Int J Hematol (2014) 100:485–489 DOI 10.1007/s12185-014-1658-z
ORIGINAL ARTICLE
Tumor lysis syndrome as a risk factor for posterior reversible encephalopathy syndrome in children with hematological malignancies Daisuke Suzuki • Ryoji Kobayashi • Akihiro Iguchi • Hirozumi Sano • Kenji Kishimoto Kazue Yasuda • Kunihiko Kobayashi
•
Received: 18 March 2014 / Revised: 26 August 2014 / Accepted: 1 September 2014 / Published online: 13 September 2014 Ó The Japanese Society of Hematology 2014
Abstract Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by seizures, altered mental status and visual disorders, along with characteristic radiological findings. It is strongly related to hypertension induced by steroids and other immunosuppressive agents. There are an increasing number of reports regarding PRES arising during the course of chemotherapy for hematological malignancies. To clarify the risk factors for this phenomenon, we retrospectively analyzed pediatric patients undergoing treatment for hematological malignancies. Of 161 patients, six patients (3.7 %) developed PRES with characteristic clinical and radiographic findings. Univariate analysis revealed that tumor lysis syndrome (TLS) was a significant risk factor for the onset of PRES. TLS is a significant risk factor for the development of PRES in pediatric patients receiving chemotherapy for hematological malignancies. Keywords Posterior reversible encephalopathy syndrome Tumor lysis syndrome Hematological malignancy
Introduction Posterior reversible encephalopathy syndrome (PRES) was first described by Hinchey et al. [1]. As a disorder characterized by headaches, altered mental status and cortical blindness along with the radiographic abnormalities on magnetic resonance imaging (MRI), PRES predominantly affects the subcortical white matter of posterior lobe, which is clearly detected as high-intensity lesions in fluid attenuation inversion recovery (FLAIR) or T2-weighted image on MRI. However, it may also affect the basal ganglia, cerebellar hemisphere and brainstem [1–3]. The onset of PRES is strongly associated with hypertension induced by various drugs, especially steroids and other immunosuppressive drugs [4–8]. Recognition of PRES has increased over the past decade, resulting in a growing number of reports regarding PRES among pediatric cancer patients [9–11]. The neurological complications of PRES, such as epilepsy, are not always reversible [12, 13]. Therefore, it is critical to prevent the development of PRES in order to avoid such unfavorable complications. The goal of this retrospective study of pediatric patients with hematological malignancies was to identify factors that could predict the onset of PRES during initial chemotherapy.
Patients and methods D. Suzuki (&) R. Kobayashi H. Sano K. Kishimoto K. Yasuda K. Kobayashi Department of Pediatrics, Sapporo Hokuyu Hospital, Higashi-Sapporo 6-6, Shiroishiku, Sapporo 003-0006, Japan e-mail: [email protected] A. Iguchi Department of Pediatrics, Hokkaido University Hospital, Sapporo 060-8648, Japan
A total of 161 pediatric patients with hematological malignancies who received chemotherapy at our hospital between January 2000 and October 2010 were enrolled. Those who previously received stem cell transplantation were excluded. Of these patients, 99 were boys, and 61 were girls. Age of patients at the onset of their respective diseases was 4 months to 16 years (median 5 years). Thirty-six
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Table 1 Profiles of patients with hematological malignancies who developed PRES Case
Age
Sex
Disease
Cumulative dose of chemotherapeutic drugs before the onset of PRES
Onset of PRES (days after initiation of treatment)
Symptom
HT
CNS involvement
TLS
Onset of TLS (days after initiation of treatment)
Supportive and preventive therapy for TLS
Sequela
1
6
M
B-LBL
VCR: 3.0 mg/m2
11
Cortical blindness
?
-
?
2
Allopurinol
-
PSL: 480 mg/m
2
Hydration
CPM: 600 mg/m2
Furosemide
THP-ADR: 50 mg/m2
Alkalization Hemodialysis
2
6
F
BCPALL
PSL: 225 mg/m2 IT-MTX
6
Altered mental status
?
-
?
3
3
5
M
B-LBL
VCR: 1.5 mg/m2
10
Altered mental status
?
-
-
-
Seizure
?
AMD: 0.075 mg/ m2
Allopurinol Hydration
-
Alkalization Allopurinol
-
Hydration Alkalization
CPM: 2,200 mg/ m2 4
11
M
BCPALL
VCR: 6.0 mg/m2
35
-
-
-
2
Allopurinol
Epilepsy
Hydration Alkalization
DEX: 70 mg/m PSL: 875 mg/m2 THP-ADR: 40 mg/m2 L-asp: 36,000 u/ m2
5
13
M
T-ALL
PSL: 165 mg/m2
5
Seizure
?
-
?
1
28
Seizure
?
-
?
2
IT-MTX
Rasburicase hydration
-
G-I therapy 6
13
M
T-ALL
VCR: 6.0 mg/m2 DEX: 70 mg/m2
Rasburicase
Epilepsy
Hydration
PSL: 805 mg/m2 THP-ADR: 40 mg/m2 L-asp: 36,000 u/ m2 PRES posterior reversible encephalopathy syndrome, HT hypertension, CNS central nervous system, TLS tumor lysis syndrome, B-LBL B-cell lymphoblastic lymphoma, BCP-ALL B-precursor acute lymphoblastic leukemia, T-LBL T-cell lymphoblastic lymphoma, VCR vincristine, PSL prednisolone, CPM cyclophosphamide, THP-ADR THP-adriamycin, IT triple intrathecal injection, MTX methotrexate, AraC cytarabine, HDC hydrocortisone, DEX examethasone, AMD actinomycin D
patients had acute myeloid leukemia (AML), and 108 patients had acute lymphoblastic leukemia (ALL), consisting of B-precursor ALL (87 cases), T cell ALL (12 cases), mixed lineage ALL (six cases) and acute unclassified leukemia (three cases). Fifteen patients had non-Hodgkin lymphoma (NHL), consisting of T-precursor lymphoblastic lymphoma (three cases), B-precursor lymphoblastic lymphoma (five cases), anaplastic large cell lymphoma (four cases) and mature B-NHL (three cases). Two patients had Hodgkin lymphoma. Patients with AML were treated with cytarabine, etoposide and mitoxantrone under the AML 99 protocol (26 cases) and the AML05 protocol (10 cases)
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conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG). Patients with lymphoid malignancies were treated with the ALL97 protocol (25 cases) and the ALL02 protocol (82 cases) conducted by the Japan Association of Childhood Leukemia Study (JACLS). Other patients were treated with the ALB-NHL03 protocol (10 cases), the LLB-NHL03 protocol (one case), the ALCL99 protocol (four cases) and the B-NHL03 protocol (three cases) conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG), receiving multiple chemotherapeutic drugs including steroids (prednisolone, dexamethasone), vincristine, cyclophosphamide, THP-
Tumor lysis syndrome as a risk factor for PRES in children with hematological malignancies
adriamycin, l-asparaginase, actinomycin D, methotrexate and cytarabine during their induction therapy. Cumulative doses of chemotherapeutic drugs administered before the onset of PRES are shown in Table 1, respectively. Posterior reversible encephalopathy syndrome (PRES) was defined as the development of neurological symptoms, such as headaches, seizures and visual disorders, along with characteristic MRI findings of high-intensity lesions on subcortical white matter on T2-weighted or FLAIR imaging [1]. Patients were diagnosed with tumor lysis syndrome (TLS) when they met the criteria for laboratory or clinical TLS. Laboratory TLS was defined as a 25 % change from baseline values or the presence of serum levels above normal laboratory values in any two or more of the following parameters: potassium, uric acid, phosphate and calcium. Clinical TLS was defined as the presence of laboratory TLS and at least one of the following TLSrelated complications in the absence of any other recognizable cause: oliguric renal failure, need for hemodialysis, electrocardiographic signs of hyperkalemia, cardiac arrhythmia, tetany or seizures [14].
Statistical analysis A t test or Chi square test was used to compare patients with and without PRES. When comparing the PRES group and the non-PRES group, univariate analysis was used to determine the independence of following variables: age, gender, white blood cell count at the beginning of chemotherapy, lineage type (myeloid or lymphoid) and an episode of TLS. Statistical analyses were performed using Dr SPSS II for Windows (release 11.0.1J, SPSS Japan, Inc.). P \ 0.05 was considered to indicate statistical significance.
Results Of the 161 patients, six (3.7 %) patients developed PRES. As shown in Table 1, three patients were [10 years old, and five patients were boys. All of these patients had lymphoid malignancies and developed PRES during their initial induction therapy. The median time from the initiation of treatment to onset of PRES was 10.5 days (range 6–35 days). The initial symptoms of PRES were seizure, altered mental status and cortical blindness. Hypertension was observed in all patients. No patients had CNS involvement of the disease at diagnosis. Four patients (cases 1, 2, 5, 6) had TLS during their initial chemotherapy prior to the onset of PRES. Two patients (cases 4, 6) developed epilepsy with abnormality on
487
Table 2 Comparison of variables between patients with and without PRES Variable
PRES (n = 6)
Non-PRES (n = 155)
P value
Median age
8 years
5 years
0.123
(range)
(5–13)
(0–16)
5 (83.3 %)
94 (65.8 %)
1 (16.7 %)
61 (34.2 %)
12.2
7.9
1.20–160.0
0.60–355.0
Lymphoid
6 (100.0 %)
119 (76.8 %)
Myeloid
0 (0.0 %)
36 (23.2 %)
Yes
4 (66.7 %)
6 (3.9 %)
No
2 (33.3 %)
149 (96.1 %)
Sex Male Female WBC count (9109/L) (range)
0.407 0.691
Disease 0.339
Episode of TLS 0.029
PRES posterior reversible encephalopathy syndrome, TLS tumor lysis syndrome
electroencephalogram; even after they finished chemotherapy successfully, these patients required continuous antiepileptic drug therapy. As for TLS, it was observed in 8 cases (one in AML, five in ALL and two in NHL). Univariate analysis showed that TLS was a risk factor for PRES (Table 2). By contrast, age, gender, white blood cell count and lineage type (myeloid or lymphoid) were not associated with PRES.
Representative case Case 5 was a 13-year-old boy who was referred to our hospital due to back pain and difficulty breathing. Chest X-ray and computed tomography (CT) revealed thymus enlargement and pleural effusion along with bilateral renal leukemic infiltration (Fig. 1). Laboratory studies revealed a total leukocyte count of 20.27 9 109/l with 5 % abnormal cells, red blood cells of 5.41 9 1012/l and a platelet cell count of 340 9 109/l. C-reactive protein level was 1.53 mg/dl, lactate dehydrogenase level was 1,093 IU/l, and uric acid level was 8.9 mg/dl. The examination of bone marrow and pleural effusion revealed abnormal lymphoblasts accounting for 92.4 and 94 %, respectively, and surface markers of both cells were positive for CD2, CD4, CD5, CD7, CD8 and CD10, leading to the diagnosis of T-lymphoblastic leukemia. Before starting chemotherapy, sufficient hydration and rasburicase were administered with the hope of reducing the risk of TLS. Although serum uric acid level quickly decreased to nearly zero, serum potassium and inorganic phosphate levels increased gradually,
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Fig. 1 CT scan at diagnosis representing bilateral renal leukemic infiltration
Fig. 2 Brain MRI (FLAIR image) showing high-intensity lesions in the posterior lobe
ultimately resulting in renal failure and hyperkalemia that required glucose–insulin therapy. He then developed hypertension and had a seizure on the fifth day after the treatment. MRI revealed several high-intensity lesions on the parietal and occipital part of the brain (Fig. 2). His condition improved after initiation of treatment with antihypertensive and antiepileptic drugs, and he was able to continue subsequent chemotherapy without any neurological symptoms.
Discussion Although the mechanisms of the onset of PRES have not been fully determined, one of the hypotheses proposed to
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explain the etiology of PRES involves increased permeability and endothelial cell damage of blood vessels induced by a sudden rise of blood pressure, with resultant vasogenic edema of the brain [1, 15]. Immunosuppressive drugs (e.g., cyclosporine, tacrolimus, steroids, chemotherapeutic agents) are common triggers of PRES [4–9]. PRES has been reported in association with stem cell transplantation in patients receiving immunosuppressive drugs, such as cyclosporine and tacrolimus [16, 17], and reports of PRES occurring in the course of initial chemotherapy for childhood cancer are also on the rise [10, 11, 15, 18], as well as in adult patients [19]. One overview of PRES in childhood cancer described 56 PRES cases [15]. The patient ages ranged from 3 to 17 years old. Most cases (n = 41; 73.2 %) were lymphoid malignancies, including ALL and malignant lymphoma, while only two (3.6 %) cases were acute myeloid leukemia. This predisposition of lymphoid malignancies to PRES might be due to the increased use of steroids in the treatment of lymphoid malignancies when compared with myeloid diseases. In our study, patients who developed PRES were exclusively those with lymphoid malignancies. Regarding lymphoid tumors (ALL and NHL), TLS is still significant for the onset of PRES with P value of 0.036; however, when the patients are limited to ALL cases, TLS is not a significant factor. This is possibly due to the low number of patients enrolled. Larger scale study is necessary to fully determine the validity of this study. Several case reports have focused on the association between TLS and PRES [20–22]. Greenwood et al. [20], Ozkan et al. [21] and Kaito et al. [22] described patients with B-cell ALL, Burkitt’s lymphoma and B-cell lymphoma who each developed PRES after an episode of TLS. Those investigators stressed the importance of the awareness of TLS as a contributory factor for PRES. Our study is the first report that statistically validated the strong relationship between TLS and PRES. In a state of TLS, massive release of cytokines, such as TNFa, IL-6, IL-8 and IL-10, may cause systemic inflammation along with electrolyte imbalance and vascular damages [23]. We speculate the damages to the vascular endothelium of the brain that occurred after TLS may be aggravated by concomitant chemotherapy. This fact might be a predisposing factor for TLS-related PRES. High blood pressure has already been considered as one of the significant risk factors for PRES [1], and we speculate that it is also a crucial factor in developing PRES after TLS. Although the direct relationship between TLS and hypertension is unclear and we had difficulty in conducting the multivariate analysis by using the blood pressure measurement because of the fact that the normal range of blood pressure varies widely among children from infants to adolescence, the vascular damages after TLS and ensuing
Tumor lysis syndrome as a risk factor for PRES in children with hematological malignancies
renal damage along with the use of drugs such as steroids can be attributable to hypertension that may trigger TLSrelated PRES. There is also a possible relationship between PRES and renal leukemic infiltration. Renal leukemic infiltration can cause hypertension and subsequent renal parenchymal damage [24–26]. De Laat et al. [18] reported that one of the two patients who had renal leukemic infiltration developed TLS and subsequently required hemodialysis. This is analogous to the representative case described above. Further assessment is necessary to explain the association between PRES and renal leukemic infiltration. Further, two patients (cases 4, 6) developed prolonged radiographic abnormality on MRI and epilepsy that required long-term antiepileptic drug therapy. A previous report suggested that, in children with hemato-oncological disorders, PRES may occur beyond the posterior lobe with abnormalities on electroencephalogram and abnormal MRI findings that last a long time [15]. This is consistent with cases encountered in the present series. Prevention of PRES in the clinical course of chemotherapy is paramount, as PRES can lead to long-term neurological complications. Proper prophylactic measures against TLS (e.g., sufficient hydration, use of rasburicase) and careful blood pressure control are essential to reduce the occurrence of PRES in the course of initial chemotherapy in pediatric patients with hematological malignancies.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
References 1. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500. 2. Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J. 2001;77:24–8. 3. Pavlakis SG, Frank Y, Kalina P, Chandra M, Lu D, et al. Occipital-parietal encephalopathy: a new name for an old syndrome. Pediatr Neurol. 1997;16:145–8. 4. Tam CS, Galanos J, Seymour JF, Pitman AG, Stark RJ, Prince HM. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol. 2004;77:72–6. 5. Wong R, Beguelin GZ, de Lima M, Giralt SA, Hosing C, Ippoliti C, et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2003;122:128–34. 6. Lewis MB. Cyclosporin neurotoxicity after chemotherapy. Cyclosporin causes reversible posterior leukoencephalopathy syndrome. BMJ. 1999;319:54–5. 7. Ito Y, Arahata Y, Goto Y, Hirayama M, Nagamutsu M, Yasuda T, et al. Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome. AJNR Am J Neuroradiol. 1998;19:415–7. 8. Hwang TL, Yung WK, Estey EH, Fields WS. Central nervous system toxicity with high-dose Ara-C. Neurology. 1985;35:1475–9. 9. Sanchez-Carpintero R, Narbona J, Lopez de Mesa R, Arbizu J, Sierrasesumaga L, et al. Transient posterior encephalopathy
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induced by chemotherapy in children. Pediatr Neurol. 2001;24:145–8. Shin RK, Stern JW, Janss AJ, Hunter JV, Liu GT. Reversible posterior leukoencephalopathy during the treatment of acute lymphoblastic leukemia. Neurology. 2001;56:388–91. Suminoe A, Matsuzaki A, Kira R, Fukunaga N, Nishio T, Hoshina T, et al. Reversible posterior leukoencephalopathy syndrome in children with cancers. J Pediatr Hematol Oncol. 2003;25:236–9. Lucchini G, Grioni D, Colombini A, Contri M, De Grandi C, Rovelli A, et al. Encephalopathy syndrome in children with hemato-oncological disorders is not always posterior and reversible. Pediatr Blood Cancer. 2008;51:629–33. Antunes NL, Small TN, George D, Boulad F, Lis E. Posterior Leukoencephalopathy syndrome may not be reversible. Pediatr Neurol. 1999;20:241–3. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767–78. Lucchini G, Grioni D, Colombini A, Contri M, De Grandi C, Rovelli A, et al. Encephalopathy syndrome in children with hemato-oncological disorders is not always posterior and reversible. Pediatr Blood Cancer. 2008;51:629–33. Hammerstrom AE, Howell J, Gulbis A, Rondon G, Champlin RE, Popat U. Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. Am J Hematol. 2013;88:301–5. Cordelli DM, Masetti R, Bernardi B, Barcia G, Gentile V, Biagi C, et al. Status epilepticus as a main manifestation of posterior reversible encephalopathy syndrome after pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2012;58:785–90. de Laat P, Te Winkel ML, Devos AS, Catsman-Berrevoets CE, Pieters R, van den Heuvel-Eibrink MM. Posterior reversible encephalopathy syndrome in childhood cancer. Ann Oncol. 2011;22:472–8. Tsukamoto S, Takeuchi M, Kawajiri C, Tanaka S, Nagao Y, et al. Posterior reversible encephalopathy syndrome in an adult patient with acute lymphoblastic leukemia after remission induction chemotherapy. Int J Hematol. 2012;95:204–8. Greenwood MJ, Dodds AJ, Garrick R, Rodriguez M. Posterior leukoencephalopathy in association with the tumour lysis syndrome in acute lymphoblastic leukemia-a case with clinicopathological correlation. Leuk Lymphoma. 2003;44:719–21. Ozkan A, Hakyemez B, Ozkalemkas F, Ali R, Ozkocaman V, Ozcelik T, et al. Tumor lysis syndrome as a contributory factor to the development of reversible posterior leukoencephalopathy. Neuroradiology. 2006;48:887–92. Kaito E, Terae S, Kobayashi R, Kudo K, Tha KK, Miyasaka K. The role of tumor lysis syndrome in reversible posterior leukoencephalopathy syndrome. Pediatr Radiol. 2005;35:722–7. Hijiya N, Metzger ML, Pounds S, Schmidt JE, Razzouk BI, Rubnitz JE, et al. Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia. Pediatric Blood Cancer. 2005;44:63. Olgar S, Yetgin S, Cetin M, Aras T. Can renal leukemic infiltration cause hypertension in children? J Pediatr Hematol Oncol. 2006;28:579–84. Erten N, Saka B, Caliskan YK, Besisik S, Karan MA, Tasciogu C. Acute renal failure due to leukaemic infiltration in chronic lymphocytic leukaemia: case report. Int J Clin Pract Suppl. 2005;147:53–5. Turkmen K, Altintepe L, Guney I, Aydogdu I, Koc O, Erkut MA, et al. Uncontrolled hypertension secondary to leukemic cell infiltration of kidneys in a hemodialysis patient. Int J Nephrol Renovasc Dis. 2010;3:65–8.
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ORIGINAL ARTICLE
Tumor lysis syndrome as a risk factor for posterior reversible encephalopathy syndrome in children with hematological malignancies Daisuke Suzuki • Ryoji Kobayashi • Akihiro Iguchi • Hirozumi Sano • Kenji Kishimoto Kazue Yasuda • Kunihiko Kobayashi
•
Received: 18 March 2014 / Revised: 26 August 2014 / Accepted: 1 September 2014 / Published online: 13 September 2014 Ó The Japanese Society of Hematology 2014
Abstract Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by seizures, altered mental status and visual disorders, along with characteristic radiological findings. It is strongly related to hypertension induced by steroids and other immunosuppressive agents. There are an increasing number of reports regarding PRES arising during the course of chemotherapy for hematological malignancies. To clarify the risk factors for this phenomenon, we retrospectively analyzed pediatric patients undergoing treatment for hematological malignancies. Of 161 patients, six patients (3.7 %) developed PRES with characteristic clinical and radiographic findings. Univariate analysis revealed that tumor lysis syndrome (TLS) was a significant risk factor for the onset of PRES. TLS is a significant risk factor for the development of PRES in pediatric patients receiving chemotherapy for hematological malignancies. Keywords Posterior reversible encephalopathy syndrome Tumor lysis syndrome Hematological malignancy
Introduction Posterior reversible encephalopathy syndrome (PRES) was first described by Hinchey et al. [1]. As a disorder characterized by headaches, altered mental status and cortical blindness along with the radiographic abnormalities on magnetic resonance imaging (MRI), PRES predominantly affects the subcortical white matter of posterior lobe, which is clearly detected as high-intensity lesions in fluid attenuation inversion recovery (FLAIR) or T2-weighted image on MRI. However, it may also affect the basal ganglia, cerebellar hemisphere and brainstem [1–3]. The onset of PRES is strongly associated with hypertension induced by various drugs, especially steroids and other immunosuppressive drugs [4–8]. Recognition of PRES has increased over the past decade, resulting in a growing number of reports regarding PRES among pediatric cancer patients [9–11]. The neurological complications of PRES, such as epilepsy, are not always reversible [12, 13]. Therefore, it is critical to prevent the development of PRES in order to avoid such unfavorable complications. The goal of this retrospective study of pediatric patients with hematological malignancies was to identify factors that could predict the onset of PRES during initial chemotherapy.
Patients and methods D. Suzuki (&) R. Kobayashi H. Sano K. Kishimoto K. Yasuda K. Kobayashi Department of Pediatrics, Sapporo Hokuyu Hospital, Higashi-Sapporo 6-6, Shiroishiku, Sapporo 003-0006, Japan e-mail: [email protected] A. Iguchi Department of Pediatrics, Hokkaido University Hospital, Sapporo 060-8648, Japan
A total of 161 pediatric patients with hematological malignancies who received chemotherapy at our hospital between January 2000 and October 2010 were enrolled. Those who previously received stem cell transplantation were excluded. Of these patients, 99 were boys, and 61 were girls. Age of patients at the onset of their respective diseases was 4 months to 16 years (median 5 years). Thirty-six
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Table 1 Profiles of patients with hematological malignancies who developed PRES Case
Age
Sex
Disease
Cumulative dose of chemotherapeutic drugs before the onset of PRES
Onset of PRES (days after initiation of treatment)
Symptom
HT
CNS involvement
TLS
Onset of TLS (days after initiation of treatment)
Supportive and preventive therapy for TLS
Sequela
1
6
M
B-LBL
VCR: 3.0 mg/m2
11
Cortical blindness
?
-
?
2
Allopurinol
-
PSL: 480 mg/m
2
Hydration
CPM: 600 mg/m2
Furosemide
THP-ADR: 50 mg/m2
Alkalization Hemodialysis
2
6
F
BCPALL
PSL: 225 mg/m2 IT-MTX
6
Altered mental status
?
-
?
3
3
5
M
B-LBL
VCR: 1.5 mg/m2
10
Altered mental status
?
-
-
-
Seizure
?
AMD: 0.075 mg/ m2
Allopurinol Hydration
-
Alkalization Allopurinol
-
Hydration Alkalization
CPM: 2,200 mg/ m2 4
11
M
BCPALL
VCR: 6.0 mg/m2
35
-
-
-
2
Allopurinol
Epilepsy
Hydration Alkalization
DEX: 70 mg/m PSL: 875 mg/m2 THP-ADR: 40 mg/m2 L-asp: 36,000 u/ m2
5
13
M
T-ALL
PSL: 165 mg/m2
5
Seizure
?
-
?
1
28
Seizure
?
-
?
2
IT-MTX
Rasburicase hydration
-
G-I therapy 6
13
M
T-ALL
VCR: 6.0 mg/m2 DEX: 70 mg/m2
Rasburicase
Epilepsy
Hydration
PSL: 805 mg/m2 THP-ADR: 40 mg/m2 L-asp: 36,000 u/ m2 PRES posterior reversible encephalopathy syndrome, HT hypertension, CNS central nervous system, TLS tumor lysis syndrome, B-LBL B-cell lymphoblastic lymphoma, BCP-ALL B-precursor acute lymphoblastic leukemia, T-LBL T-cell lymphoblastic lymphoma, VCR vincristine, PSL prednisolone, CPM cyclophosphamide, THP-ADR THP-adriamycin, IT triple intrathecal injection, MTX methotrexate, AraC cytarabine, HDC hydrocortisone, DEX examethasone, AMD actinomycin D
patients had acute myeloid leukemia (AML), and 108 patients had acute lymphoblastic leukemia (ALL), consisting of B-precursor ALL (87 cases), T cell ALL (12 cases), mixed lineage ALL (six cases) and acute unclassified leukemia (three cases). Fifteen patients had non-Hodgkin lymphoma (NHL), consisting of T-precursor lymphoblastic lymphoma (three cases), B-precursor lymphoblastic lymphoma (five cases), anaplastic large cell lymphoma (four cases) and mature B-NHL (three cases). Two patients had Hodgkin lymphoma. Patients with AML were treated with cytarabine, etoposide and mitoxantrone under the AML 99 protocol (26 cases) and the AML05 protocol (10 cases)
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conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG). Patients with lymphoid malignancies were treated with the ALL97 protocol (25 cases) and the ALL02 protocol (82 cases) conducted by the Japan Association of Childhood Leukemia Study (JACLS). Other patients were treated with the ALB-NHL03 protocol (10 cases), the LLB-NHL03 protocol (one case), the ALCL99 protocol (four cases) and the B-NHL03 protocol (three cases) conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG), receiving multiple chemotherapeutic drugs including steroids (prednisolone, dexamethasone), vincristine, cyclophosphamide, THP-
Tumor lysis syndrome as a risk factor for PRES in children with hematological malignancies
adriamycin, l-asparaginase, actinomycin D, methotrexate and cytarabine during their induction therapy. Cumulative doses of chemotherapeutic drugs administered before the onset of PRES are shown in Table 1, respectively. Posterior reversible encephalopathy syndrome (PRES) was defined as the development of neurological symptoms, such as headaches, seizures and visual disorders, along with characteristic MRI findings of high-intensity lesions on subcortical white matter on T2-weighted or FLAIR imaging [1]. Patients were diagnosed with tumor lysis syndrome (TLS) when they met the criteria for laboratory or clinical TLS. Laboratory TLS was defined as a 25 % change from baseline values or the presence of serum levels above normal laboratory values in any two or more of the following parameters: potassium, uric acid, phosphate and calcium. Clinical TLS was defined as the presence of laboratory TLS and at least one of the following TLSrelated complications in the absence of any other recognizable cause: oliguric renal failure, need for hemodialysis, electrocardiographic signs of hyperkalemia, cardiac arrhythmia, tetany or seizures [14].
Statistical analysis A t test or Chi square test was used to compare patients with and without PRES. When comparing the PRES group and the non-PRES group, univariate analysis was used to determine the independence of following variables: age, gender, white blood cell count at the beginning of chemotherapy, lineage type (myeloid or lymphoid) and an episode of TLS. Statistical analyses were performed using Dr SPSS II for Windows (release 11.0.1J, SPSS Japan, Inc.). P \ 0.05 was considered to indicate statistical significance.
Results Of the 161 patients, six (3.7 %) patients developed PRES. As shown in Table 1, three patients were [10 years old, and five patients were boys. All of these patients had lymphoid malignancies and developed PRES during their initial induction therapy. The median time from the initiation of treatment to onset of PRES was 10.5 days (range 6–35 days). The initial symptoms of PRES were seizure, altered mental status and cortical blindness. Hypertension was observed in all patients. No patients had CNS involvement of the disease at diagnosis. Four patients (cases 1, 2, 5, 6) had TLS during their initial chemotherapy prior to the onset of PRES. Two patients (cases 4, 6) developed epilepsy with abnormality on
487
Table 2 Comparison of variables between patients with and without PRES Variable
PRES (n = 6)
Non-PRES (n = 155)
P value
Median age
8 years
5 years
0.123
(range)
(5–13)
(0–16)
5 (83.3 %)
94 (65.8 %)
1 (16.7 %)
61 (34.2 %)
12.2
7.9
1.20–160.0
0.60–355.0
Lymphoid
6 (100.0 %)
119 (76.8 %)
Myeloid
0 (0.0 %)
36 (23.2 %)
Yes
4 (66.7 %)
6 (3.9 %)
No
2 (33.3 %)
149 (96.1 %)
Sex Male Female WBC count (9109/L) (range)
0.407 0.691
Disease 0.339
Episode of TLS 0.029
PRES posterior reversible encephalopathy syndrome, TLS tumor lysis syndrome
electroencephalogram; even after they finished chemotherapy successfully, these patients required continuous antiepileptic drug therapy. As for TLS, it was observed in 8 cases (one in AML, five in ALL and two in NHL). Univariate analysis showed that TLS was a risk factor for PRES (Table 2). By contrast, age, gender, white blood cell count and lineage type (myeloid or lymphoid) were not associated with PRES.
Representative case Case 5 was a 13-year-old boy who was referred to our hospital due to back pain and difficulty breathing. Chest X-ray and computed tomography (CT) revealed thymus enlargement and pleural effusion along with bilateral renal leukemic infiltration (Fig. 1). Laboratory studies revealed a total leukocyte count of 20.27 9 109/l with 5 % abnormal cells, red blood cells of 5.41 9 1012/l and a platelet cell count of 340 9 109/l. C-reactive protein level was 1.53 mg/dl, lactate dehydrogenase level was 1,093 IU/l, and uric acid level was 8.9 mg/dl. The examination of bone marrow and pleural effusion revealed abnormal lymphoblasts accounting for 92.4 and 94 %, respectively, and surface markers of both cells were positive for CD2, CD4, CD5, CD7, CD8 and CD10, leading to the diagnosis of T-lymphoblastic leukemia. Before starting chemotherapy, sufficient hydration and rasburicase were administered with the hope of reducing the risk of TLS. Although serum uric acid level quickly decreased to nearly zero, serum potassium and inorganic phosphate levels increased gradually,
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Fig. 1 CT scan at diagnosis representing bilateral renal leukemic infiltration
Fig. 2 Brain MRI (FLAIR image) showing high-intensity lesions in the posterior lobe
ultimately resulting in renal failure and hyperkalemia that required glucose–insulin therapy. He then developed hypertension and had a seizure on the fifth day after the treatment. MRI revealed several high-intensity lesions on the parietal and occipital part of the brain (Fig. 2). His condition improved after initiation of treatment with antihypertensive and antiepileptic drugs, and he was able to continue subsequent chemotherapy without any neurological symptoms.
Discussion Although the mechanisms of the onset of PRES have not been fully determined, one of the hypotheses proposed to
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explain the etiology of PRES involves increased permeability and endothelial cell damage of blood vessels induced by a sudden rise of blood pressure, with resultant vasogenic edema of the brain [1, 15]. Immunosuppressive drugs (e.g., cyclosporine, tacrolimus, steroids, chemotherapeutic agents) are common triggers of PRES [4–9]. PRES has been reported in association with stem cell transplantation in patients receiving immunosuppressive drugs, such as cyclosporine and tacrolimus [16, 17], and reports of PRES occurring in the course of initial chemotherapy for childhood cancer are also on the rise [10, 11, 15, 18], as well as in adult patients [19]. One overview of PRES in childhood cancer described 56 PRES cases [15]. The patient ages ranged from 3 to 17 years old. Most cases (n = 41; 73.2 %) were lymphoid malignancies, including ALL and malignant lymphoma, while only two (3.6 %) cases were acute myeloid leukemia. This predisposition of lymphoid malignancies to PRES might be due to the increased use of steroids in the treatment of lymphoid malignancies when compared with myeloid diseases. In our study, patients who developed PRES were exclusively those with lymphoid malignancies. Regarding lymphoid tumors (ALL and NHL), TLS is still significant for the onset of PRES with P value of 0.036; however, when the patients are limited to ALL cases, TLS is not a significant factor. This is possibly due to the low number of patients enrolled. Larger scale study is necessary to fully determine the validity of this study. Several case reports have focused on the association between TLS and PRES [20–22]. Greenwood et al. [20], Ozkan et al. [21] and Kaito et al. [22] described patients with B-cell ALL, Burkitt’s lymphoma and B-cell lymphoma who each developed PRES after an episode of TLS. Those investigators stressed the importance of the awareness of TLS as a contributory factor for PRES. Our study is the first report that statistically validated the strong relationship between TLS and PRES. In a state of TLS, massive release of cytokines, such as TNFa, IL-6, IL-8 and IL-10, may cause systemic inflammation along with electrolyte imbalance and vascular damages [23]. We speculate the damages to the vascular endothelium of the brain that occurred after TLS may be aggravated by concomitant chemotherapy. This fact might be a predisposing factor for TLS-related PRES. High blood pressure has already been considered as one of the significant risk factors for PRES [1], and we speculate that it is also a crucial factor in developing PRES after TLS. Although the direct relationship between TLS and hypertension is unclear and we had difficulty in conducting the multivariate analysis by using the blood pressure measurement because of the fact that the normal range of blood pressure varies widely among children from infants to adolescence, the vascular damages after TLS and ensuing
Tumor lysis syndrome as a risk factor for PRES in children with hematological malignancies
renal damage along with the use of drugs such as steroids can be attributable to hypertension that may trigger TLSrelated PRES. There is also a possible relationship between PRES and renal leukemic infiltration. Renal leukemic infiltration can cause hypertension and subsequent renal parenchymal damage [24–26]. De Laat et al. [18] reported that one of the two patients who had renal leukemic infiltration developed TLS and subsequently required hemodialysis. This is analogous to the representative case described above. Further assessment is necessary to explain the association between PRES and renal leukemic infiltration. Further, two patients (cases 4, 6) developed prolonged radiographic abnormality on MRI and epilepsy that required long-term antiepileptic drug therapy. A previous report suggested that, in children with hemato-oncological disorders, PRES may occur beyond the posterior lobe with abnormalities on electroencephalogram and abnormal MRI findings that last a long time [15]. This is consistent with cases encountered in the present series. Prevention of PRES in the clinical course of chemotherapy is paramount, as PRES can lead to long-term neurological complications. Proper prophylactic measures against TLS (e.g., sufficient hydration, use of rasburicase) and careful blood pressure control are essential to reduce the occurrence of PRES in the course of initial chemotherapy in pediatric patients with hematological malignancies.
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