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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 118-125

Tumor lysis syndrome in pediatric patients with hematological malignancies


Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia

Date of Submission22-Dec-2020
Date of Acceptance06-Oct-2021
Date of Web Publication15-Sep-2022

Correspondence Address:
Dr. Lamis Hani Elkhatib
Department of Pediatric Oncology and Hematology, King Faisal Specialist Hospital and Research Centre, P.O. Box 40047, Jeddah 21499
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_243_20

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  Abstract 

BACKGROUND: Tumor lysis syndrome (TLS) is a common complication of hematological malignancies and consists of either hyperkalemia, hyperphosphatemia, hyperuricemia, or hypocalcemia. These metabolic derangements may result in clinical tumor lysis syndrome in the form of acute kidney injury (AKI), arrhythmias, seizures, and sudden death.
OBJECTIVES: This study was conducted to determine the incidence and outcome of TLS and to identify local risk factors in children with hematological malignancies.
PATIENTS AND METHODS: This was a retrospective chart review of children ≤18 years diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia, or non-Hodgkin lymphoma between 2014 and 2018. TLS was diagnosed and stratified according to the risk of developing tumor lysis using the Cairo and Bishop definition and Cairo stratification.
RESULTS: Among 180 patients, only 11 patients (6%) developed TLS. Four patients had laboratory TLS (LTLS) (36.3%) and six had CLTS (54.5%). The male-to-female ratio was high (2.4:1 in the TLS group). Hyperphosphatemia and hypocalcemia were the most frequently occurring criteria for LTLS (81.8%). The strongest predictors for TLS were hyperuricemia and hypocalcemia at presentation (P < 0.001) followed by diagnosis of T-cell ALL, preceding AKI splenomegaly, high initial white blood cell, and lactate dehydrogenase, with P < 0.05. AKI secondary to tumor lysis occurred in six patients (54.5%), of which five needed dialysis. One patient had seizures secondary to tumor lysis (9.1%) and no patient died from TLS.
CONCLUSION: There is a wide variation in reported incidence of TLS from 6% to 45%, likely due to different TLS definitions applied, diverse cohorts and duration. A universal definition and risk-stratified approach to prevent tumor lysis in patients with hematologic malignancies is needed to help in proper comparison between studies.

Keywords: Pediatric hematological malignancies, Saudi Arabia, tumor lysis syndrome


How to cite this article:
Elkhatib LH, Bayoumy MS, Ahmed AM, Alam MM, Abosoudah IF, Altrabolsi HA. Tumor lysis syndrome in pediatric patients with hematological malignancies. J Appl Hematol 2022;13:118-25

How to cite this URL:
Elkhatib LH, Bayoumy MS, Ahmed AM, Alam MM, Abosoudah IF, Altrabolsi HA. Tumor lysis syndrome in pediatric patients with hematological malignancies. J Appl Hematol [serial online] 2022 [cited 2022 Oct 7];13:118-25. Available from: https://www.jahjournal.org/text.asp?2022/13/3/118/356092


  Introduction Top


Advances in treatment have brought hope for pediatric hematology patients. However, treatment-related complications still remain a challenge. Tumor lysis syndrome (TLS) is a well-known oncological emergency; if not addressed and treated early, it may lead to significant morbidity and mortality. TLS was first described in 1929 by Bedrna and Polcák.[1] It constitutes the following metabolic derangements, hyperuricemia, hyperphosphatemia hyperkalemia, and hypocalcemia, that result from the breakdown of highly proliferative and large tumors including hematological malignancies such as acute leukemias and large non-Hodgkin lymphomas (NHLs). It may also occur in bulky solid tumors, however, it is uncommon in pediatric patients. TLS may be spontaneous or following chemotherapy initiation.[2],[3],[4] Acute kidney injury (AKI) may occur in hematological malignancies at presentation due to renal infiltration by disease, infections, and volume depletion.[5] Pretreatment AKI may aggravate the development of TLS. Early identification of high-risk patients and initiation of prophylactic measures decreases the frequency and severity of TLS and will therefore improve outcomes.

The objectives of this study were to describe the prevalence of TLS the baseline characteristic of TLS and outcomes; to study the predictors of tumor lysis and to assess the efficacy of prophylactic and therapeutic measures used at our center; and to assess the sensitivity of a risk stratification tool developed by Cairo and Bishop that can later be implemented to identify patients that could be at low risk but are subjected unnecessarily to additional monitoring and laboratory investigations.


  Patients and Methods Top


A retrospective chart review of 180 patients was conducted at King Faisal Specialist Hospital and Research Centre (KFSH and RC), Jeddah, Saudi Arabia, from 2006 to 2018. Inclusion criteria included treatment-naïve patients aged 18 years and younger with a confirmed diagnosis of acute leukemia and NHL during the period 2006–2018, whereas patients with relapse and/or referred after initiating chemotherapy were excluded from the study. The study proposal was reviewed and approved by the institution review board at KFSH and RC IRB (Study # 2018-37).

For diagnosis of TLS, the Cairo and Bishop scoring system was adopted [Table 1].[6] The patients were then risk stratified according to the recommendations by expert panel consensus by Cairo et al. summarized in [Table 2].[7]
Table 1: Definitions of laboratory and clinical tumor lysis syndrome[6]

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Table 2: Patient risk stratification[7]

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Definitions

Hyperkalemia was defined potassium >5.5 mmol/L, hyperphosphatemia phosphate >1.9 mmol/L, hypocalcemia calcium <2.0 mmol/L, hyperuricemia uric acid > 416.5 umol/L, blood urea nitrogen and serum creatinine more than institutionally sex/age - defined upper limit of normal. The CTCAE v4.0 was used for pretreatment and postchemotherapy AKI.

Hepatomegaly was defined as liver more than 3 cm on palpation or documented by ultrasonography. Splenomegaly was defined as spleen palpable more than 2 cm below costal margin or reported by ultrasonography.

Treatment

Almost all patients received intensive hydration 3000 ml/m2/24 h and allopurinol 10 mg/kg/day with close monitoring once they were admitted. Patients with high-risk features for tumor lysis received rasburicase either prophylactically or as a second line.

Acute leukemias were diagnosed by bone marrow biopsy and aspiration, and classified according to immunohistochemistry and flow cytometry. NHL was diagnosed by biopsy and immunohistostaining. The murphy staging system was used as it is the most widely used schema for childhood NHL.

Patients with acute lymphoblastic leukemia (ALL) were treated with either 3 or 4 drug induction according to risk as per the Children's Oncology Group protocols including vincristine, daunorubicin, asparaginase, and prednisolone or dexamethasone. All patients with acute myeloid leukemia (AML) received daunorubicin, cytarabine, and etoposide except acute promyelocytic leukemia received all-trans-retinoic acid with or without idarubicin according to risk. NHL patients received cyclophosphamide, vincristine, and prednisolone for induction with or without rituximab.

Laboratory investigations were collected during a period that was previously defined as high risk for TLS that is starting from the day of presentation to the day of starting chemotherapy (day 0), and for 7 days postchemotherapy (day 7). If more than one result was there for the same day, the highest value was recorded for serum potassium, phosphate, creatinine, and uric acid, whereas the lowest value was recorded for serum calcium. Serum calcium was not corrected for hypoalbuminemia to maintain consistency with other studies.

The outcomes of interest were treatment received for tumor lysis such as phosphate binders (aluminum hydroxide and sevelamer hydrochloride), Hyperkalemia threatment (sodium polystyrene sulfonate, insulin, and salbutamol), and intravenous calcium for hypocalcemia. Requirment of PICU admission, dialysis, and development of acute kidney injury, arrhythmias, seizures, and sudden death were also recorded.

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences, version 21.0 (SPSS, Chicago, IL, USA). Baseline characteristics and demographic data were described using frequencies and percentages for categorical values. Univariate analysis was performed using the Student's t-test for unequal sample sizes, and P < 0.05 was considered to be statistically significant.


  Results Top


A total of 180 patients were included in the study, out of which 106 were male and 74 were female. ALL was the most frequent diagnosis 72.2%, whereas AML was 17.2% and NHL was the least frequent 10.5%. The mean age at diagnosis was 6.4 years, with a median age of 5.47 (range: 4 months–18 years). As per Cairo tumor lysis risk classification [Table 2], 11.1% were low risk, 52.8% were intermediate risk, and 36.1% were high risk. AKI was present in 6 (3.3%) of all patients at admission, with Stage 2 being the most frequent stage. The most common metabolic derangement at presentation was hyperphosphatemia seen in 24 patients (13.3%) and hyperuricemia in 16 patients (9%). Hyperkalemia was the least with 5 patients (2.7%). [Table 2], [Table 3], [Table 4] further describe patients according to diagnosis.
Table 3: Clinical characteristics of study population

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Table 4: Clinical characteristics of acute lymphoblastic leukemia patients

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Tumor lysis occurred in 11 patients (6.1%), out of which 4 (36.4%) had only laboratory tumor lysis and 6 (54.5%) had clinical tumor lysis syndrome (CTLS). One (9.1%) patient met all four criteria for laboratory tumor lysis, six (54.5%) met three criteria, and four (36.4%) met two criteria.

The most frequent criteria for laboratory TLS were hyperphosphatemia and hypocalcemia (9 patients, 81.8%), and the least frequent was hyperkalemia (5 patients, 45.4%). For CTLS, five patients had one criterion that is rising creatinine. One patient had two criteria rising creatinine and seizures. Spontaneous tumor lysis, i.e., before initiation of chemotherapy, occurred in five patients (45.5%), with an average duration of onset 1.8 days before chemotherapy. Six patients (54.5%) developed tumor lysis after initiation of chemotherapy with an average time of onset of 1.3 days, out of which one patient had tumor lysis on the same day of starting chemotherapy.

For hyperphosphatemia and hypocalcemia, five patients received sevelamer and one patient received calcium chloride. For hyperkalemia, five patients received albuterol nebulization, six received sodium polystyrene, eight received Lasix, and five received insulin.

PICU admission was needed for seven patients (63.6%), four patients were admitted for leukocytosis with TLS, two patients for respiratory distress and TLS, and one patient was admitted for AKI for dialysis.

Regarding outcome, out of 11 patients, 6 developed AKI (54.5%), of which 5 needed dialysis (45.5%). One patient (9.1%) had seizures. No patient died from tumor lysis.

However, two patients died from septic shock and multi-organ failure.


  Discussion Top


Lack of universal definitions for diagnosis of tumor lysis made analysis of different studies difficult because of the inconsistent diagnostic criteria applied. The reported incidence of TLS in studies varied. Tony H Truong et al. studied 328 patients with ALL aged ≤18 years between 1998 and 2004 at a hospital for sick children in Toronto. Twenty-three percent met TLS criteria. Factors that significantly predicted tumor lysis (P < 0.0001) were age >10 years, splenomegaly, mediastinal mass, T-cell phenotype lactate dehydrogenase (LDH) ≥2000, and white blood cell (WBC) ≥20,000.[8] In another large study by Wössmann et al. from Germany, the incidence and complications of TLS in children with Burkitt's lymphoma/leukemia who were enrolled in the multicenter NHL BFM 90 and 95 studies were analyzed, and out of the total 1791 children, 78 children developed TLS (4%).[9]

Ahn et al., used Cairo and Bishop definition to diagnose TLS in 396 Korean patients aged <20 years with a median age of 6.9 years. Out of them cases of ALL, AML and NHL were 50%, 25% and 26% respectively. The Cairo and Bishop definition was used to diagnose TLS. Tumor lysis occurred in 68 patients (17.2%), laboratory TLS in 32 (47%), and CTLS in 36 patients (53%). 42.6% of the patients who developed tumor lysis required dialysis. Out of those who developed tumor lysis, 70.6% were high risk, whereas 27.7% were high risk in those who did not develop TLS.[10] In a study by Sevinir et al. in Turkey from December 1997 to January 2007, 327 newly diagnosed patients were included, of which 35% were NHL and 65% ALL. The mean age at the time of diagnosis was 6.2 years. Among the patients with NHL, 68% had B-cell, 28% had lymphoblastic, and 4% had anaplastic large cell lymphoma. With regard to disease stage, 2.7% were Stage II, 77% were Stage III, and 20.3% had Stage III disease. The Cairo and bishop scoring system was used. Tumor lysis incidence was 5.8% (19 patients). Laboratory tumor lysis was seen in 26.3% of the TLS patients and CTLS in 73.7%.[11] In Egypt, a study by Abdel Baset et al. included 60 patients diagnosed with ALL aged ≤18 years and 27 patients developed TLS (45%). The strongest predictors for TLS were high WBC count >20,000 at presentation, initial LDH ≥1000, T-cell immunophenotyping (P = 0.0002), and splenomegaly (P = 0.008).[12]

Al Bagshi et al. in Riyadh studied 398 patients <14 years of age diagnosed with ALL between January 2000 and December 2005. They used the Hande and Garrow definitions for TLS and 74 patients met the criteria (19%). The male-to-female ratio in the TLS group was similar to our study 2.4:1 (P = 0.005). Lymphomatous presentation, male sex, high WBC >50,000 prior to treatment, and central nervous system involvement were significant risk factors for development of TLS. Hyperphosphatemia was the most frequent metabolic derangement occurring in 95% of the patients. Hemodialysis was needed in 8% of the patients.[13]

Our overall incidence of TLS is 6.1%, which is similar to previously reported incidence of TLS between 5% and 45%. We believe it reflects a cautionary approach in our institutional setting in an attempt to preemptively treat any accompanying complications to reduce morbidity. It may be also due to growing awareness of TLS and starting patients with prophylactic hydration and allopurinol at referring centers. The variation in incidence reported in the literature is secondary to variation in the types of cancers, different responses to treatment, different prophylactic measurements, and study duration.

Regarding our study population, pediatric patients represented 92% of the study population and adolescent-aged patients were only 7.8%. The maximum age in the tumor lysis group was 13.6 years. In ALL patients, four out of the eight patients with tumor lysis were >10 years old at diagnosis. However, unlike what was reported by Abdel Baset et al. age >10 years in our study was not a significant predictor of TLS (P = 0.192).

We observed a high male-to-female ratio in TLS (2.6:1), however, it was not statistically significant (P = 0.324) as what was reported by Truong et al., Abdel-Baset et al., and Al Baghsi.[8],[12],[13]

In our study, we observed that the incidence of tumor lysis was higher in NHL patients, i.e., 10%, when compared to ALL (6%) and AML (3%). This is because the majority of NHL patients had a high risk to develop TLS, whereas the majority of ALL patients were intermediate risk and AML patients were low risk. Despite ALL having a lower incidence of TLS than NHL, T-cell phenotype was a significant predictor for tumor lysis by univariate analysis (P < 0.05). [Table 4], [Table 5], [Table 6] show the clinical characterisitics of each group.
Table 5: Clinical characteristics of acute myeloid leukemia patients

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Table 6: Clinical characteristics of non-Hodgkin's lymphoma patients

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Hyperuricemia (despite the availability of rasburicase) and hypocalcemia at presentation were the strongest predictors of tumor lysis (P < 0.001) in our study. [Table 7] shows the rest of predictors after univariate analysis.
Table 7: Predictors of tumor lysis syndrome by univariate analysis

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Pretreatment AKI was present in 50% of the patients with TLS and was a significant risk factor (P < 0.05) as concluded by Ahn et al. and Zhang et al.[10],[14]

Regarding risk stratification of patients, none of the low-risk patients developed TLS. Only one intermediate-risk patient out of 95 had tumor lysis. In the tumor lysis group, 90.1% were high risk versus 0.6% in the nontumor lysis group (P < 0.001). This helped us conclude that the risk stratification tool recommended by Cairo et al. is highly sensitive and effective. Adopting this tool can help reduce subjecting patients without high-risk feature to excessive blood sampling for monitoring.

We observed that the incidence of tumor lysis in patients prophylactically treated with rasburicase was lower (31%) than patients who received rasburicase as a second line after allopurinol (50%). This implies the lack of efficacy of delayed use of rasburicase in reducing tumor lysis.

For outcomes, our results were comparable to other studies. AKI secondary to TLS was reported as high as 63.6% by Darmon et al., whereas AKI in the absence of tumor lysis was 18.9%.[15] Another study by Khalil et al. observed an incidence of 64.3% of the patients that developed TLS had resultant AKI.[16] The difference of length of stay between TLS and non-TLS was not significant, with a median of 25 days in the TLS group and 15 days in the TLS absent group. This may be explained by difference in diagnosis and difference in protocols used.

The limitation of this study includes its retrospective nature. The small number of patients that had tumor lysis made multivariate analysis difficult. It was difficult to study the effect of initiating management at referring centers which may have played a role in the low occurrence of tumor lysis. The results should be confirmed in a multicentric cohort study using a universal definition and similar population to develop a clinical profile reliably detecting patients at risk of developing TLS.


  Conclusion Top


A high percentage of the study population were intermediate- and high-risk patients for developing TLS (88.8%), however, the incidence of TLS was low (6.1%). The reported incidences varied from 6% to 45%. This is due to different definitions of TLS used, different populations, and durations.

Our cohort may help serve as a baseline estimate for incidence of TLS in our region and may be used as a comparison group in the future.

Patients without high-risk features may be subjected to prophylactic measures and monitoring similar to those in high-risk features. Therefore, treatment of tumor lysis must be aimed at a risk-stratified approach to prevent its complications in patients with hematologic malignancies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bedrna J, Polcák J. Acute ureteral occlusion after radiation chronic leukemia with x-rays. Med Klin 1929;25:01.  Back to cited text no. 1
    
2.
Baeksgaard L, Sørensen JB. Acute tumor lysis syndrome in solid tumors – A case report and review of the literature. Cancer Chemother Pharmacol 2003;51:187-92.  Back to cited text no. 2
    
3.
Chang JE, Medlin SC, Kahl BS, Longo WL, Williams EC, Lionberger J, et al. Augmented and standard Berlin-Frankfurt-munster chemotherapy for treatment of adult acute lymphoblastic leukemia. Leuk Lymphoma 2008;49:2298-307.  Back to cited text no. 3
    
4.
Mirrakhimov AE, Voore P, Khan M, Ali AM. Tumor lysis syndrome: A clinical review. World J Crit Care Med 2015;4:130-8.  Back to cited text no. 4
    
5.
Rajendran A, Bansal D, Marwaha RK, Singhi SC. Tumor lysis syndrome. Indian J Pediatr 2013;80:50-4.  Back to cited text no. 5
    
6.
Cairo MS, Bishop M. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3-11.  Back to cited text no. 6
    
7.
Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: An expert TLS panel consensus. Br J Haematol 2010;149:578-86.  Back to cited text no. 7
    
8.
Truong TH, Beyene J, Hitzler J, Abla O, Maloney AM, Weitzman S, et al. Features at presentation predict children with acute lymphoblastic leukemia at low risk for tumor lysis syndrome. Cancer 2007;110:1832-9.  Back to cited text no. 8
    
9.
Wössmann W, Schrappe M, Meyer U, Zimmermann M, Reiter A. Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase. Ann Hematol 2003;82:160-5.  Back to cited text no. 9
    
10.
Ahn YH, Kang HJ, Shin HY, Ahn HS, Choi Y, Kang HG. Tumour lysis syndrome in children: Experience of last decade. Hematol Oncol 2011;29:196-201.  Back to cited text no. 10
    
11.
Sevinir B, Demirkaya M, Baytan B, Güneş AM. Hyperuricemia and tumor lysis syndrome in children with non-Hodgkin's lymphoma and acute lymphoblastic leukemia. Turk J Haematol 2011;28:52-9.  Back to cited text no. 11
    
12.
Abdel-Baset HA, Eldin EN, Eltayeb AA, Hussein AM. Clinical and laboratory approach for the identification of the risk for tumour lysis syndrome in children with acute lymphoblastic leukemia. Life Sci J 2012;9:189-95.  Back to cited text no. 12
    
13.
Al Bagshi M. Tumor lysis syndrome in children with acute leukemia: Incidence and outcome. J Appl Hematol 2013;4:100.  Back to cited text no. 13
    
14.
Zhang Q, Liu KQ, Liu BC, Zhou CL, Li W, Lin D, et al. Analysis of tumor lysis syndrome in 380 cases of acute leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2015;23:61-4.  Back to cited text no. 14
    
15.
Darmon M, Vincent F, Camous L, Canet E, Bonmati C, Braun T, et al. Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. Research Group in Respiratory Resuscitation and Onco-Hematology (GRRR_OH). Br J Haematol 2013;162:489-97.  Back to cited text no. 15
    
16.
Khalil MA, Latif H, Rehman A, Kashif WU, Awan S, Khalil Z, et al. Acute kidney injury in lymphoma: A single centre experience. Int J Nephrol 2014;2014:272961.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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