Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
Department of Internal Medicine, Division of Hematology and Oncology, Chi-Mei Hospital, Tainan, Taiwan
Tai-Cheng Stem Cell Therapy Center, National Taiwan University Hospital, Taipei, Taiwan
Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan
Abstract
Background
Clinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited.
Methods
A total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed.
Results
A total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%,
Conclusions
The incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies.
Background
In adult patients with hematological malignancies, infection is the most common complication. Intracranial hemorrhage (ICH) is the second most common complication, and is associated with high morbidity and mortality
Patients with lymphoid malignancy more frequently experience central nervous system (CNS) involvement than do patients with myeloid leukemia
Methods
Patients and hospital setting
National Taiwan University Hospital (NTUH) is a 2,600-bed teaching hospital in northern Taiwan that provides both primary and tertiary care. We retrospectively analyzed the demographic features, hematological disease status, underlying medical diseases, laboratory and microbiological data, and outcomes of all adult patients with hematological malignancies from January 2001 to December 2010 at NTUH. The laboratory data was collected promptly after onset of ICH. We also assessed the overall 30-day mortality of these patients. This research conformed to the Helsinki Declaration and local legislation, and was approved by the National Taiwan University Hospital Research Ethics Committee.
Chemotherapy in patients with hematological malignancies
Induction chemotherapy consisted of cytarabine and anthracycline for patients with acute myeloid leukemia (AML). Consolidation chemotherapy consisted of high-dose cytarabine-based regimens. Patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA) and combined anthracycline-based chemotherapy. Patients diagnosed with acute lymphoblastic leukemia received a Cancer and Leukemia Group B 8811 (CALGB8811)
Hyperviscosity
Hyperviscosity syndrome is defined by the presence of elevated serum immunoglobulins in conjunction with clinical constitutional symptoms, bleeding, ocular, neurological, and cardiovascular manifestations
Policy of platelet transfusion in patients with hematological malignancy
The platelet counts were checked three times per week during chemotherapy in patients with hematological malignancies until the neutrophil counts recovered. The platelet counts were checked once to three times per week after neutrophil counts recovered according to clinical judgment. The complete blood counts were checked once per day in patients with freshly diagnosed acute promyelocytic leukemia until complete remission. Prophylactic platelet transfusions were used to maintain the platelet level above 20,000 cells/μl in patients receiving chemotherapy. Among patients with acute promyelocytic leukemia, active bleeding, and sepsis, the platelet counts were maintained above 50,000 cells/μl or more according to clinical judgment.
Diagnosis of ICH and inclusion/exclusion criteria
Each patient's ICH diagnosis was determined from both clinical and neuroimaging findings. Either computed tomogram or magnetic resonance imaging was required to confirm the clinical diagnosis of ICH. Patients for whom ICH was suspected but unproven were excluded. Patients with ischemic stroke and subsequent hemorrhagic transformation were also excluded. Types and locations of intracranial hemorrhage were determined from radiology reports. According to the neuroimaging results, hemorrhages were classified into four types, namely intraparenchymal hemorrhage (IPH), subarachnoid hemorrhage (SAH), subdural hemorrhage (SDH), and epidural hemorrhage (EDH)
End points and overall survival
The starting point was the date of diagnosis of ICH. The primary end point was ICH-related death within 30 days. Survival time was the time interval from diagnosis of ICH to events such as death from any cause.
Statistical analysis
For continuous variables, data are reported as the median with the range shown in brackets. For nominal variables, data are reported as the number of patients, unless specified otherwise. Survival curves were plotted using Kaplan-Meier analysis, and differences between curves were analyzed by log rank. All factors in the univariate analyses were also enrolled in multivariate analysis using Cox proportional-hazard testing. All statistical analyses were performed using SPSS 18.0 for Windows (SPSS, Chicago, IL, USA), and
Results
ICH among patients of hematological malignancies
A total of 2,574 adult patients with hematological malignancies were admitted to National Taiwan University Hospital between 2001 and 2010. During that period, 72 episodes of ICH developed in 72 of these patients (48 men and 24 women); the median age of the ICH group was 56 years (range: 18 to 86 years). The ICH patients included 52 (6.3%) of 818 patients who had AML, 5 (2.0%) of 250 patients with acute lymphoblastic leukemia (ALL), 7 (0.7%) of 1,001 patients with lymphoma, and 8 (2.7%) of 291 patients with myeloma. Of the 214 patients who had chronic myeloid leukemia or chronic lymphoid leukemia, none developed ICH. Our results indicated an overall ICH incidence of 2.8% among adult patients with hematological malignancies. Patients with AML displayed a particularly high incidence of ICH compared with patients with other hematological malignancies (6.3% vs 1.1%;
Clinical characteristics of intracranial hemorrhage among patients of different types of hematological malignancies
Number of patients
Subtype
AML (n = 43)
APL (n = 9)
ALL (n = 5)
Lymphoma (n = 7)
Myeloma (n = 8)
Age:
0.094
≥60 years
19
2
1
6
4
<60 years
24
7
4
1
4
Gender:
0.461
Male
32
5
2
4
5
Female
11
4
3
3
3
Underlying hypertension:
0.428
Yes
12
3
0
3
1
No
31
6
5
4
7
Diabetes mellitus:
0.274
Yes
3
1
0
2
0
No
40
8
5
5
8
Sepsis:
0.096
Yes
16
5
5
4
4
No
27
4
0
3
4
Post HSCT:
0.347
Yes
8
0
0
0
1
No
35
9
5
7
7
Disease status:
0.409
Remission
6
2
0
0
0
Active
37
7
5
7
8
CNS involvement:
<0.001
Yes
0
0
0
5
1
No
43
9
5
2
7
Leukocyte count:
0.642
≥100,000 cells/μl
9
2
0
1
0
<100,000 cells/μl
34
7
5
6
8
Platelet count:
0.560
≥20,000 cells/μl
27
6
3
6
4
<20,000 cells/μl
16
3
2
1
4
Prothrombin time:
0.493
INR ≥1.5
10
2
1
1
1
INR <1.5
32
7
4
6
7
Location:
Cerebral cortex
37
7
5
4
5
0.326
Basal ganglia
9
1
1
1
1
0.941
Brainstem
4
0
0
1
0
0.628
Cerebellum
4
2
0
1
3
0.213
Multiple
20
5
0
3
5
0.240
Type:
Intraparenchymal hemorrhage
35
7
5
4
5
0.336
Subarachnoid hemorrhage
8
2
2
0
3
0.349
Subdural hemorrhage
11
2
1
4
4
0.307
Epidural hemorrhage
1
0
0
0
2
0.041
Intraventricular hemorrhage
10
4
1
3
2
0.618
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; APL = acute promyelocytic leukemia; CNS = central nervous system; HSCT = hematopoietic stem cell transplantation; INR = international normalized ratio.
Among the 72 patients with ICH, 46 (64%) had thrombocytopenia (platelets less than 20,000 cells/μl), 34 (47%) had sepsis, and 15 (21%) had prolongation of prothrombin time. Thrombocytopenia, sepsis and prolongation of prothrombin time are proposed as the potential major causes of ICH. In all, 28 patients had brain magnetic resonance angiography to survey the vascular abnormality during ICH. Neither aneurysm nor arteriovenous malformation was detected in this study. The clinical characteristics, including age, sex, hypertension, sepsis, remission status, and allogeneic stem cell transplantation were not statistically different among ICH patients with various hematological malignancies.
ICH patients who were diagnosed with lymphoma and myeloma had higher rates of CNS involvement than patients with other hematological malignancies (
Thrombocytopenia and prolongation of prothrombin time have been recognized as risk factors for CNS hemorrhage in patients with hematological malignancy
Locations and types of ICH
The locations and types of ICH in patients with different types of hematological malignancies are shown in Table
The correlations between clinical characteristics and types of ICH are shown in Table
Clinical characteristics and types of intracranial hemorrhage
IPH (n = 56)
SDH (n = 22)
SAH (n = 15)
Gender:
0.137
0.180
0.552
Male
40
12
9
Female
16
10
6
Age:
0.009
0.002
>0.999
≥60 years
20
16
7
<60 years
36
6
8
Underlying hypertension:
0.335
0.565
0.324
Yes
13
7
2
No
43
15
13
Sepsis:
0.168
0.306
0.384
Yes
29
8
9
No
27
14
6
Remission status:
>0.999
0.421
0.669
Yes
6
1
2
No
50
21
13
CNS involvement:
0.609
0.361
>0.999
Yes
4
3
1
No
52
19
14
Leukocyte count:
0.056
0.090
0.060
≥100,000 cells/μl
12
1
0
<100,000 cells/μl
44
21
15
Platelet count:
>0.999
0.603
0.376
≥20,000 cells/μl
36
9
7
<20,000 cells/μl
20
13
8
Prothrombin time:
0.495
0.127
0.069
INR ≥1.5
43
2
6
INR <1.5
13
20
9
CNS = central nervous system; INR = international normalized ratio; IPH = intraparenchymal hemorrhage; SAH = subarachnoid hemorrhage; SDH = subdural hemorrhage.
Correlated clinical manifestation and outcome in patients with ICH
In total, 25 patients (35%) died within 72 h of the onset of ICH, and 46 patients (64%) died within 30 days of ICH. Mortality was high among patients with EDH (3/3,100%) and SAH (14/15, 93%), but was relatively lower in patients with SDH (11/22, 50%). Most patients received conservative component therapy only, but 11 patients (15%) underwent craniotomy and hematoma evacuation (6 patients with IPH, 2 patients with SDH, 2 patients with both IPH and SDH, and 1 patient with SDH and EDH). Seven patients survived for 30 days (four patients with IPH, two patients with SDH, and one patient with both IPH and SDH). Five of seven survivors had long-term survival (more than 1 year) with minimal neurological sequelae. Surgical intervention showed a trend of improved 30-day outcome (
To clarify the clinical manifestations for the 30-day outcome in patients with hematological malignancies, we analyzed clinical prognostic factors as shown in Table
Univariate analysis of 30-day outcome of ICH among patients with hematological malignancies.
Alive (n = 26)
Dead (n = 46)
Univariate analysis,
Multivariate analysis,
Gender:
0.604
Male
16
32
Female
10
14
Age
>0.999
≥60 years
12
20
<60 years
14
26
Hematological malignancies
0.679
AML
14
29
APL
5
4
ALL
2
3
Lymphoma
3
4
Myeloma
2
6
Remission status
0.448
Yes
4
4
No
22
42
Post HSCT
0.473
Yes
2
7
No
24
39
Underlying hypertension
>0.999
Yes
7
12
No
19
34
Sepsis
0.050
Yes
8
26
No
18
20
CNS involvement
>0.999
Yes
2
4
No
24
42
Subarachnoid hemorrhage
0.007
0.021 (10.9; 1.3 to 88.9)
Yes
1
14
No
25
32
Multifocal hemorrhage
0.006
0.026 (4.7; 1.6 to 14.0)
Yes
6
27
No
20
19
Surgical intervention
0.085
Yes
7
4
No
19
41
Leukocyte count
>0.999
≥100,000 cells/μl
4
8
<100,000 cells/μl
22
38
Platelet count
0.802
≥20,000 cells/μl
16
30
<20,000 cells/μl
10
16
Prolongation of prothrombin time
0.013
0.008 (10.9; 1.3 to 85.5)
INR ≥1.5
1
14
INR <1.5
24
32
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; APL = acute promyelocytic leukemia; CNS = central nervous system; HSCT = hematopoietic stem cell transplantation; ICH = intracranial hemorrhage; INR = international normalized ratio.
All covariates with a
Discussion
The cause of ICH is very important and holds implications for further therapy. Since no patient received autopsy after ICH, the definite cause of ICH in patients with hematological malignancies is inconclusive. Among the 72 patients with ICH, 46 (64%) patients had thrombocytopenia (platelets less than 20,000 cells/μl), 34 (47%) had sepsis, and 15 (21%) had prolongation of prothrombin time. Consequently, thrombocytopenia, sepsis and prolongation of prothrombin time are the major predisposing factors for ICH.
The definite causes of ICH could be further investigated by autopsy study. Occurrence of ICH in patients with acute leukemia has been reported
The incidence of ICH is less common in patients with lymphoma and myeloma, among those with intracranial involvement. ICH occurred more frequently in patients with CNS involved lymphoid malignancy relative to those with CNS involved acute leukemia. The pathogenesis of ICH among patients with various hematological malignancies may be different. Leukemias are circulating precursors of lymphoblastic or myeloid neoplasm that involve the bone marrow and peripheral blood. Leukemias often exert an indirect effect on the nervous system, causing thrombocytopenia, coagulation factor deficiency, sepsis, therapy-related complications, and vessel wall abnormalities
Patients with CNS lymphoma or myeloma involvement should be aware of the increased risk of ICH
The types and locations of ICH events in patients with hematological malignancies are also rarely reported
We found most (78%) ICH events in patients with hematological malignancies tended to be IPH, which was congruent with prior reports
In the current study, SAH affected only 21% patients with hematological malignancies but the mortality rate in the SAH group was 90%. Advances have been made in surgical intervention for SAH
Multivariate analysis using Cox's proportional hazard test revealed that ICH in patients with hematological malignancies was associated with three independent factors. These were prolonged prothrombin duration (
A total of 11 patients underwent craniotomy and hematoma evacuation. Surgical intervention showed a trend of improved 30-day outcome (
There were some limitations to this study. First, we tried to investigate all the adult patients with hematological malignancies. However, this study is a retrospective cohort in a single university hospital between 2001 and 2010. Given the secular changes in the rapidly evolving field of hematology, patients may have received different chemotherapy protocols and supportive management. Second, thrombocytopenia (64%), sepsis (47%) and prolongation of prothrombin time (21%) were the most common risk factors of ICH. However, there was no patient autopsied for the definite cause of ICH. Furthermore, a prospective multicenter clinical study should be conducted to define the incidence of ICH in this population. We limited the definition of cases to patients with positive neuroimaging study to prevent confounding factors. Consequently, a few patients with refractory leukemia and lymphoma who did not consent to neuroimaging studies were excluded from this study.
Conclusions
ICH is more common in patients with AML than in patients with other types of hematological malignancy. ICH occurred in patients with lymphoma when there was CNS neoplastic involvement. Prognosis did not differ according to type of hematological malignancy. Prolonged prothrombin duration, SAH, and multiple-site hemorrhage were all independent prognostic factors of ICH in patients with hematological malignancies. Neuroimaging studies of the location and type of ICH could assist with outcome prediction for patients with hematological malignancies.
Competing interests
The authors declare they have no competing interests.
Authors' contributions
C-YC, C-HT, H-CW, and J-HL participated in the study design. S-YH, WT, MY, P-YC, J-LT and H-FT participated in data collection and analysis. C-YC, C-HT, AC, and H-FT participated in editing and proofreading. All authors read and approved the final manuscript.
Acknowledgements
This study was supported in part by the Taiwan National Scientific Council (grant NSC 99-2314-B-002-027-MY3). We thank the staff of the Eighth Core Laboratory, Department of Medical Research, National Taiwan University Hospital, for their technical support during the study.
Pre-publication history
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