onset
  • Outcome
    • GVHD
    • NRM
  • Relapse and OS
• Discussion
• Acknowledgments
• References
• Copyright

Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150mg/m² in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140mg/m² (n=119), cyclophosphamide (Cy) 120mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval [CI] 11-23). CNS complications included nonfocal encephalopathies in 11 patients, meningoencephalitis in 5 patients, and stroke or hemorrhage in 4. PNS complications consisted of 5 cases of mononeuropathies and 3 cases of polyneuropathies. Drug-related toxicity was responsible for 10 of the 31 events (32%) (8 caused by CsA). Interestingly, 14 of the 23 CNS events (61%) and only 1 of the 8 PNS complications (13%) appeared before day +100 (P=.01). Overall, patients presenting NC showed a trend for higher 1-year nonrelapse mortality (NRM) (37% versus 20%, P=.08). In patients with CNS involvement, 1-year NRM was significantly worse (42% versus 20%, P=.02). CNS NC also had a negative impact on 4-year overall survival (OS; 33% versus 45%, P=.05). In conclusion, our study showed that NC are observed after allo-RIC and have diverse features. NC affecting the CNS have earlier onset and worse outcome than those involving the PNS.

Key Words: Neurologic complications, Neurology, Stem cell transplantation, Reduced-intensity conditioning, CNS complications, RIC

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Introduction 

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after myeloablative (MA) conditioning is a consolidated treatment for several hematologic and nonhematologic diseases. Because of its toxicity, this procedure is usually restricted to young (<55 years) and medically fit patients. For those who are ineligible for high-dose therapy, reduced-intensity conditioning regimens (allo-RIC) have been developed. Although nonrelapse mortality (NRM) is lower in patients receiving allo-RIC than in those treated with MA conditioning [1], graft-versus-host disease (GVHD), infections, and organ toxicities (including lung, kidney, gastrointestinal [GI], liver, and neurologic toxicities) limit the success of this new transplantation approach. To improve the outcome, better understanding and prevention of the complications of the procedure are necessary.

Despite neurologic complications (NC) after allo-HSCT representing a major cause of morbidity and mortality, they have not been well characterized to date. Most studies about NC were focused on heterogeneous groups of patients, including autologous and allogeneic transplants, RIC and conventional preparative regimens, and different stem cell sources 2, 3, 4. The characteristics of NC in a specific setting (ie, allo-RIC) are unclear, because very few studies were exclusively conducted in this setting 5, 6. Furthermore, data on long-term NC developing beyond 1 year are limited because of the relatively short follow-up in most studies 2, 3, 4, 5, 7. In the first year after transplantation, the incidence of central nervous system (CNS) complications ranged from 8-56% 2, 3, 4. Postransplant peripheral nervous system (PNS) complications were less frequent, with reported incidences of <5% 5, 7.

In the vast majority of studies, metabolic and drug-related toxicities were the most common causes of NC after transplantation. More specifically, toxicity from radiation or drugs (mainly fludarabine [Flu], busulfan [Bu], and calcineurin inhibitors), infections resulting from immunodeficiency and tissue barrier breakthrough, bleeding because of thrombocytopenia, steroid treatment for GVHD, and disease relapse were reported as etiologies and/or risk factors of NC after allo-HSCT 3, 5, 6, 8. Main neurologic symptoms were seizures and impaired consciousness 2, 8, 9, 10. Because of the diversity of causes, clinical features, and nervous systems affected (CNS or PNS) the study of NC remains a challenge.

In view of these limitations, we considered it interesting to investigate the incidence, characteristics, and etiologies of NC after allo-RIC. As an additional novelty, the prolonged follow-up of the study presented here allowed differentiating between early and late CNS and PNS complications.

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Patients and Methods 

Patients 

The study included all 191 consecutive patients who underwent allo-RIC in our institution between January 1999 and December 2006. RIC was chosen instead of MA conditioning in view of age (older than 50 years, n=121), severe comorbidities (n=11), or heavy pretreatment (n=59), as described elsewhere 11, 12. Most patients received peripheral blood stem cell (PBSC) grafts (93%). All patients gave written informed consent for inclusion in the transplant studies. The transplant protocol was approved by the national and local ethics committees.

Conditioning Regimen and GVHD Prophylaxis 

Conditioning regimens were described elsewhere [13]. Briefly, Flu 150mg/m² was combined with Bu 8-10mg/kg (myelogenous malignancies), with melphalan (Mel) 70-140mg/m² (multiple myeloma [MM] and lymphoid malignancies) or with cyclophosphamide (Cy) 120mg/kg (solid tumor), or Cy 120mg/kg combined with low-dose total body irradiation (TBI) 2Gy (chronic myelogenous leukemia [CML]). Alemtuzumab (n=3) or antithymocytic globulin (ATG) (n=20) was given as a part of the conditioning to patients with Hodgkin lymphoma (HL) transplanted from unrelated donors and to recipients of HLA single mismatch transplants. GVHD prophylaxis consisted of cyclosporine A (CsA) plus either methotrexate (MTX) or mycophenolate mofetil (MMF). CsA was started on day −7, at a dose of 1mg/kg 2 times a day in most patients, and then adjusted to blood levels (between 200 and 300 μg/mL). MTX was administered on days +1, +3, and +6 (10mg/m²), with folinic acid rescue being administered within 24hours after MTX. MMF was instituted on day 0 (at least 10hours after the infusion of progenitors) at a dose of 15mg/kg every 8hours. MMF was continued until day +30. Phenytoin prophylaxis was given to all patients receiving Bu-based conditioning at a starting load dose of 300mg every 6hours the day before, and 300mg/day until the day after of discontinuation of Bu. All patients received antimicrobial prophylaxis with acyclovir, fluconazole, and ciprofloxacin during the neutropenia and until engraftment.

Evaluation and Classification of Neurologic Complications 

A multidisciplinary panel of local neurologists and hematologists conceived a classification of NC, according to the criteria most widely used in studies regarding allo-HSCT 2, 3, 5, 14, 15 (Table 1). Neurology and hematology specialists retrospectively reviewed all medical records of patients with neurologic symptoms after allo-RIC. All patients had been diagnosed by a consultant neurologist either in the hospitalization unit, the emergency room, or in the outpatient clinic. Because all the transplanted patients are followed for an unlimited time in our unit, even if they are also followed in their original center, late neurologic events were always captured. If any event occurred outside our institution, we always contacted the treating physicians to discuss diagnosis, management, and eventual referral to our unit. Management of patients with neurologic events followed international clinical guidelines 16, 17, 18. When pharmacologic toxicity was suspected, treatment was always discontinued in the case of encephalopathy or neuropathy with severe clinical impairment. Infectious complications were treated according to the current antimicrobial protocol at the unit. To define clinical presentation, reviewers considered the main neurologic symptom leading to diagnosis suspicion. This symptom could develop together with other neurologic or nonneurologic symptoms. Only major neurologic syndromes were considered. Unspecific multifactorial symptoms such as tremor, mild reversible headache, and corticosteroid myopathy and/or encephalopathy in the context of premortem multiorgan failure were not included in the study. Patients with NC resulting from neurologic relapse of their malignancies were excluded from the analysis, but are explained as an aside.

Table 1. Definition and Diagnosis Classification of Neurologic Complications

CT indicates computed tomography; MRI, magnetic resonance imaging; CNS, central nervous system; PNS, peripheral nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram.

Statistical Analysis and Endpoints 

The primary endpoint was to describe and classify NC in the allo-RIC setting. Secondary objectives were to estimate the incidence of NC and its impact on overall survival (OS) and NRM, and to identify the possible risk factors of such complications. OS and NRM were defined as the time from day 0 of the transplant to death from any cause and death from any cause but relapse, respectively. Patients who died or relapsed before engraftment were not considered evaluable for acute GVHD (aGVHD) analysis. Patients who died or relapsed before day +100 were not considered evaluable for chronic GVHD (cGVHD) analysis. The incidences of NC, aGVHD, cGVHD, NRM, and relapse were calculated using cumulative incidence estimates, taking into account the competing risks 19, 20. To analyze the impact of GVHD in the development of NC, these variables were entered as time-dependent covariates. We considered prior relapse as a competitive event for these items. The probability of OS was estimated from the time of transplantation using Kaplan-Meier curves [21] and compared using the Taron-ware and the Log rank tests. Comparison between baseline characteristics in patients categorized as with NC and without NC was performed using 2×2 tables made by means of chi-squared or Fisher's exact t-tests. Median times were compared by means of the Wilcoxon rank sum test. All tests of significance were 2 sided, with a significance level of P ≤ .05. All statistical analyses were performed using SPSS version 15.0 (SPSS, Chicago, IL), with the exception of the cumulative incidence analyses, which were carried out with NCSS 2004 (Number Cruncher Statistical System, Kaysville, UT).

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Results 

Patients' Characteristics 

One hundred ninety-one consecutive adult patients who received an allo-RIC at the Hospital de la Santa Creu i Sant Pau were included in this study. Median follow-up for survivors was 48 months (range: 3-98). Detailed characteristics of patients are summarized in Table 2.

Table 2. Patients' Characteristics

	All Patients (n=191)	Patients with NC (n=27)	Patients without NC (n=164)	P
Median age, years (range)	51 (18-71)	53 (27-68)	50 (18-71)	.2
Male sex, n (%)	121 (63)	20 (74)	101 (62)	.3
Underlying disease, n (%)
Myeloid	69 (36)	9 (33)	60 (37)	.8
Lymphoid	113 (59)	18 (67)	95 (58)	.5
Other	9 (5)	0 (0)	9 (6)	.4
Donors, n (%)
HLA ident.sibling	157 (82)	19 (70)	138 (84)	.1
Alternative donors∗	34 (18)	8 (30)	26 (16)	.1
Sex mismatch
Female to male, n (%)	51 (27)	9 (33)	42 (26)	.5
Prior HSCT, n (%)	74(39)	13 (48)	61 (37)	.3
Conditioning regimen, n (%)
Fludarabine-melphalan,	119 (62)	20 (74)	99 (60)	.2
Fludarabine-busulfan	61 (32)	6 (22)	55 (34)	.3
Other	11 (6)	1 (4)	10 (6)	1.0
GVHD prophylaxis, n (%)
CsA+MTX	134 (70)	19 (70)	115 (70)	1.0
CsA+MMF	52 (27)	8 (30)	44 (27)	.8
CsA	3 (2)	0 (0)	3 (2)	1.0
Other	2 (1)	0 (0)	2 (1)	1.0
Graft composition
CD34+ ×106/kg, mean (range)	6.3 (1.6-15.6)	6.7 (3.1-15.5)	6.2 (1.6-15.6)	.5
CMV serology
D+/Re+, n (%)	123 (64)	17 (63)	106 (65)	1.0
Stem cell source, n (%)
Peripheral blood	178 (93)	27 (100)	151 (92)	.2
Bone marrow	13 (7)	0 (0)	13 (8)	.2

Ident indicates identical; HSCT, hematopoietic stem cell transplantation; CsA, cyclosporine A; MTX, methotrexate; MMF, mycophenolate mofetil; D, donor; Re, receptor; GVHD, graft-versus-host disease; NC, neurologic complications.

Incidence, Type of Complications, Etiology, and Risk Factors 

Twenty-seven (14%) patients developed a total of 31 NC. Twenty-three patients had only 1 event, whereas 4 had 2. Two of the latter 4 patients developed 2 neurologic events affecting CNS and 2 presented 1 CNS and 1 PNS event. Twenty-three (74%) of 31 NC involved the CNS, whereas 8 (26%) involved the PNS. Twenty-five (81%) of 31 events occurred in patients receiving immunosuppressive drugs (11 events with CsA, 6 with CsA and prednisone, 2 with CsA and MMF, 2 with MMF and prednisone, 2 with prednisone alone, 1 with MMF and sirolimus, and 1 with MMF alone). The cumulative incidence of NC at 4 years was 16% (95% confidence interval [CI] 11-23). Cumulative incidences of CNS and PNS complications were 11% (95% CI 7-18) and 4% (95% CI 2-10), respectively.

We did not identify any risk factors for the development of NC among type of conditioning, type of donor, GVHD prophylaxis regimen, previous autologous HSCT, underlying disease or patients' comorbidities (Table 2, Table 4). In the same way, we did not observe higher incidence of NC in patients with prior neurovascular events (Table 4). Two patients with prior neurovascular events developed NC, both involving the CNS. One of them developed seizures attributed to severe hypophosphatemia and died 58 days later. The other patient developed PML and died 87 days later.

According to the classification used (Table 1), toxic-metabolic encephalopathy was the main type of CNS complication in this series (n=11, 48%) followed by infectious meningoencephalitis (n=5, 22%) (Table 3). Drug-related toxicity was directly responsible for 8 (35%) CNS events. One of these was related to Bu and 7 to CsA. Despite the known neurotoxicity of Flu, this drug was not identified as the primary cause of any of the NC. Among the other 3 cases of toxic-metabolic encephalopathy, 1 was caused by hypophosphatemia and 1 by hyponatremia. The third case consisted of seizures during infusion of rituximab for posttransplant lymphoproliferative disorder.

Table 3. Type, Cause, and Time of Appearance of Neurologic Complications (According to Table 1)

CNS indicates central nervous system; PNS, peripheral nervous system.

Among the cases of infectious meningoencephalitis, 1 was due to CNS aspergillosis and 3 were caused by viral infections: 2 herpes simplex (HSV) and 1 adenovirus. There was an additional case of progressive multifocal leukoencephalopathy (PML) diagnosed by clinical features and magnetic resonance imaging (MRI) findings. In this case, the JC virus was not isolated.

Regarding cerebrovascular events, 3 were ischemic, whereas 1 was hemorrhagic in a patient with arterial hypertension.

Regarding PNS, 5 patients developed a mononeuropathy and 3 a polyneuropathy (including 1 Guillain-Barré syndrome). Among mononeuropathies 1 was related to CsA, 1 to Foscarnet, and 1 to Human Herpes Virus (HHV) type 6. A well-established cause could not be identified for the remaining mononeuropathies or for the polyneuropathies.

Clinical Presentation and Time of Onset 

The most frequent presentation (n=8, 26%) of NC was a focal syndrome (such as hemiparesis and dysarthria). Other features were seizures (n=6) and peripheral sensory motor disturbances (n=6), each in 19% of events. Less frequent clinical pictures were diffuse high cerebral function disturbance (n=4, 13%) (such as behavioral abnormalities and hallucinations), impairment of consciousness (n=3, 10%), and headache (n=2, 6%).

Median time of onset for NC was 115 days after transplantation (range: 0-1685). The median time of appearance for CNS complications was 60 days (range: 0-1685) and 233 days (range: 59-1089) for PNS complications. The presentation of CNS NC was more often observed in the first 100 days after allo-RIC; 14 of 23 (61%) of them were observed within this period. In contrast, PNS NC were more delayed, with only 1 of 8 (13%) being observed during this period (P=0.01). Of note, 4 (13%) of 31 NC were considered late events (after 1 year). Of them, 2 affected CNS (median 1188 days, range: 691-1685) and 2 PNS (median: 725 days, range: 369-1081).

Outcome 

One hundred eighty-seven (98%) patients were evaluable for aGVHD assessment. Of these, 101 (54%) developed aGVHD, with a cumulative incidence of grade II-IV aGVHD of 28% (95% CI 22-35). There were no differences in the development of aGVHD between patients with and without NC (Table 4).

Table 4. Risk Factors Evaluation

	Patients with NC Complications (n=27)	Patients without NC Complications (n=164)
Comorbidities
Creatinine (μmol/L)	98 (54-150)	91 (55-231)	.1
Smoking	11 (41)	77 (47)	.5
AT	4 (15)	37 (23)	.7
Cardiac failure	3 (11)	26 (16)	.8
Arrhythmia	2 (7)	4 (2)	.2
Alcoholism	0 (0)	19 (12)	.08
Psychiatric disturbance	0 (0)	14 (9)	.2
Diabetes Mellitus	3 (11)	19 (12)	1
Neurovascular disease	2 (7)	6 (4)	.3
Seizures	1 (4)	3 (2)	.5
TBI-based regimen	1 (4)	3 (2)	.5
CNS radiation (for any reason)	1 (4)	11 (7)	1
In vivo T cell depletion	5 (19)	18 (11)	.2
Cum. Inc aGVHD I-IV	62% (CI 95%45-83)	56% (CI 95% 46-61)	.4
Cum. Inc aGVHD II-IV	28% (CI95% 22-35)	31% (CI95% 17-55)	.7
Cum.Inc cGVHD	65% (CI95% 47-90)	79% (CI 95% 72-88)	.5
Cum Inc Ext cGVHD	19% (CI95% 8-46)	27% (CI95% 20-36)	.3
Cum. Inc Relapse at 1 year	18% (CI95% 8-41)	28% (CI95% 22-36)	.3

NC indicates neurologic complications; Cum. Inc, cumulative incidence; CI, confidence interval; AT, arterial hypertension; TBI, total body irradiation; GVHD, graft-versus-host disease: aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; CR, conditioning regimen; Ext, extended.

One hundred forty-two (74%) patients were evaluable for cGVHD. One hundred (70%) of these patients developed cGVHD with a 4-year cumulative incidence of 72% (95% CI 53-85). There were no statistically significant differences between those patient who developed NC and those who did not (Table 4).

Fifty-three (28%) patients died from NRM after a median follow-up for the whole group of 19 months (range: 0.3-99). Median time to death was 118 days (range: 8-1730). The cumulative incidence of NRM for the whole group was 29% (95% CI 23-38) at 19 months. The most common causes of NRM were GVHD and infections (25 patients died from GVHD with infection, 17 from GVHD without infection, and 8 from infection without GVHD). Among the 27 patients with NC, 15 (56%) (14 CNS and 1 PNS events) died at a median of 79 days (range: 0-533). Six of them (40%) died within the first 30 days after developing CNS NC (3 toxic-metabolic encephalopathies, 2 meningoencephalitis, and 1 vascular hemorrhage). Twelve (44%) of 27 patients remained alive, 6 with neurologic sequelae. Among them, 2 patients remained with hemiparesis (vascular events), 2 with paresthesia and neuropathic pain (one with mononeuropathy and 1 with polyneuropathy), 1 with mild dysphagia (mononeuropathy), and 1 with a progressive dementia (included in the others category).

The cumulative incidence of NRM at 1 year for patients who developed NC was 37% (95% CI 22-63) compared to 20% (95% CI 15-27) for those who did not (P=.08). This difference was even higher when we compared those with CNS involvement, 42% (95% CI 25-71) with those without (PNS complications and no NC) 20% (95% CI 15-17) (P=.02) (Figure 1).

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• Figure 1 

  One-year NRM according to the development of central nervous system complications. ^a Patients without CNS NC include patients with PNS complications and patients without any NC.

Relapse and OS 

The cumulative incidence of 1-year relapse was 27% (CI 95% 21-34) for the whole group. There were no differences in the relapse rate between the 2 groups (Table 4). Of note, all baseline disease CNS relapses belonged to solid organ malignancies (n=4).

OS at 4 years was 43%. It was 42% versus 43% for patient with and without NC, respectively (P=.4) (Figure 2). However, OS was lower in patients who developed CNS complications than in those who did not (33% versus 45%, P=.05) (Figure 3).

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• Figure 2 

  OS according to the development of neurological complications.

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• Figure 3 

  OS in patients with/without CNS involvement. ^a Patients without CNS NC include patients with PNS complications and patients without any NC.

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Discussion 

The cumulative incidence of 16% in our series indicates that NC remain an important clinical issue after allo-HSCT, even when RIC is used. The impact of conditioning regimen in the development of NC is controversial. One study in adults [3] conducted mainly in patients receiving MA allo-HSCT reported higher 1-year incidences of NC (cumulative incidence of 23%) than in our study, and identified the use of MA conditioning as a risk factor for CNS complications. However, other studies in adults [10] and pediatric patients [2] did not confirm the impact of MA regimens in the development of NC and reported similar incidences to those in the present study. Obviously, because all of our patients received an allo-RIC, we could not explore the impact of conditioning regimen in the development of NC after transplant, but considering these controversial results we think that it needs to be further explored in future studies including patients receiving MA and RIC regimens.

The incidences of CNS and PNS complications in our study were 11% and 4%, respectively. These values are slightly higher than in other studies focused on NC in adult Allo-RIC patients 5, 6. Kishi et al. [6] reported a cumulative incidence for CNS complications at day +100 after allo-RIC of 7.8%, but they did not consider PNS complications or NC occurring beyond day +100 after transplantation. Avivi et al. [5] reported an NC (CNS and PNS) incidence of 8.9% during the first year after transplant, in a series of 85 patients who received alemtuzumab-based Allo-RIC. Despite the lack of major differences between these studies and our own, the slightly higher incidence of NC in our patients could be explained by the fact that we included not only CNS, but also PNS involvement, and because the longer follow-up of our study allowed us to identify late complications in 4 (15%) of the 27 patients. Another difference that could influence the trend toward a higher NC incidence in our study is that nearly all (>90%) of our allo-RIC patients received Flu and/or CsA, both identified as risk factors for NC [22]. This circumstance did not allow us to analyze the possible impact of the concomitant use of both drugs on the occurrence of NC.

In line with prior reports 8, 23, the most frequent causes for NC in our series were toxic-metabolic disorders (13 of 31 NC, 42%), infections (19%), and vascular events (13%). CsA was identified as the primary cause (26% in our study) of NC, as was found by other authors [2]. CsA has a marked neurologic toxicity on the CNS and the PNS. Clinical manifestations frequently range from postural tremor or palmar paresthesias to generalized tonic-clonic seizures or posterior reversible encephalopathy syndrome. The mechanisms of CsA neurotoxicity are diverse, and most of them remain under investigation. One in vitro model study has suggested that CsA may induce neuronal apoptosis and selective oligodendrocyte death [24]. Other proposed mechanisms are the induction of ischemic disturbances in the brain by endothelial damage (such as in the thrombotic microangiopathy) and the interaction with adrenergic receptors on cranial vessels [25]. The development of CsA-induced hypomagnesemia may also contribute to its neurotoxic effects [26].

We did not identify any risk factors for the development of NC (Table 4). This could be from the limited statistical power of the study and the limited number of patients. Type of transplant, disease status, MA conditioning, acute myelogenous malignancy, GVHD greater than grade II, use of CsA, use of alemtuzumab, female sex, the use of umbilical cord blood (UCB) as stem cell source and TBI as part of conditioning regimen have been suggested as risk factors for NC after allo-HSCT by several groups 3, 14. Some of these factors, such as the use of CsA, Flu, or Bu, have well-established biologic correspondence and have been recognized as common chemotherapeutic agents that might cause CNS toxicity [27]. The use of radiation on the CNS (either in the conditioning regimen for the allo-RIC [n=4] or its previous use in those patients who had received an autologous transplant [n=7], or as a treatment for baseline disease before transplant [n=1]) did not have any influence on the development of NC in our series (Table 4). Avivi et al. [5] observed several PNS complications in patients treated with alemtuzumab, and suggested that this drug could be a possible risk factor in the development of these complications. The proposed mechanism would be that lymphopenia could facilitate viral infections causing radiculoneuropathy and myelitis. However, we did not find an association between TCD cell depletion (TCD; Alemtuzumab or ATG) and the development of PNS complications in our series (PNS complications appeared in 4.5% of transplants with TCD and in 3% of those without TCD, P=.5). Further studies are therefore needed to elucidate the role of TCD on PNS toxicity in the allo-RIC setting.

Fifteen of the 31 NC (48%) appeared before day +100. A group from Canada also identified the first 100 days posttransplant as a high-risk period for neurologic events, with 69% of the CNS complications of their series occurring within this period [3]. Of note, we also identified late NC, such as dementia (included in the “others” categories in our classification), mononeuropathies, and polyneuropathies. Some of these events appeared more than 3 years after transplantation. These and another group's findings [14] enhance the importance of longer observation periods in clinical studies regarding NC after HSCT.

Interestingly, we found that neurologic events involving CNS appeared earlier (median of 60 days, 0-1685) than those affecting PNS (median of 233 days, range: 59-1089). Because infections, hemorrhages, and acute pharmacologic toxicity (the main causes for CNS complications) appear more frequently within the first months after transplantation, the finding is not surprising. In contrast, PNS complications are usually related to long-term pharmacologic toxicity or cGVHD. To the best of our knowledge, no previous data to the reported here gave insights on the median time to PNS complications in this setting.

As reported in a previous study, NC had a negative impact on outcome [3]. In this series, a trend to higher 1-year NRM was observed in patients with NC. Of note, patients with CNS involvement had a significantly higher 1-year NRM (42% versus 20%, P=.02), reflected in a lower OS (33% versus 45%, P=.05). These findings enhance the suggestion that NC and especially CNS complications constitute an important cause of mortality after allo-HSCT. It is of interest that a quarter of the patients in our series survived the NC, but had clinically significant impairment. In line with other studies, these results emphasize the negative impact that NC have, not only on mortality, but also on morbidity and quality of life of the patients 3, 7, 15.

In conclusion, the study reported here confirms that NC have diverse causes and clinical features. Complications involving the CNS had earlier onset and more severity than PNS complications.

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Acknowledgments 

Financial disclosure: J.L Piñana is supported by grant from the Instituto de Salud Carlos III (CM06/00139, Ministerio de Sanidad, Spain). This study was supported in part by grant RD06/0020/0101 from the Instituto de Salud Carlos III, Ministerio de Sanidad, Spain, and from the Fundació d'Investigació Sant Pau (Ferrer-Salat Award). We thank Carolyn Newey for her contribution in the revision of the manuscript.

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