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Keywords:

  • predictive;
  • low risk;
  • tumor lysis syndrome;
  • children;
  • cancer;
  • leukemia

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

Tumor lysis syndrome (TLS) is a well-recognized complication of acute lymphoblastic leukemia (ALL). The ability to predict children at differing risk of TLS would be an early step toward risk-based approaches. The objectives of the current study were 1) to describe the prevalence and predictors of TLS in childhood ALL and 2) to develop a sensitive prediction rule to identify patients at lower risk of TLS.

METHODS.

Health records of children aged ≤18 years who were diagnosed with ALL between 1998 and 2004 were reviewed. TLS was defined by the presence of ≥2 laboratory abnormalities occurring in the time frame of interest. Predictors of TLS were determined using univariate and multiple logistic regression analyses.

RESULTS.

Among 328 patients, 23% met criteria for TLS. Factors predictive of TLS were male sex (odds ratio [OR], 1.8; P = .041), age ≥10 years (OR, 4.5; P < .0001), splenomegaly (OR, 3.3; P < .0001), mediastinal mass (OR, 12.2; P < .0001), T-cell phenotype (OR, 8.2; P < .0001), central nervous system involvement (OR, 2.8; P = .026), lactate dehydrogenase ≥2000 U/L (OR, 7.6; P < .0001), and white blood count (WBC) ≥20 × 109/L (OR, 4.7; P < .0001). Among variables that were available at presentation, multiple regression analysis identified age ≥10 years, splenomegaly, mediastinal mass, and initial WBC ≥20 × 109/L as independent predictors of TLS. When all 4 of those predictors were absent at presentation (n = 114 patients), the negative predictive value of developing TLS was 97%, with a sensitivity of 95%.

CONCLUSIONS.

Clinical and laboratory features at the time of presentation identified a group of children with ALL at low risk for TLS that may benefit from a risk-stratified approach directed at reduced TLS monitoring and prophylaxis. Cancer 2007. © 2007 American Cancer Society.

Tumor lysis syndrome (TLS) consists of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and may result in renal failure. It is well recognized that TLS occurs before or after the initiation of chemotherapy for malignancies, such as childhood acute lymphoblastic leukemia (ALL) and Burkitt lymphoma.1, 2 Standard preventative approaches to minimize this complication include hyperhydration, urine alkalization, xanthine oxidase inhibitors (allopurinol), and, more recently, recombinant urate oxidase.3–5

Previous studies focused primarily on identifying patients at increased risk of TLS for the purpose of selecting those who may benefit from increased laboratory monitoring or urate oxidase therapy.6–9 Risk factors have included presentation with a high initial white blood cell (WBC) count; evidence of large tumor burden (bulky disease, hepatosplenomegaly); high blood lactate dehydrogenase (LDH)10 or uric acid levels; pre-existing dehydration, oliguria, or renal failure9, 11, 12; and malignancies with high chemosensitivity.13, 14

However, the majority of children with newly diagnosed ALL who are treated with standard TLS prophylactic measures do not experience clinically significant laboratory abnormalities either before or shortly after chemotherapy.1 Yet patients without high-risk features may be subjected to prophylactic measures and monitoring similar to those used in patients with high-risk features.

With the long-term aim of a risk-stratified approach to the prevention of TLS, the objectives of the current study were 1) to describe the prevalence and predictors of TLS in childhood ALL and 2) to develop a sensitive prediction rule to identify patients who are at low risk for TLS.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Medical records from all children aged ≤18 years who were diagnosed with ALL between 1998 and 2004 at the Hospital for Sick Children in Toronto, Canada, were reviewed. We included all patients with ALL but excluded those with 1) French-American-British (FAB) classification L3 ALL, 2) patients who were treated initially at another institution, 3) patients who were transferred to another institution within the time frame of interest (from the date of presentation to the seventh day after initiation of chemotherapy), and 4) patients who did not receive initial ALL therapy.

There were 342 children diagnosed with ALL during the study period. Fourteen patients were excluded for the following reasons: 6 patients had FAB L3 morphology, 5 patients were diagnosed at another center before arrival at our institution, 1 patient was transferred to another institution during the time frame of interest, 1 patient received up-front palliative care because of an unrelated underlying medical condition, and medical records were missing for 1 child. In total, 328 patients met inclusion criteria and were reviewed. This study was approved by the Research Ethics Board at the Hospital for Sick Children.

Outcomes Assessed

The primary outcome was the development of laboratory TLS, which was defined as the occurrence of any 2 or more of the following 5 laboratory abnormalities during the time frame of interest: hyperkalemia (potassium ≥5.5 mmol/L), hyperphosphatemia (phosphate ≥2.26 mmol/L), hypocalcemia (calcium ≤2.0 mmol/L), hyperuricemia (uric acid ≥475 μmol/L), and azotemia (creatinine ≥1.5 times the age-defined upper limit of normal). Our institutionally defined upper limit of normal of creatinine for both sexes, by specific age groups, were: ages 7 to 60 days, 66 μmol/L; ages 2 months to 5 years, 44 μmol/L; ages 6 to 9 years, 62 μmol/L; ages 10 to 13 years, 90 μmol/L; aged >14 years, 100 μmol/L. Laboratory data were collected during the time frame of interest, starting from the date of presentation, through to the day of chemotherapy initiation (Day 0), and for each of the following 7 days (Day +7), a time frame that previously defined a higher risk for TLS.3 This laboratory definition was modified from previously published definitions of TLS3, 11, 15, 16 to be more inclusive for the purpose of the current study. Because our focus was on identifying a low-risk subset, we purposefully wanted to ensure that our definition maximized sensitivity and minimized false-negative results. We did not examine clinical TLS (seizures, arrhythmia, dialysis, or death) as a separate endpoint.

If multiple measurements for a given electrolyte were obtained on the same day, then the highest daily value was recorded for serum potassium, phosphate, creatinine, and uric acid; whereas the lowest daily value was recorded for serum calcium. To maintain consistency with previous studies, serum calcium was not corrected for hypoalbuminemia.

Other outcomes of interest were measures used in the prophylaxis or treatment of TLS, namely, the initial intravenous fluid hydration rate on admission to hospital; the duration of urine alkalinization; the administration of allopurinol, urate oxidase, phosphate binders (aluminum hydroxide, sevelamer hydrochloride), antihyperkalemic treatments (sodium polystyrene sulfonate, insulin, salbutamol), and intravenous calcium; and the need for leukopheresis and/or dialysis. The number of peripheral venipunctures before the insertion of a central venous line was recorded as a measure of the impact of TLS laboratory monitoring on each patient.

Potential Predictors Evaluated

The data collected at presentation on potential predictors of TLS included laboratory features, such as WBC and LDH, and clinical indicators of bulk disease, such as the presence of a mediastinal mass on chest radiographs, hepatomegaly (defined as a palpable liver ≥3 cm below the right costal margin), and splenomegaly (defined as a palpable spleen ≥2 cm below the left costal margin) as assessed by the physical examination on admission. These cutoff values were chosen a priori based on what were considered clinically reasonable limits for deciding whether it was clear that the liver or spleen was larger than normal. Other potential predictors examined were central nervous system (CNS) status at diagnosis and renal involvement by leukemia as inferred by renal enlargement on abdominal imaging studies, when available. A cutoff value for LDH of ≥2000 U/L was chosen, because that level represents an elevation at least 2 times the upper limit of normal for any age and sex and has been used in previous publications.3 The degrees of derangement of the initial serum potassium, phosphate, creatinine, uric acid, and calcium levels at presentation were not examined as potential predictors, because such an analysis would have been incorrect methodologically, in that those values would contribute toward the definition of the outcome (development of TLS).

The following induction chemotherapy protocols were in use during the study period for patients with precursor B-cell ALL: from 1998 to 1999, either Pediatric Oncology Group (POG) Protocol 9201, or 9605, or 9406 or our standard, institutional 3-drug (Protocol AB) or 4-drug (Protocol C) induction regimen17; and, from 2000 to 2004, the POG 9900 protocol series, which is divided into a 3-drug induction and a 4-drug induction. Patients with T-cell ALL received either Protocol C (4-drug induction) from 1998 to 1999 or Children's Oncology Group (COG) Protocol A5971, after August 2000. Patients with Infant ALL were treated according to POG 9407 (1998–2004). Protocols that contained a 3-drug induction during the first week of chemotherapy included POG 9201 and POG 9605 (daily prednisone; vincristine on Days 0 and 7; and L-asparaginase on Days 1, 4, and 7), Protocol AB (daily prednisone; vincristine on Days 0 and 7; and L-asparaginase on Days 1, 3, and 5), and the POG 9900 3-drug induction (daily dexamethasone; vincristine on Days 0 and 7; and pegylated asparaginase on Day 4, 5, or 6). Protocols that contained a 4-drug induction in the first week of chemotherapy included POG 9406 (daily prednisone; vincristine on Days 0 and 7; L-asparaginase on Days 1, 4, and 7; and daunomycin on Day 7), Protocol C (daily prednisone; vincristine on Days 0 and 7; daunomycin on Days 0 and 7; and L-asparaginase on Days 0, 3, 5, and 7), the POG 9900 4-drug induction (daily prednisone; vincristine on Days 0 and 7; daunomycin on Day 7; and L-asparaginase on Days 2, 4, and 7), COG A5971 (Regimen B1: daily prednisone; vincristine on Days 0 and 7; daunomycin on Days 0 and 7; and L-asparaginase on Days 3, 5, and 7), and POG 9407 (daily prednisone; vincristine on Day 0; daunomycin on Days 0 and 1; L-asparaginase on Days 3, 5, and 7; and cyclophosphamide on Days 2 and 3).

Statistical Analysis

Baseline characteristic and demographic data were described using frequencies and percentages for categorical variables and means ± standard deviation or interquartile range (IQR) for continuous variables. Potential predictors of TLS were determined using univariate logistic regression analyses. However, a clinically useful prediction rule to identify those at lower risk of TLS would incorporate factors available at presentation. Therefore, only this subset of factors was considered for the multiple logistic regression model. Factors that were associated with TLS at P < .1 were entered into a forward selection model.

All statistical analyses were performed using the SAS statistical program (SAS-PC, version 9.1; SAS Institute Inc., Cary, NC). All tests of significance were 2-sided, and statistical significance was defined as P < .05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

In total, 328 patients were included, and their demographics, clinical features, and induction chemotherapy protocols are shown in Table 1. TLS, which was defined as the presence of at least 2 laboratory abnormalities during the time frame of interest, occurred in 74 of 328 children (22.6%). The single laboratory abnormality encountered most often was hypocalcemia (148 of 328 patients; 45.1%), whereas the least frequent abnormality was azotemia (14 of 328 patients; 4.3%). The most common laboratory abnormality pair for TLS was hypocalcemia and hyperuricemia (40 of 328 patients; 12%), followed by concurrent abnormalities of calcium and phosphate (11%) (Table 2). The peak laboratory values of potassium, phosphate, uric acid, and creatinine as well as the nadir of calcium are shown in Table 3, which compares those laboratory values between patients with and without TLS. The day on which these peaks/nadirs occurred is shown relative to the day of chemotherapy initiation (Day 0) for both groups.

Table 1. Demographics of the Study Population
CharacteristicNo. of patients (%), N = 328
  • CNS indicates central nervous system.

  • *

    Protocols that contained a 4-drug induction regimen.

Male sex206 (62.8)
Acute lymphoblastic leukemia immunophenotype
 Precursor B-cell285 (86.9)
 T-cell38 (11.6)
 Other (biphenotypic)5 (1.5)
CNS-positive disease status21 (6.4)
Mediastinal mass26 (7.9)
Ward of admission
 Inpatient ward307 (93.6)
 Intensive care unit21 (6.4)
Induction chemotherapy protocol
 3-Drug induction171 (52.1)
 4-Drug induction136 (41.5)
 Children's Oncology Group protocol A5971*16 (4.9)
 Pediatric Oncology Group Protocol 9407*5 (1.5)
 Prednisone cytoreductive prophase9 (2.7)
Table 2. Prevalence of Laboratory Abnormalities in Childhood Acute Lymphoblastic Leukemia From the Date of Presentation to 7 Days After Treatment
Laboratory parameter*No. of patients (%), N = 328
  • *

    Abnormal laboratory parameters were defined as follows: hyperkalemia, serum potassium ≥5.5 mmol/L; hypocalcemia, serum calcium ≤2.0 mmol/L; hyperphosphatemia, serum phosphate ≥2.26 mmol/L; hyperuricemia, serum uric acid ≥475 μmol/L; azotemia, serum creatinine ≥1.5 times the age-defined upper limit of normal.

Hypocalcemia148 (45.1)
Hyperuricemia54 (16.5)
Hyperphosphatemia52 (15.9)
Hyperkalemia33 (10.1)
Azotemia14 (4.3)
Hypocalcemia and hyperuricemia40 (12.2)
Hypocalcemia and hyperphosphatemia35 (10.7)
Hyperphosphatemia and hyperuricemia26 (7.9)
Hyperkalemia and hypocalcemia22 (6.7)
Hyperkalemia and hyperuricemia13 (4)
Hyperkalemia and hyperphosphatemia12 (3.7)
Hypocalcemia and azotemia10 (3)
Hyperphosphatemia and azotemia8 (2.4)
Hyperuricemia and azotemia5 (1.5)
Hyperkalemia and azotemia2 (0.6)
Table 3. Peak or Nadir of Laboratory Abnormality and Time Relative to Chemotherapy Initiation: Comparison of Patients With and Without Tumor Lysis Syndrome
Laboratory parameterTLS absent, N = 254TLS present, N = 74P
Mean95% CIMean95% CI
  • TLS indicates tumor lysis syndrome; 95% CI, 95% confidence interval.

  • *

    Mean days are expressed relative to chemotherapy initiation (Day 0). A negative value refers to day(s) prior to chemotherapy initiation.

Potassium peak, mmol/L4.764.72–4.805.285.15–5.41<.0001
Phosphate peak, mmol/L1.921.89–1.942.492.33–2.64<.0001
Calcium nadir, mmol/L2.042.02–2.061.771.71–1.84<.0001
Uric acid peak, μmol/L288275.6–300.4533.5464.6–602.5<.0001
Creatinine peak, μmol/L51.649.7–53.490.165.6–114.8.003
Mean d to potassium peak*2.452.12–2.792.271.73–2.81.6
Mean d to phosphate peak*0.660.42–0.911.140.79–1.48.03
Mean d to calcium nadir*2.482.15–2.822.21.75–2.66.33
Mean d to uric acid peak*−0.98−1.35 to −0.62−1.58−1.92 to −1.25.02
Mean d to creatinine peak*−0.13−0.44 to 0.190−0.55 to 0.55.71

Factors that were associated with TLS in univariate logistic regression analyses are shown in Table 4. Mediastinal mass was the strongest predictor of TLS (odds ratio [OR], 12.2; 95% confidence interval; [95% CI], 4.9–30.4; P < .0001) and was identified in 58% of children with T-cell ALL (22 of 38 patients) compared with 1.4% of children with precursor B-cell ALL (4 of 290 patients). Of these potential predictors, only those risk factors that were available immediately at the time of presentation were entered into a multiple regression analysis. Thus, CNS status and status of leukemic renal involvement were not entered, because these potential predictors generally are not known until several hours or days after presentation. The initial LDH value was a strong predictor of TLS (OR, 7.6; P < .0001); however, because only 33 LDH samples were determined on the day of presentation to hospital, this variable could not be included in the multiple regression analysis. Of the remaining 7 variables (sex, age, WBC, mediastinal mass, hepatomegaly, splenomegaly, and T-cell immunophenotype), 4 variables were identified in multiple regression as independent predictors of TLS: age ≥10 years (adjusted OR, 5.1; 95% confidence interval, 2.6–10; P < .0001), splenomegaly (adjusted OR, 2.5; 95% CI, 1.3–4.6; P = .005), mediastinal mass (adjusted OR, 6; 95% CI, 2.2–16.6; P = .0005), and initial WBC ≥20 × 109/L (adjusted OR, 3.7; 95% CI, 2–7.1; P < .0001). Two-thirds of all patients (214 of 328 patients; 65%) had 1 or more of these 4 independent predictors of TLS at presentation; and of these, 70 of 214 patients (33%) developed TLS.

Table 4. Predictors of Tumor Lysis Syndrome by Univariate Analysis
VariableNo. of patients (%)OR95% CIP*
TLS present (N = 74)TLS absent (N = 254)
  • TLS indicates tumor lysis syndrome; OR, odds ratio; 95% CI, 95% confidence interval; WBC, white blood count; LDH, lactate dehydrogenase; CNS, central nervous system.

  • *

    P value from univariate logistic regression analyses.

  • Initial LDH was defined as the first level obtained within 3 days of admission (N = 237).

  • Inferred from abdominal ultrasound as enlargement of the kidneys (ultrasound studies were obtained only when clinically indicated; N = 37).

Male sex54 (73)152 (59.8)1.81–3.2.041
Age ≥10 y32 (43.2)37 (14.6)4.52.5–8<.0001
Splenomegaly48 (64.9)91 (35.8)3.31.9–5.7<.0001
Hepatomegaly38 (51.4)95 (37.4)1.81–3.033
Mediastinal mass19 (25.7)7 (2.8)12.24.9–30.4<.0001
Initial WBC ≥20×109/L49 (66.2)75 (29.5)4.72.7–8.1<.0001
Initial LDH ≥2000 U/L43 (58.1)44 (17.3)7.64–14.7<.0001
T-cell immunophenotype24 (32.4)14 (5.5)8.24–17<.0001
CNS-positive disease9 (12.2)12 (4.7)2.81.1–6.9.026
Renal involvement11 (14.9)4 (1.6)10.93.4–35.4<.0001

The absence of all 4 predictors of TLS was used to define a group at low risk of developing TLS (the low-risk TLS group). Of those who fulfilled low-risk TLS criteria, 110 of 114 patients did not develop TLS, resulting in a negative predictive value of 96.5% (95% CI, 91.3–98.6%) and a sensitivity of 94.6% (95% CI, 87–98%). However, within this low-risk group, 4 of 114 patients (3.5%) also met our definition for TLS. One of these 4 patients met criteria for TLS, because this child presented with septic shock related to streptococcal bacteremia and subsequently developed renal failure and required dialysis. The remaining 3 patients had only mild perturbations in potassium, phosphate, and/or calcium that did not require significant interventions beyond the prophylactic use of phosphate lowering agents, increased hydration, and increased laboratory monitoring.

A further analysis was done to refine our primary definition of TLS to include only those patients who had TLS laboratory abnormalities occurring within any 48-hour time frame. In total, 54 patients (16.5%) met this stricter definition of TLS. Multiple regression analysis indicated that the same 4 factors remained independent predictors of the stricter definition of TLS: age ≥10 years (adjusted OR, 3.4; 95% CI, 1.6–7.2; P = .002), splenomegaly (adjusted OR, 2.8; 95% CI, 1.4–5.6; P = .003), mediastinal mass (adjusted OR, 3.7; 95% CI, 1.4–9.7; P = .0001), and initial WBC ≥20 × 109/L (adjusted OR, 5.1; 95% CI, 2.4–10.8; P < .0001). Of those who fulfilled the low risk of TLS criteria, 112 of 114 patients did not develop TLS according to the more strict definition, resulting in a slightly improved negative predictive value of 98.2% (95% CI, 93.8–99.5) and a sensitivity of 96.3% (95% CI, 87.5–99).

The extremes of laboratory abnormalities and the day of the extreme value relative to chemotherapy initiation are shown in Table 5 according to those at low risk (n = 114 patients) and those not at low risk (n = 214 patients) for TLS. Overall, most laboratory abnormalities occurred within 3 days after the initiation of chemotherapy. Those in the low-risk TLS group had milder laboratory abnormalities compared with the nonlow-risk group. Generally, the laboratory abnormalities occurred later in the low-risk group compared with those in the nonlow-risk group.

Table 5. Peak or Nadir of Laboratory Abnormality and Time Relative to Chemotherapy Initiation: Comparison of Patients at Low Risk Versus Patients Not at Low Risk of Tumor Lysis Syndrome
Laboratory parameterAt low risk of TLS, N = 114Not at low risk of TLS, N = 214P
Mean95% CIMean95% CI
  • TLS indicates tumor lysis syndrome; 95% CI, confidence interval.

  • *

    Mean days are expressed relative to chemotherapy initiation (Day 0). A negative value refers to day(s) prior to chemotherapy initiation.

Potassium peak, mmol/L4.744.68–4.814.954.88–5.01<.0001
Phosphate peak, mmol/L1.951.90–22.12.03–2.16.001
Calcium nadir, mmol/L2.072.04–2.101.931.90–1.96<.0001
Uric acid peak, μmol/L267.8247.0–288.6383.7354.4–412.9<.0001
Creatinine peak, μmol/L49.146.2–5266.257.4–75.1.0003
Mean d to potassium peak*2.471.91–3.042.382.06–2.70.77
Mean d to phosphate peak*0.390.03–0.750.970.73–1.22.007
Mean d to calcium nadir*2.712.16–3.262.271.95–2.58.17
Mean d to uric acid peak*−0.82−1.45 to −0.18−1.3−1.58 to −0.98.19
Mean d to creatinine peak*0.14−0.38 to 0.66−0.22−0.54 to 0.09.24

Hyperkalemia ≥6.0 mmol/L occurred in 11 of 328 patients (3.4%) during the time frame of interest, all of whom also met both the conventional and more strict definitions of TLS. Reassuringly, none of these patients satisfied our prediction rule criteria for the low-risk TLS group.

Measures taken to prevent TLS are presented in Table 6. Leukopheresis was used at diagnosis for an extremely high initial WBC in 11 patients. Three patients required renal dialysis; 2 for acute renal failure secondary to TLS and 1 because of overwhelming sepsis.

Table 6. Use of Prophylactic Measures and Interventions for Tumor Lysis Syndrome: Comparison of Patients at Low Risk Versus Patients Not at Low Risk for Tumor Lysis Syndrome
TLS prophylactic or interventional measureNo. of patients (%)P
At low risk of tls, N = 114Not at low risk of TLS, N = 214
  • TLS indicates tumor lysis syndrome; SD, standard deviation.

  • *

    Patients who required leukopheresis included 5 patients with precursor B-cell acute lymphoblastic leukemia (ALL), 5 patients with T-cell ALL, and 1 patient with mixed-lineage ALL.

  • Patients who required dialysis included 2 patients with T-cell ALL and 1 patient with precursor B-cell ALL.

Initial intravenous fluid hydration rate, cc/m2/h, mean ± SD94 ± 27.8122.1 ± 50.2<.0001
D of urine alkalinization, mean ± SD5.9 ± 2.36.2 ± 2.6.41
D of allopurinol, mean ± SD7 ± 1.97.3 ± 2.5.25
Use of urine alkalinization112 (98.2)207 (96.7).50
Allopurinol114 (100)208 (97.2).1
Urate oxidase0 (0)20 (9.3).002
Aluminum hydroxide16 (14)49 (22.9).08
Sevelamer hydrochloride011 (5.1).01
Sodium polystyrene sulfonate014 (6.5).003
Insulin01 (0.5)1.0
Intravenous calcium07 (3.3).1
Leukopheresis*011 (5.1).01
Dialysis1 (0.9)2 (0.9)1.0

The median number of times blood was drawn on the first, second, and third full day of hospitalization was 3 times (IQR, 2–3 times), 2 times (IQR, 1–3 times), and 2 times (IQR, 2–3 times), respectively. Central venous lines were placed an average of 7.2 days (IQR, 4–9 days) from the date of presentation (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

By using a very inclusive definition of TLS, we observed that the prevalence of TLS in children with ALL before and within 1 week of chemotherapy initiation was 23%. We used the absence of 4 independent risk factors at presentation (age ≥10 years, splenomegaly, mediastinal mass, and initial WBC ≥20 × 109/L) to develop a prediction rule for identifying those at low risk of TLS. In the absence of all 4 factors, there was a 97% probability that TLS would not occur; and, in our series, those cases that did occur (n = 4) were relatively mild, were identified early, and did not require significant interventions.

Although many studies have attempted to identify a group of children at high risk for TLS, we believe that the current study is important, because it is the first attempt to our knowledge to delineate a low-risk population. Our prediction rule is designed to be applied at the time of initial hospital presentation, thus enabling the early identification of a group of children at low risk for developing TLS who may be candidates for less intensive TLS monitoring and prophylactic interventions.

Generally, peripheral venipuncture is the only means of drawing blood until a central venous catheter can be inserted, which, at our institution, is accomplished on average 1 week from the date of presentation. Reducing the frequency of unnecessary laboratory monitoring would minimize trauma to young patients but should be considered only as long as reduced monitoring would not compromise the ability to detect TLS early enough to upgrade prophylactic measures or institute treatments. The use of urine alkalinization in an attempt to increase uric acid solubility remains controversial. Titration of sodium bicarbonate infusions to maintain a urine pH between 6.5 and 7.5 is a burden to nursing staff, whereas calcium-phosphate precipitation and subsequent nephrocalcinosis is more likely in alkali settings.4, 18 Furthermore, over-alkalinization may lead to precipitation of uric acid precursors, such as hypoxanthine or xanthine.5, 19, 20 Although urine alkalization still is considered the standard of care in many institutions and treatment protocols,21 the ability to stop this maneuver in a low-risk group of children would be beneficial. In addition, although it is demonstrably effective at lowering uric acid levels and eliminating the need for alkalinization, urate oxidase is very expensive; and the definition of a low-risk group would be valuable to help avoid that unnecessary expense and the rare but real risk of hemolysis in glucose-6-phosphate dehydrogenase-deficient patients. Our data indicate that clinicians indeed are identifying correctly those children at low risk of TLS, because none of these children received urate oxidase (Table 6), and the intensity of their prophylaxis/intervention was far less compared with the intensity for the group that was not at low risk of TLS. However, our findings may help to standardize this clinical gestalt and further reduce TLS preventative measures (such as alkalinization) and limit laboratory monitoring in the low-risk population.

Although our prediction model had a 97% negative predictive value, further predictive capability by the addition of the initial LDH value at presentation is conceivable. In our study, a small minority of patients had an LDH value obtained on the day of presentation (n = 33 patients); therefore, we could not incorporate this factor into a model that was intended for use at initial presentation. However, results from 237 LDH samples collected over the first 3 days after presentation indicated that LDH elevation is a very significant risk factor for TLS (OR, 7.6). Thus, future research may be focused on determining the additive value of this potential predictor of TLS.

The current study was limited, because the low-risk factors that we identified were demonstrated in the setting of standard TLS preventive measures. Although there is no guarantee that these same children would remain at low risk of TLS in the absence of measures like urine alkalinization, it seems to be a reasonable assumption, because some institutions have ceased using this intervention for children with ALL. Nonetheless, the current study provides a baseline estimate for TLS in a low-risk cohort that may be used as a comparison group in future research. We conclude that a group of children with ALL at who are at low risk for TLS can be identified at the time of hospital presentation and may benefit from reduced intensity of laboratory monitoring and limited TLS prophylactic measures.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Carol Winter, Olena Shatokhina, and Loreto Lecce for their assistance with data management and Camille Flynn for her assistance with data entry.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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