Pediatric Hematology and Oncology, 31:647–655, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.918681
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ORIGINAL ARTICLE Acute Lymphoblastic Leukemia
Relationship Between Modified CT Severity Index and Clinical Features of L-Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia Hyeon Jeong Oh,1 Soo Ah Im,1 Jae Wook Lee,2 Nak Gyun Chung,2 and Bin Cho2 1
Department of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea; 2 Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
Purpose: To describe clinical and CT features of L-asparaginase-associated pancreatitis (L-AP) and to correlate CT grades with clinical parameters. Methods: A total of 16 children (M:F = 9:7; mean age, 8.1 years) who developed L-AP after L-asparaginase (L-asp) treatment and underwent abdominal CT scan were included. We retrospectively reviewed clinical data (age, sex, signs, and symptoms related to pancreatic toxicity and its complications, the number of L-asp doses receiving before L-AP); laboratory test results (serum amylase, lipase, C-reactive protein (CRP), calcium, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glucose, and serum albumin); and clinical course (the number of days of hospitalization, number of NPO days, use of nasogastric tube, intravenous (IV) narcotics, total parenteral nutrition (TPN) or any surgical intervention). We also reviewed CT images and modified CT severity index (MCSI) for grading the severity of AP and classified to three groups (mild, moderate, and severe) or two groups (low and high score) according to MCSI. Results: L-AP typically occurred early in the course of therapy. Use of IV narcotics (P = .014) and peak amylase (P = .009) showed a significant difference between mild and severe L-AP groups according to MCSI. Between the low and high score groups, Use of IV narcotics (P = .046), BUN (P = .039), and peak amylase level (P = .013) was significantly different. However, the L-asp dose, hospital day, and other clinical date associated with prognosis did not show any significant difference. Conclusion: In L-AP with pediatric ALL patients, MCSI may correlate with usage of IV narcotics, BUN, and peak amylase levels. Keywords acute lymphoblastic leukemia (ALL), computed tomography, L-asparaginase, pancreatitis
INTRODUCTION Since the introduction of a multiagent regimen for pediatric acute lymphoblastic leukemia (ALL) in the 1970s, L-asparaginase (L-asp) has become an important treatment modality. In childhood ALL, treatment response to L-asp ranged from 20% to 68%, depending on dosage and injection schedule [1, 2]. Although it has Received 27 January 2014; accepted 23 April 2014. Address correspondence to Dr. Soo Ah Im, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. E-mail: [email protected]
H. J. Oh et al.
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played an important role in increasing the survival rate of childhood ALL, it can cause various adverse effects, including hypersensitivity reactions, hypoproteinemia, abnormal liver function test results, acute pancreatitis (AP), hyperglycemia, hypertriglyceridemia, and thrombosis [2–10]. L-asp-associated pancreatitis (L-AP) occurs in 2.5% to 16% of the treated patients [4]. L-AP is usually diagnosed on the basis of clinical symptoms, laboratory test results, and radiologic findings. Especially contrast-enhanced computed tomography (CT) is known to be the golden standard for staging severity and assessing complications. CT is also widely used in the follow-up examination [11]. However, relationships between CT grades and clinical findings have not been completely evaluated. The aim of this study was to describe CT grading of L-AP and to correlate findings of L-AP with clinical parameters.
MATERIALS AND METHODS 1. Patients Our institutional review board approved this retrospective study and waived the requirement for informed consent. Between November 2008 and September 2013, we reviewed the clinical course and CT images of all children with ALL diagnosed with L-AP at our hospital. Data collected for analysis were as follows: age, sex, signs and symptoms related to pancreatic toxicity complications, number of L-asp doses receiving before L-AP, laboratory findings; serum amylase, lipase, C-reactive protein (CRP), calcium, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glucose, and serum albumin, CT findings, and clinical course; the number of days of hospitalization, number of NPO days, use of nasogastric tubes, intravenous (IV) narcotics, total parenteral nutrition (TPN), or any surgical intervention. 2. Chemotherapy Protocol The chemotherapy schedule used at our center for induction remission included nine doses of L-asp derived from Escherichia coli (6000 units/m2 ) three times per week, weekly vincristine (1.5 mg/m2 ) on days 1, 8, 15, and 22, daunorubicin (45 mg/m2 ) on day 1, daily oral prednisolone (60 mg/m2 /d) for 3 weeks, followed by a 1-week taper, and three doses of intrathecal chemotherapy. Consolidation therapy did not include L-asp. Patients with low or standard risk ALL received six further doses of L-asp during delayed intensification, while those with high-and very high-risk ALL received 11 and 14 doses, respectively. All patients received maintenance therapy, including daily mercaptopurine, weekly methotrexate, pulses of vincristine and prednisolone every 4 weeks, and high-dose methotrexate with intrathecal chemotherapy every 12 weeks during a period of 96 weeks. 3. Pancreatitis L-AP was defined as AP in patients that were receiving L-asp treatment at the time of AP onset. The revised Atlanta criteria for AP requires two of the following three features: abdominal pain strongly suggestive of AP, serum amylase and/or lipase activity at least three times greater than the upper limit of normal, and characteristic findings of AP on transabdominal ultrasonography or contrast-enhanced CT [12]. We excluded patients who underwent ultrasonography only due to interobserver variability in ultrasonography. All abdominal CT scans were obtained within 72 hours of symptom onset. We also classified the patients into three CT severity groups (mild, moderate, and severe) using modified CT severity index (MCSI) by Mortele et al. (Table 1) and into two groups (low and high score) [13]. Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL TABLE 1
Modified CT Severity Index by Mortele et al. with Incidence in 16 Patients
Prognostic indicator
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Pancreatic inflammation Normal pancreas Intrinsic pancreatic abnormalities with inflammatory changes in the peri-pancreatic fat Pancreatic or peri-pancreatic fluid collection or peri-pancreatic fat necrosis Pancreatic necrosis None 30% Extra-pancreatic complications pleural effusion ascites vascular complications (venous thrombosis, arterial hemorrhage, or pseudoaneurysm formation) parenchymal complications (infarction, hemorrhage, or sub-capsular fluid collection) GI involvement (inflammation, perforation, or intramural fluid collection)
Score
Incidence in our 16 patients (%)
0 2
2 (12.5%) 4 (25%)
4
10 (62.5%)
0 2 4
11 (68.8%) 4 (25%) 1 (6.3%)
2
8 (50%) 12 (75%) 0 (0%) 1 (6.3%) 3 (18.8%)
4. Statistical Analysis Statistical analysis was performed using SPSS v.19.0 (IBM Corp., Armonk, NY, USA). A P value of less than .05 indicated statistical significance. Quantitative variables are expressed as mean ± SD, categorical variables as percentages. Continuous variables in mild versus moderate versus severe pancreatitis were compared by the Kruskal-Wallis test and the Mann-Whitney U test. RESULTS Twenty-three patients developed AP after L-asp treatment for 5 years. But, four patients underwent ultrasonography only and three patients were lost to follow-up. Thus, 16 patients were included in the study (M:F = 9:7; mean age, 8.1 years [2–15 years]). L-AP generally occurred within the first few weeks (mean, 19 days; range, 3 to 60 days) of therapy. In 10 cases (62.5%), L-AP developed during the induction–remission treatment. All patients with L-AP presented with abdominal pain, and 14 patients (87.5%) also complained of nausea or vomiting. Table 2 shows the clinical parameters and CT findings of 16 patients with ALL who developed L-AP. Mean initial pancreatic enzymes levels during the first 24 to 48 hours after symptom onset were as follows: serum amylase, 550 IU/dL (range, 125–2650; normal 45–160) and serum lipase, 570 IU/dL (range, 21–4488 IU/dL; normal 13–60 IU/dL). The mean peak serum amylase level was 1127 IU/dL (range, 160–2810 IU/dL), and the mean peak serum lipase level was 1440 IU/dL (range, 86–4488 IU/dL). The mean amylase normalizing time was 8.3 days (range, 1–26 days). The amylase level was chosen for laboratory normalizing time because lipase levels required a longer time to become normalized during the follow-up period, and some patients discontinued follow-up examination because their symptoms improved before normalization of lipase levels. The clinical course of the patients is summarized in Table 3. Fifteen patients (93.8%) were managed with supportive therapy in NPO state and 12 patients (75%) received TPN with a mean administration time of 9.5 days. IV narcotics were administered to eight patients (50%). One patient died of graft-versus-host disease and disseminated intravascular coagulation. No patients C Informa Healthcare USA, Inc. Copyright
H. J. Oh et al.
TABLE 2 Clinical Parameters and CT Findings of 16 Patients who Developed L-Asparaginase-Associated Pancreatitis with Acute Lymphoblastic Leukemia
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Number Laboratory Patient of L-asp Peak Peak normalizing number Sex Age dose amylase lipase time (days) BUN 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
F M M M M M F F F M F M M F M F
7 7 10 5 11 14 15 4 9 2 8 5 9 11 7 6
13 10 9 9 9 11 9 9 9 9 23 8 5 5 9 5
378 377 343 854 2650 1850 1417 926 1212 160 2810 2274 994 253 826 702
1245.2 600 2406 1096 4488 2994.7 1073.5 1035.4 1304.4 86.2 1929 2017.5 1434.5 119.5 474.1 736.4
10 12 8 – 11 26 7 9 6 1 7 13 4 1 2 8
CRP
14.5 0.71 14.3 1.74 4.6 0.37 97.1 190.59 28.3 210.11 28.2 10.18 28.2 13.16 20.0 4.47 23.6 5 19.5 ND∗ 41.1 4.68 29.8 6.79 28.5 16.53 16.6 0.21 6.9 0.15 20.8 10.13
Calcium MCSI 8.4 8.9 8.4 8.1 8.6 11.2 7.9 8.5 9 8.7 9.7 9.3 9.7 8.8 8.0 8.6
2 2 2 2 6 6 8 8 8 2 6 10 8 6 4 6
MCSI = Modified CT severity index Normal value; amylase (45–160 IU/dL), lipase (13–60 IU/dL), BUN (7–20 mg/dL), CRP (0–0.3 mg/dL), calcium (8–10 mg/dL) ∗ ND = not done – = not known because the patient expired
died due to direct complications of L-AP. After recovery from L-AP, no patients developed chronic pancreatitis or glucose intolerance. All contrast-enhanced CT were reviewed. On CT images, pancreatic abnormalities were seen in 14 patients (87.5%). Pleural effusion was observed in eight patients (50%), and ascites in 12 patients (75%). Pancreatic parenchymal necrosis was seen in five patients (31.3%) and infarction was observed in one patient (6.3%) (Table 1). Five patients (31.3%) were classified as having mild AP (mild AP group) (Figure 1), six patients (37.5%) as having moderate AP (moderate AP group) (Figure 2) and five patients (31.3%) as having severe AP (severe AP group) (Figure 3). The peak amylase level (P = .009) and use of IV narcotics (P = .014) were significantly different between the mild and severe AP groups, and use of IV narcotics (P = .029) was significantly different between the moderate and severe AP groups (Table 4). However, the number of L-asp doses, hospital stays, amylase normalizing time, and other clinical values associated with prognosis, such as CRP, calcium, and BUN,
TABLE 3 Clinical Course of Patients with L-Asparaginase-Associated Pancreatitis with Acute Lymphoblastic Leukemia (n = 16) Days in hospital (mean)
37.4 days
Treatment of pancreatitis NPO Days of NPO (mean) Nasogastric tube TPN∗ Days of TPN (mean) IV narcotics
15 (93.8%) 13.2 days 11(68.8%) 12 (75%) 9.5 days 8 (50%)
∗
TPN: Total parenteral nutrition Pediatric Hematology and Oncology
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L-Asparaginase-Associated Pancreatitis in ALL
FIGURE 1 L-asparaginase-associated pancreatitis. CT scan shows pancreatic swelling without parenchymal necrosis or extrapancreatic complication. MCSI score is 2 and it is classified as mild or low score group.
FIGURE 2 L-asparaginase-associated pancreatitis. CT scan shows pancreas swelling with peripancreatic fluid collection and ascites. MCSI score is 6. It is classified as moderate or high score group.
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FIGURE 3 L-sparaginase-associated pancreatitis. A, B. CT scan shows pancreas necrosis (>30%) with peripancreatic fluid collection, ascites, and bilateral pleural effusion. MCSI score is 8. It is classified as severe or high score group.
did not show significant difference between the mild and moderate AP groups and between the moderate and severe AP groups. Statistical significance of LDH, AST, blood glucose, and serum albumin could not be evaluated because these parameters were examined only in a few patients. We also divided the patients with L-AP into two groups according to MCSI [14]: those with an MCSI of 0–4 (low MCSI group) and those with an MCSI of 6–10 (high MCSI group). Six patients belonged to the low MCSI group, and 10 patients belonged Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL
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TABLE 4 Relation Between Three Groups by Modified CT Severity Index and Clinical Parameters Mild vs. Moderate
Moderate vs. Severe
Mild vs. Severe
0.201 0.100 0.100 0.584 0.462 0.460 0.361 0.593 0.637 0.465 0.565
0.201 0.465 0.855 0.855 0.917 0.190 0.522 0.927 0.029 0.855 0.562
0.465 0.251 0.009 0.465 0.221 0.751 0.117 0.539 0.014 0.754 0.060
Initial amylase Initial lipase Peak amylase Peak lipase CRP Calcium BUN Laboratory normalizing time IV narcotics Hospital day Number of L-asparaginase dose
Three groups by MCSI: Mild, 0∼2; Moderate, 4∼6; Severe, 8∼10 TABLE 5 Relation Between Two Groups (low and High Score) by Modified CT Severity Index and Clinical Parameters P value Initial amylase Initial lipase Peak amylase Peak lipase CRP Calcium BUN Laboratory normalizing time IV narcotics Hospital day Number of L-asp dose
0.448 0.233 0.013 0.193 0.258 0.583 0.039 0.902 0.046 0.914 0.263
Two groups by MCSI: low, 0–4; high, 6–10
to the high score group. The peak amylase level (P = .013), BUN level (P = .039), and use of IV narcotics (P = 0.046) were significantly more elevated in the high MCSI group (Table 5). The degree of pancreatic enzyme elevation did not correlate with other laboratory results or clinical parameters, such as CRP, calcium, hospitalization days, NPO time, or TPN duration. When we divided the patients into two groups according to Balthazar score, six patients were mild (Balthazar score A-C), 10 patients were severe. Initial lipase level was significantly more elevated in the severe group (mean ± SD, 843.01 ± 1344.85 IU/dL) rather than low group (mean ± SD, 113.78 ± 79.36) (P = .039). Other clinical parameters, including peak amylase level (P = .065), BUN level (P = .254), and use of IV narcotics (P = .317) were not significantly differenced. DISCUSSION L-asp has become an essential drug for the treatment of pediatric ALL since 1966 [1, 2]. The toxicities of L-asp are various. These include hypersensitivity reactions, central nervous system dysfunction, altered liver function, thrombosis, hypoinsulinemia with resulting hyperglycemia, severe hyperlipidemia, and pancreatitis [2–10]. One of the most serious adverse events of L-asp is AP, which is the most common reason for stopping treatment [2, 4, 7, 9]. Pathophysiologic mechanisms behind L-AP are still C Informa Healthcare USA, Inc. Copyright
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H. J. Oh et al.
unknown. However, the origin, formulation, dosage, or method of L-asp administration does not seem to influence the risk of L-AP [2, 4, 6, 7, 9]. L-AP is more common in older children or adolescents [7, 9, 15–17]. However, our study showed even distribution from the age of 2 years to 15 years. Other presenting characteristics factors are not known to be associated with the onset of pancreatitis [7]. The onset of pancreatitis was various, and more than 50% of patients occurred during the induction-remission treatment. In our study, 62.5% of patients developed L-AP during the induction-remission treatment, which is consistent with the results of previous studies indicating that L-AP occurred during early medication [4]. The total dose of L-asp is not related to pancreatitis. Therefore, AP seems to be a side effect caused by hypersensitivity reactions rather than dose-related or doseaccumulated reaction [6, 16, 18–21]. In our study, the dose of L-asp was not significantly different between the mild, moderate, and severe AP groups related to the CT severity group. There are several prognostic scoring systems of AP, including Ranson’s prognostic criteria, APACHE II, Glasgow criteria, and Balthazar’s criteria [22, 23]. Since Balthazar’s original system, numerous other morphological scoring systems have been proposed, each with their own flaws. Mortele et al. [13, 22] modified CT severity index on a 10-point scale, taking into account pancreatic inflammation, necrosis, and extra-pancreatic complications, which showed a stronger correlation between outcome and severity than the original. The severity of AP is determined to predict the prognosis of the disease [22, 23]. Parameters associated with the prognosis of pancreatitis have been reported to be age, white cell count, LDH, AST, blood glucose, serum calcium, BUN, serum albumin, and CRP [22, 23]. In one study, most patients showed mild and self-limited progression [4]. Our patients were evenly distributed in the three AP groups: five patients in the mild AP group, six patients in the moderate AP group, five patients in the severe AP group. The peak amylase level (P = .009) and dose of IV narcotics (P = .014) were significantly different between the mild and severe AP groups. When our patients were divided into 2 MCSI groups, the peak amylase level, BUN level, and use of IV narcotics were significantly higher in the high MCSI group. Amylase and lipase are usually elevated in AP, although the degree of elevation does not correlate with disease severity [24]. Thus, amylase and lipase are not included in prognostic factors. However, in our study, the peak amylase level correlated with MCSI. The dose of IV narcotics was significantly different between the three AP groups severity group. The CT grade is one of the factors that reflect the severity of the disease. Therefore, the higher the CT grade, the more severe and longer the clinical symptoms. It seems that IV narcotics may be frequently used in more severe AP groups. When using Balthazar grading system, only initial lipase was significantly different between the mild and severe groups. The original Balthazar grading and MCSI showed different clinical parameters that compare clinical relevance between the mild and severe group. However, it was difficult to determine which was better in predicting prognosis because of the limited sample size and no incidence of chronic complication. The results of this study are subject to some limitations of this study. First, this is a retrospective study. Several laboratory test results were not available. Second, we did not take into account the other causes of hospitalization. If patients had other concurrent diseases, their clinical outcome may have been different. Third, follow-up CT was not performed on patients who had pancreatic necrosis. However, laboratory findings and clinical symptoms were improved in our patients. In summary, the results of this study suggest that MCSI may be related to the peak amylase, BUN level and use of IV narcotics in ALL patients with L-AP. More research with a larger group of patients is needed to confirm our results.
Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REFERENCES [1] Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32:554–563. [2] Treepongkaruna S, Thongpak N, Pakakasama S, et al. Acute pancreatitis in children with acute lymphoblastic leukemia after chemotherapy. J Pediatr Hematol Oncol. 2009;31:812–815. [3] Lashkari HP, Lancaster D, Atra A, et al. Symptomatic severe hypertriglyceridaemia with asparaginase therapy in acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma: is rechallenging safe? Int J Hematol. 2011;94:571–575. [4] Flores-Calderon J, Exiga-Gonzalez E, Moran-Villota S, et al. Acute pancreatitis in children with acute lymphoblastic leukemia treated with L-asparaginase. J Pediatr Hematol Oncol. 2009;31:790–793. [5] Mekitarian Filho E, de Carvalho WB, Silva FD. Acute pancreatitis in pediatrics: a systematic review of the literature. J Pediatr (Rio J). 2012;88:101–114. [6] Raja RA, Schmiegelow K, Frandsen TL. Asparaginase-associated pancreatitis in children. British J Haematol. 2012;159:18–27. [7] Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB. Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer. 2009;53:162–167. [8] Sahu S, Saika S, Pai SK, Advani SH. L-asparaginase (Leunase) induced pancreatitis in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1998;15:533–538. [9] Knoderer HM, Robarge J, Flockhart DA. Predicting asparaginase-associated pancreatitis. Pediatric Blood & Cancer. 2007;49:634–639. [10] Muller HJ, Boos J. Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol. 1998;28:97–113. [11] Kwon Y, Park HS, Kim YJ, et al. Multidetector row computed tomography of acute pancreatitis: utility of single portal phase CT scan in short-term follow up. Eur J Radiol. 2012;81:1728–1734. [12] Thoeni RF. The revised Atlanta classification of acute pancreatitis: its importance for the radiologist and its effect on treatment. Radiology. 2012;262:751–764 [13] Bharwani N, Patel S, Prabhudesai S, et al. Acute pancreatitis: the role of imaging in diagnosis and management. Clin Radiol. 2011;66:164–175. [14] Trout AT, Elsayes KM, Ellis JH, Francis IR. Imaging of acute pancreatitis: prognostic value of computed tomographic findings. J Comput Assist Tomogr. 2010;34:485–495. [15] Haskell CM, Canellos GP, Leventhal BG, et al. L-asparaginase: therapeutic and toxic effects in patients with neoplastic disease. N Engl J Med. 1969;281:1028–1034. [16] Alvarez OA, Zimmerman G. Pegaspargase-induced pancreatitis. Med Pediatr Oncol. 2000;34:200–205. [17] Weetman RM, Baehner RL. Latent onset of clinical pancreatitis in children receiving L-asparaginase therapy. Cancer. 1974;34:780–785. [18] Land VJ, Sutow WW, Fernbach DJ, et al. Toxicity of L-asparginase in children with advanced leukemia. Cancer. 1972;30:339–347. [19] Laugel V, Escande B, Entz-Werle N, et al. Severe acute pancreatitis in children receiving asparaginase: multicenter retrospective study. Arch Pediatr. 2005;12:34–41. [20] Mallory A, Kern F, Jr. Drug-induced pancreatitis: a critical review. Gastroenterology. 1980;78:813–820. [21] Riemenschneider TA, Wilson JF, Vernier RL. Glucocorticoid-induced pancreatitis in children. Pediatrics. 1968;41:428–437. [22] Triester SL, Kowdley KV. Prognostic factors in acute pancreatitis. J Clin Gastroenterol. 2002;34:167–176. [23] Pavlidis TE, Pavlidis ET, Sakantamis AK. Advances in prognostic factors in acute pancreatitis: a minireview. Hepatobiliary Pancreat Dis Int. 2010;9:482–486. [24] Winslet M, Hall C, London NJ, Neoptolemos JP. Relation of diagnostic serum amylase levels to aetiology and severity of acute pancreatitis. Gut. 1992;33:982–986.
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ORIGINAL ARTICLE Acute Lymphoblastic Leukemia
Relationship Between Modified CT Severity Index and Clinical Features of L-Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia Hyeon Jeong Oh,1 Soo Ah Im,1 Jae Wook Lee,2 Nak Gyun Chung,2 and Bin Cho2 1
Department of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea; 2 Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
Purpose: To describe clinical and CT features of L-asparaginase-associated pancreatitis (L-AP) and to correlate CT grades with clinical parameters. Methods: A total of 16 children (M:F = 9:7; mean age, 8.1 years) who developed L-AP after L-asparaginase (L-asp) treatment and underwent abdominal CT scan were included. We retrospectively reviewed clinical data (age, sex, signs, and symptoms related to pancreatic toxicity and its complications, the number of L-asp doses receiving before L-AP); laboratory test results (serum amylase, lipase, C-reactive protein (CRP), calcium, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glucose, and serum albumin); and clinical course (the number of days of hospitalization, number of NPO days, use of nasogastric tube, intravenous (IV) narcotics, total parenteral nutrition (TPN) or any surgical intervention). We also reviewed CT images and modified CT severity index (MCSI) for grading the severity of AP and classified to three groups (mild, moderate, and severe) or two groups (low and high score) according to MCSI. Results: L-AP typically occurred early in the course of therapy. Use of IV narcotics (P = .014) and peak amylase (P = .009) showed a significant difference between mild and severe L-AP groups according to MCSI. Between the low and high score groups, Use of IV narcotics (P = .046), BUN (P = .039), and peak amylase level (P = .013) was significantly different. However, the L-asp dose, hospital day, and other clinical date associated with prognosis did not show any significant difference. Conclusion: In L-AP with pediatric ALL patients, MCSI may correlate with usage of IV narcotics, BUN, and peak amylase levels. Keywords acute lymphoblastic leukemia (ALL), computed tomography, L-asparaginase, pancreatitis
INTRODUCTION Since the introduction of a multiagent regimen for pediatric acute lymphoblastic leukemia (ALL) in the 1970s, L-asparaginase (L-asp) has become an important treatment modality. In childhood ALL, treatment response to L-asp ranged from 20% to 68%, depending on dosage and injection schedule [1, 2]. Although it has Received 27 January 2014; accepted 23 April 2014. Address correspondence to Dr. Soo Ah Im, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. E-mail: [email protected]
H. J. Oh et al.
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played an important role in increasing the survival rate of childhood ALL, it can cause various adverse effects, including hypersensitivity reactions, hypoproteinemia, abnormal liver function test results, acute pancreatitis (AP), hyperglycemia, hypertriglyceridemia, and thrombosis [2–10]. L-asp-associated pancreatitis (L-AP) occurs in 2.5% to 16% of the treated patients [4]. L-AP is usually diagnosed on the basis of clinical symptoms, laboratory test results, and radiologic findings. Especially contrast-enhanced computed tomography (CT) is known to be the golden standard for staging severity and assessing complications. CT is also widely used in the follow-up examination [11]. However, relationships between CT grades and clinical findings have not been completely evaluated. The aim of this study was to describe CT grading of L-AP and to correlate findings of L-AP with clinical parameters.
MATERIALS AND METHODS 1. Patients Our institutional review board approved this retrospective study and waived the requirement for informed consent. Between November 2008 and September 2013, we reviewed the clinical course and CT images of all children with ALL diagnosed with L-AP at our hospital. Data collected for analysis were as follows: age, sex, signs and symptoms related to pancreatic toxicity complications, number of L-asp doses receiving before L-AP, laboratory findings; serum amylase, lipase, C-reactive protein (CRP), calcium, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glucose, and serum albumin, CT findings, and clinical course; the number of days of hospitalization, number of NPO days, use of nasogastric tubes, intravenous (IV) narcotics, total parenteral nutrition (TPN), or any surgical intervention. 2. Chemotherapy Protocol The chemotherapy schedule used at our center for induction remission included nine doses of L-asp derived from Escherichia coli (6000 units/m2 ) three times per week, weekly vincristine (1.5 mg/m2 ) on days 1, 8, 15, and 22, daunorubicin (45 mg/m2 ) on day 1, daily oral prednisolone (60 mg/m2 /d) for 3 weeks, followed by a 1-week taper, and three doses of intrathecal chemotherapy. Consolidation therapy did not include L-asp. Patients with low or standard risk ALL received six further doses of L-asp during delayed intensification, while those with high-and very high-risk ALL received 11 and 14 doses, respectively. All patients received maintenance therapy, including daily mercaptopurine, weekly methotrexate, pulses of vincristine and prednisolone every 4 weeks, and high-dose methotrexate with intrathecal chemotherapy every 12 weeks during a period of 96 weeks. 3. Pancreatitis L-AP was defined as AP in patients that were receiving L-asp treatment at the time of AP onset. The revised Atlanta criteria for AP requires two of the following three features: abdominal pain strongly suggestive of AP, serum amylase and/or lipase activity at least three times greater than the upper limit of normal, and characteristic findings of AP on transabdominal ultrasonography or contrast-enhanced CT [12]. We excluded patients who underwent ultrasonography only due to interobserver variability in ultrasonography. All abdominal CT scans were obtained within 72 hours of symptom onset. We also classified the patients into three CT severity groups (mild, moderate, and severe) using modified CT severity index (MCSI) by Mortele et al. (Table 1) and into two groups (low and high score) [13]. Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL TABLE 1
Modified CT Severity Index by Mortele et al. with Incidence in 16 Patients
Prognostic indicator
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Pancreatic inflammation Normal pancreas Intrinsic pancreatic abnormalities with inflammatory changes in the peri-pancreatic fat Pancreatic or peri-pancreatic fluid collection or peri-pancreatic fat necrosis Pancreatic necrosis None 30% Extra-pancreatic complications pleural effusion ascites vascular complications (venous thrombosis, arterial hemorrhage, or pseudoaneurysm formation) parenchymal complications (infarction, hemorrhage, or sub-capsular fluid collection) GI involvement (inflammation, perforation, or intramural fluid collection)
Score
Incidence in our 16 patients (%)
0 2
2 (12.5%) 4 (25%)
4
10 (62.5%)
0 2 4
11 (68.8%) 4 (25%) 1 (6.3%)
2
8 (50%) 12 (75%) 0 (0%) 1 (6.3%) 3 (18.8%)
4. Statistical Analysis Statistical analysis was performed using SPSS v.19.0 (IBM Corp., Armonk, NY, USA). A P value of less than .05 indicated statistical significance. Quantitative variables are expressed as mean ± SD, categorical variables as percentages. Continuous variables in mild versus moderate versus severe pancreatitis were compared by the Kruskal-Wallis test and the Mann-Whitney U test. RESULTS Twenty-three patients developed AP after L-asp treatment for 5 years. But, four patients underwent ultrasonography only and three patients were lost to follow-up. Thus, 16 patients were included in the study (M:F = 9:7; mean age, 8.1 years [2–15 years]). L-AP generally occurred within the first few weeks (mean, 19 days; range, 3 to 60 days) of therapy. In 10 cases (62.5%), L-AP developed during the induction–remission treatment. All patients with L-AP presented with abdominal pain, and 14 patients (87.5%) also complained of nausea or vomiting. Table 2 shows the clinical parameters and CT findings of 16 patients with ALL who developed L-AP. Mean initial pancreatic enzymes levels during the first 24 to 48 hours after symptom onset were as follows: serum amylase, 550 IU/dL (range, 125–2650; normal 45–160) and serum lipase, 570 IU/dL (range, 21–4488 IU/dL; normal 13–60 IU/dL). The mean peak serum amylase level was 1127 IU/dL (range, 160–2810 IU/dL), and the mean peak serum lipase level was 1440 IU/dL (range, 86–4488 IU/dL). The mean amylase normalizing time was 8.3 days (range, 1–26 days). The amylase level was chosen for laboratory normalizing time because lipase levels required a longer time to become normalized during the follow-up period, and some patients discontinued follow-up examination because their symptoms improved before normalization of lipase levels. The clinical course of the patients is summarized in Table 3. Fifteen patients (93.8%) were managed with supportive therapy in NPO state and 12 patients (75%) received TPN with a mean administration time of 9.5 days. IV narcotics were administered to eight patients (50%). One patient died of graft-versus-host disease and disseminated intravascular coagulation. No patients C Informa Healthcare USA, Inc. Copyright
H. J. Oh et al.
TABLE 2 Clinical Parameters and CT Findings of 16 Patients who Developed L-Asparaginase-Associated Pancreatitis with Acute Lymphoblastic Leukemia
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Number Laboratory Patient of L-asp Peak Peak normalizing number Sex Age dose amylase lipase time (days) BUN 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
F M M M M M F F F M F M M F M F
7 7 10 5 11 14 15 4 9 2 8 5 9 11 7 6
13 10 9 9 9 11 9 9 9 9 23 8 5 5 9 5
378 377 343 854 2650 1850 1417 926 1212 160 2810 2274 994 253 826 702
1245.2 600 2406 1096 4488 2994.7 1073.5 1035.4 1304.4 86.2 1929 2017.5 1434.5 119.5 474.1 736.4
10 12 8 – 11 26 7 9 6 1 7 13 4 1 2 8
CRP
14.5 0.71 14.3 1.74 4.6 0.37 97.1 190.59 28.3 210.11 28.2 10.18 28.2 13.16 20.0 4.47 23.6 5 19.5 ND∗ 41.1 4.68 29.8 6.79 28.5 16.53 16.6 0.21 6.9 0.15 20.8 10.13
Calcium MCSI 8.4 8.9 8.4 8.1 8.6 11.2 7.9 8.5 9 8.7 9.7 9.3 9.7 8.8 8.0 8.6
2 2 2 2 6 6 8 8 8 2 6 10 8 6 4 6
MCSI = Modified CT severity index Normal value; amylase (45–160 IU/dL), lipase (13–60 IU/dL), BUN (7–20 mg/dL), CRP (0–0.3 mg/dL), calcium (8–10 mg/dL) ∗ ND = not done – = not known because the patient expired
died due to direct complications of L-AP. After recovery from L-AP, no patients developed chronic pancreatitis or glucose intolerance. All contrast-enhanced CT were reviewed. On CT images, pancreatic abnormalities were seen in 14 patients (87.5%). Pleural effusion was observed in eight patients (50%), and ascites in 12 patients (75%). Pancreatic parenchymal necrosis was seen in five patients (31.3%) and infarction was observed in one patient (6.3%) (Table 1). Five patients (31.3%) were classified as having mild AP (mild AP group) (Figure 1), six patients (37.5%) as having moderate AP (moderate AP group) (Figure 2) and five patients (31.3%) as having severe AP (severe AP group) (Figure 3). The peak amylase level (P = .009) and use of IV narcotics (P = .014) were significantly different between the mild and severe AP groups, and use of IV narcotics (P = .029) was significantly different between the moderate and severe AP groups (Table 4). However, the number of L-asp doses, hospital stays, amylase normalizing time, and other clinical values associated with prognosis, such as CRP, calcium, and BUN,
TABLE 3 Clinical Course of Patients with L-Asparaginase-Associated Pancreatitis with Acute Lymphoblastic Leukemia (n = 16) Days in hospital (mean)
37.4 days
Treatment of pancreatitis NPO Days of NPO (mean) Nasogastric tube TPN∗ Days of TPN (mean) IV narcotics
15 (93.8%) 13.2 days 11(68.8%) 12 (75%) 9.5 days 8 (50%)
∗
TPN: Total parenteral nutrition Pediatric Hematology and Oncology
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L-Asparaginase-Associated Pancreatitis in ALL
FIGURE 1 L-asparaginase-associated pancreatitis. CT scan shows pancreatic swelling without parenchymal necrosis or extrapancreatic complication. MCSI score is 2 and it is classified as mild or low score group.
FIGURE 2 L-asparaginase-associated pancreatitis. CT scan shows pancreas swelling with peripancreatic fluid collection and ascites. MCSI score is 6. It is classified as moderate or high score group.
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FIGURE 3 L-sparaginase-associated pancreatitis. A, B. CT scan shows pancreas necrosis (>30%) with peripancreatic fluid collection, ascites, and bilateral pleural effusion. MCSI score is 8. It is classified as severe or high score group.
did not show significant difference between the mild and moderate AP groups and between the moderate and severe AP groups. Statistical significance of LDH, AST, blood glucose, and serum albumin could not be evaluated because these parameters were examined only in a few patients. We also divided the patients with L-AP into two groups according to MCSI [14]: those with an MCSI of 0–4 (low MCSI group) and those with an MCSI of 6–10 (high MCSI group). Six patients belonged to the low MCSI group, and 10 patients belonged Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL
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TABLE 4 Relation Between Three Groups by Modified CT Severity Index and Clinical Parameters Mild vs. Moderate
Moderate vs. Severe
Mild vs. Severe
0.201 0.100 0.100 0.584 0.462 0.460 0.361 0.593 0.637 0.465 0.565
0.201 0.465 0.855 0.855 0.917 0.190 0.522 0.927 0.029 0.855 0.562
0.465 0.251 0.009 0.465 0.221 0.751 0.117 0.539 0.014 0.754 0.060
Initial amylase Initial lipase Peak amylase Peak lipase CRP Calcium BUN Laboratory normalizing time IV narcotics Hospital day Number of L-asparaginase dose
Three groups by MCSI: Mild, 0∼2; Moderate, 4∼6; Severe, 8∼10 TABLE 5 Relation Between Two Groups (low and High Score) by Modified CT Severity Index and Clinical Parameters P value Initial amylase Initial lipase Peak amylase Peak lipase CRP Calcium BUN Laboratory normalizing time IV narcotics Hospital day Number of L-asp dose
0.448 0.233 0.013 0.193 0.258 0.583 0.039 0.902 0.046 0.914 0.263
Two groups by MCSI: low, 0–4; high, 6–10
to the high score group. The peak amylase level (P = .013), BUN level (P = .039), and use of IV narcotics (P = 0.046) were significantly more elevated in the high MCSI group (Table 5). The degree of pancreatic enzyme elevation did not correlate with other laboratory results or clinical parameters, such as CRP, calcium, hospitalization days, NPO time, or TPN duration. When we divided the patients into two groups according to Balthazar score, six patients were mild (Balthazar score A-C), 10 patients were severe. Initial lipase level was significantly more elevated in the severe group (mean ± SD, 843.01 ± 1344.85 IU/dL) rather than low group (mean ± SD, 113.78 ± 79.36) (P = .039). Other clinical parameters, including peak amylase level (P = .065), BUN level (P = .254), and use of IV narcotics (P = .317) were not significantly differenced. DISCUSSION L-asp has become an essential drug for the treatment of pediatric ALL since 1966 [1, 2]. The toxicities of L-asp are various. These include hypersensitivity reactions, central nervous system dysfunction, altered liver function, thrombosis, hypoinsulinemia with resulting hyperglycemia, severe hyperlipidemia, and pancreatitis [2–10]. One of the most serious adverse events of L-asp is AP, which is the most common reason for stopping treatment [2, 4, 7, 9]. Pathophysiologic mechanisms behind L-AP are still C Informa Healthcare USA, Inc. Copyright
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H. J. Oh et al.
unknown. However, the origin, formulation, dosage, or method of L-asp administration does not seem to influence the risk of L-AP [2, 4, 6, 7, 9]. L-AP is more common in older children or adolescents [7, 9, 15–17]. However, our study showed even distribution from the age of 2 years to 15 years. Other presenting characteristics factors are not known to be associated with the onset of pancreatitis [7]. The onset of pancreatitis was various, and more than 50% of patients occurred during the induction-remission treatment. In our study, 62.5% of patients developed L-AP during the induction-remission treatment, which is consistent with the results of previous studies indicating that L-AP occurred during early medication [4]. The total dose of L-asp is not related to pancreatitis. Therefore, AP seems to be a side effect caused by hypersensitivity reactions rather than dose-related or doseaccumulated reaction [6, 16, 18–21]. In our study, the dose of L-asp was not significantly different between the mild, moderate, and severe AP groups related to the CT severity group. There are several prognostic scoring systems of AP, including Ranson’s prognostic criteria, APACHE II, Glasgow criteria, and Balthazar’s criteria [22, 23]. Since Balthazar’s original system, numerous other morphological scoring systems have been proposed, each with their own flaws. Mortele et al. [13, 22] modified CT severity index on a 10-point scale, taking into account pancreatic inflammation, necrosis, and extra-pancreatic complications, which showed a stronger correlation between outcome and severity than the original. The severity of AP is determined to predict the prognosis of the disease [22, 23]. Parameters associated with the prognosis of pancreatitis have been reported to be age, white cell count, LDH, AST, blood glucose, serum calcium, BUN, serum albumin, and CRP [22, 23]. In one study, most patients showed mild and self-limited progression [4]. Our patients were evenly distributed in the three AP groups: five patients in the mild AP group, six patients in the moderate AP group, five patients in the severe AP group. The peak amylase level (P = .009) and dose of IV narcotics (P = .014) were significantly different between the mild and severe AP groups. When our patients were divided into 2 MCSI groups, the peak amylase level, BUN level, and use of IV narcotics were significantly higher in the high MCSI group. Amylase and lipase are usually elevated in AP, although the degree of elevation does not correlate with disease severity [24]. Thus, amylase and lipase are not included in prognostic factors. However, in our study, the peak amylase level correlated with MCSI. The dose of IV narcotics was significantly different between the three AP groups severity group. The CT grade is one of the factors that reflect the severity of the disease. Therefore, the higher the CT grade, the more severe and longer the clinical symptoms. It seems that IV narcotics may be frequently used in more severe AP groups. When using Balthazar grading system, only initial lipase was significantly different between the mild and severe groups. The original Balthazar grading and MCSI showed different clinical parameters that compare clinical relevance between the mild and severe group. However, it was difficult to determine which was better in predicting prognosis because of the limited sample size and no incidence of chronic complication. The results of this study are subject to some limitations of this study. First, this is a retrospective study. Several laboratory test results were not available. Second, we did not take into account the other causes of hospitalization. If patients had other concurrent diseases, their clinical outcome may have been different. Third, follow-up CT was not performed on patients who had pancreatic necrosis. However, laboratory findings and clinical symptoms were improved in our patients. In summary, the results of this study suggest that MCSI may be related to the peak amylase, BUN level and use of IV narcotics in ALL patients with L-AP. More research with a larger group of patients is needed to confirm our results.
Pediatric Hematology and Oncology
L-Asparaginase-Associated Pancreatitis in ALL
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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