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Indian Pediatr 2018;55:877-879 |
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Incidence and Risk
Factors for Hypertension During Childhood Acute Lymphoblastic
Leukemia Therapy
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Payal Malhotra, Gauri Kapoor, Sandeep Jain and Bhawna
Garg
From Department of Pediatric Hematology Oncology,
Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India.
Correspondence to: Dr Gauri Kapoor, Director,
Department of Pediatric Hematology Oncology, Rajiv Gandhi Cancer
Institute and Research Centre, Rohini sector 5, Delhi 110 085, India.
Email: [email protected]
Received: October 23, 2017;
Initial Review: March 18, 2018;
Accepted: May 23, 2018.
Published online: July 13, 2018.
PII:S097475591600125
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Objective:
To determine the incidence of hypertension among children during the
induction and re-induction phases of acute lymphoblastic leukemia (ALL)
therapy and association with possible risk factors. Methods: A
retrospective analysis of 208 consecutive pediatric (age <18 y) ALL
patients, treated per BFM-95 protocol between January 2009 and December
2013. Data were analyzed to determine the incidence of hypertension and
risk factors for its development. Results: Incidence of
hypertension requiring antihypertensive medication, was 29% (61/208)
during induction and 17% (33/198) during re-induction (P=0.003).
Median (range) age of patients developing hypertension was 4 y (4 mo to
8 y). Age <10 y and presence of constipation were independently
predictive of hypertension by multivariate analysis. Conclusion:
The present study reports a high incidence of hypertension among
children undergoing ALL induction therapy.
Keywords: Blood pressure, Childhood cancers, Complications,
Treatment.
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A
cute lymphoblastic leukemia (ALL) is the
commonest childhood malignancy and has excellent cure rates with
contemporary treatment strategies [1,2]. Glucocorticoids form the
backbone of induction and re-induction phases of ALL therapy and
hypertension is an important though often under-reported
non-hematological toxicity associated with its use [3-9]. There are no
reports from India on the risk factors for developing hypertension are
not well understood. Hence, this study was undertaken to determine the
incidence of hypertension and its association with possible risk factors
among children receiving treatment for ALL.
Methods
This was a retrospective study of 208 newly diagnosed
ALL patients <18 years of age, diagnosed between January 2009 and
December 2013, in the pediatric hematology oncology department of a
tertiary care cancer center. Exclusion criteria included previously
treated patients or those with relapse, pre-existing kidney disease or
hypertension. All patients received a 4-drug induction with prednisolone,
vincristine, daunorubicin and L-aparaginase (BFM-95 protocol) [10]. The
study was approved by the Institutional Ethics Committee.
Data regarding hypertension were retrieved from the
electronic medical records by individually reviewing all inpatient and
outpatient notes and discharge summaries for documented blood pressure
readings, use of antihypertensive medications and mention of
hypertension. Patient demographics, disease and treatment details and
induction/re-induction toxicities such as hypertension, hyperglycemia,
constipation, thrombosis, hepatopathy, neuropathy, nephropathy, febrile
neutropenia and mucositis were noted and graded by Common Terminology
Criteria for Adverse Events (CTCAE 4.03) criteria [11].
Hypertension was defined as an average daily systolic
or diastolic blood pressure value >95th percentile for the subject’s
age, gender, and height. A minimum of 3 readings per day was used to
calculate the average daily blood pressure [12]. Constipation was
considered to be present if it was persistent despite regular use of
laxatives or enema (CTCAE grade 2) or more severe.
Statistical analyses: Risk factors were analyzed
by univariate and stepwise multivariate logistic regression analysis.
P value <0.05 was considered to be statistically significant. Data
was analysed using SPSS version 20.0.
Results
The data of 208 eligible patients were analyzed. The
median age was 6 years (0.5-18 years), 76% were male, 80% had B
immunophenotype and 56% had moderate risk disease. Incidence of
hypertension was 29%. Except for age and constipation, all clinical
characteristics and incidence of induction toxicities were comparable
among the hypertensive and non-hypertensive patients (Table I).
Constipation was observed to be in 46% (28/61) hypertensive and 13.6%
(20/147) non-hypertensive children (P <0.0001). Most patients
(54) with hypertension were asymptomatic; headache not attributable to
other causes was observed in 10% (6), and one patient had posterior
reversible encephalopathy (PRES). The median time to hypertension
detection was day 10 of induction (range, 3-25 days). All 61 patients
received at least one antihypertensive medication (amlodipine) while 11
children required two or more drugs (labetalol, enalapril). Among the
hypertensive patients, 51 became normotensive within one week of
cessation of prednisolone therapy (by day 40) and the rest by day 140.
Glucocorticoid therapy was continued in all patients regardless of
severity of hypertension.
TABLE I Characterstics of Children With Acute Lymphoblastic Leukemia During Induction Therapy
|
Characteristic |
HT present |
HT absent |
P |
|
n= 61 |
n=147 |
value |
|
Age (y)* |
4 (3-8) |
6 (3-12) |
<0.01 |
|
Age >10 y |
12 (17.7) |
56 (82.3) |
<0.01 |
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Male gender |
44 (27.7) |
115 (72.3) |
0.35 |
|
BMI Z-score <-2 |
32 (30.8) |
72 (69.2) |
0.70 |
|
Initial TLC (>105/5/µL ) |
14 (31.8) |
30 (68.2) |
0.68 |
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Deranged KFT |
20 (35.0) |
37 (65.0) |
0.26 |
|
Immunophenotype |
|
B immunophenotype |
48 (29.0) |
118 (71.0) |
|
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T immunophenotype |
13 (31.7) |
28 (68.3) |
0.76 |
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Biphenotype |
0 (0.0) |
1 (100.0) |
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Risk |
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High |
14 (28.6) |
35 (71.4) |
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Moderate |
32 (27.3) |
85 (72.7) |
0.59 |
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Standard |
15 (35.0) |
27 (65.0) |
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Toxicity |
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Hyperglycemia (grade ³2) |
6 (35) |
11 (65) |
0.57 |
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Hepatopathy (grade ³2) |
3 (33) |
6 (67) |
0.72 |
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Constipation (grade ³2) |
28 (58) |
20 (42) |
<0.001 |
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Thrombosis (CSVT) |
0 (0.0) |
4 (100.0) |
0.56 |
|
Mucositis (grade ³2) |
1 (25) |
3 (75) |
1.0 |
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FN requiring hospitalization |
16 (22) |
56 (78) |
0.1 |
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Induction mortality |
0 |
2 (100) |
0.9 |
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HT: Hypertension; BMI: Body mass index; TLC: Total leukocyte
count; KFT: Kidney function test (deranged defined as >1.5 times
upper limit of normal). FN: Febrile neutropenia, CSVT: Cerebral
sino-venous thrombosis; Values in number (%) except *median
(IQR). |
On multivariate analysis, the age at diagnosis (P=0.006)
and presence of constipation (P<0.0001) were independently
predictive of hypertension. Children
£10 years had 2.9
times increased odds of developing HT as compared to older children.
Logistic regression analysis revealed that with each one year increase
in age, the risk of HT decreased by 9%, excluding infants
£12 months of age (P=0.008).
It was further observed that the odds of developing HT, was 5.9 times
higher among patients with constipation.
TABLE II Risk Factors for Hypertension During Induction Therapy
|
Characteristic |
Odds ratio (95% CI) |
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Age >10 y |
0.40 (0.20, 0.81) |
|
0.34 (0.16, 0.74)* |
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Male gender |
0.72 (0.36, 1.43) |
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BMI Z-score <-2 to 2 |
0.89 (0.49, 1.62) |
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BMI Z-score >2 |
0.56 (0.06, 5.2) |
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Hyperleukocytosis |
1.16 (0.56, 2.3) |
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Deranged KFT |
1.45 (0.75, 2.78) |
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T Immunophenotype |
1.16 (0.55, 2.42) |
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Biphenotypic |
0.81 (0.01, 76.2) |
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Moderate BFM Risk |
0.94 (0.5, 1.97) |
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Standard BFM Risk |
1.39 (0.57, 3.36) |
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Febrile neutropenia |
0.58 (0.30, 1.12) |
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Mucositis (grade ≥2) |
2.46 (0.34, 17.8) |
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Hyperglycemia (grade ≥2) |
0.72 (0.23, 2.31) |
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Hepatopathy (grade ≥2) |
1.22 (0.29, 5.02) |
Constipation (grade ≥2)
|
5.39 (2.70, 10.7)
5.93 (2.89, 12.10)* |
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KFT: Kidney function test (deranged defined as >1.5 times upper
limit of normal), BMI: Body mass index, Hyperleucocytosis; WBC
>1×105/5/µL; *By multivariate analysis. |
During re-induction, the incidence of HT and
constipation were significantly lower than induction (17% vs 29%,
P<0.001 and 14% vs 30%, P=0.04, respectively).
Hypertension was observed among 12/33 patients for the first time during
re-induction.
Discussion
In this retrospective analysis we report a high
incidence (29%) of glucocorticoid-induced hypertension requiring
antihypertensive medication in children on ALL induction. This is in
accordance with published literature (13-67%) from across the globe
[3-9]. Differences in ethnicity, definition of hypertension, nutrition
status, dose of steroids and anti-leukemic therapy are the likely
reasons contributing to this diversity [3-9].
While hypertension is a known adverse effect of the
mineralocorticoid effect of steroids, leukemic infiltration of kidney,
impact of large sodium and fluid volumes as well as influence of anemia,
pain, and stress have also been implicated as contributory factors in
induction [4-7,13]. Resolution of these factors, and use of
dexamethasone which has relatively lesser mineralocorticoid potency may
explain lower incidence of hypertension during re-induction [14].
Two important risk factors for development of
steroid-induced hypertension were age less than 10 years and
constipation (grade ³2),
which have not been previously reported. Differences in prednisolone
clearance and sensitivity of hypothalamic-pituitary axis have been
postulated as possible mechanism for increased incidence of hypertension
in young children [3-7]. Constipation is one of the established adverse
effects of vincristine related autonomic neuropathy and often leads to
abdominal pain and straining. Influence of constipation on the incidence
and severity of hypertension needs prospective evaluation.
The main limitation of this study is the
retrospective design possibly lending to underestimation of the
incidence of hypertension.
Anticipation and appropriate management of both
hypertension and constipation are simple measures that may avoid
serious, though rare, complications and end-organ damage in a curable
condition like ALL. We suggest that regular blood pressure measurement
should be an important part of the physical examination of a child
undergoing induction/re-induction phases of ALL therapy.
Contributors: PM: retrieved, compiled and
analysed the data and drafted the manuscript; GK: study concept and
design, supervision of data analysis, critical revision and finalisation
of manuscript; SJ: Helped in data analysis and revision of manuscript;
BG: statistical analysis and interpretation of data. All authors
approved the final manuscript.
Funding: None; Competing interest: None
stated.
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What This Study Adds?
•
A high incidence of hypertension
(29%) was observed in Indian children undergoing ALL induction
therapy.
•
Age <10years and constipation were independent risk factors
for development of hypertension.
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References
1. Riehm H, Feickert HJ, Schrappe M, Henze G,
Schellong G. Therapy results in five ALL-BFM studies since 1970:
Implications of risk factors for prognosis. Haematol Blood Transfus. 1987;30:139-46.
2. Arora RS, Arora B. Acute leukemia in children: A
review of the current Indian data. South Asian J Cancer. 2016;5: 155-60.
3. Kamdem LK, Hamilton L, Cheng C, Liu W, Yang W,
Julie A, et al. Genetic predictors of glucocorticoid-induced
hypertension in children with acute lymphoblastic leukemia. Pharmacogenet
Genomics. 2008;18:507-14.
4. Louis CU, Butani L. High blood pressure and
hypertension in children with newly diagnosed acute leukemia and
lymphoma. Pediatr Nephrol. 2008;23:603-9.
5. Attard-Montalto SP, Saha V, Ng YY, Kingston JE,
Eden OB. High incidence of hypertension in children presenting with
acute lymphoblastic leukemia. Pediatr Hematol Oncol.1994;11:519-25.
6. Bakk I, O’Brien S, Reed S, Koch T. Steroid-induced
hypertension during induction chemotherapy for acute lymphoblastic
leukemia in US children’s hospitals. Blood. 2014;124:3651.
7. Bakk I, Koch T, Stanek J, O’Brien SH, Reed S.
Steroid-induced hypertension during induction chemotherapy for acute
lymphoblastic leukemia in us children’s hospitals. J Pediatr Hematol
Oncol. 2018;40:27-30.
8. Juliansen A, Andriastuti M, Sudung OP, Sekartini
R. Hypertension, high-dose corticosteroids, and renal infiltration in
children with acute lymphoblastic leukemia. Paediatrica Indonesiana.
2014;54:324-9.
9. Belgaumi AF, Al-Bakrah M, Al-Mahr M, Al-Jefri A,
Al-Musa A, Saleh M, et al. Dexamethasone-associated toxicity
during induction chemotherapy for childhood acute lymphoblastic leukemia
is augmented by concurrent use of daunomycin. Cancer. 2003;97:2898-903.
10. Möricke A, Reiter A, Zimmermann M, Gadner H,
Stanulla M, Dördelmann M, et al. Risk-adjusted therapy of acute
lymphoblastic leukemia can decrease treatment burden and improve
survival: Treatment results of 2169 unselected pediatric and adolescent
patients enrolled in the trial ALL-BFM 95. Blood. 2008;111:4477-89.
11. Common Terminology Criteria for Adverse Events
(CTCAE) Version 4.03: U.S. department of health and human services
National Institutes of Health National Cancer Institute. 2009 (v4.03:
2010).
12. Bagga A, Jain R, Vijayakumar M, Kanitkar M, Ali
U. Evaluation and management of hypertension. Indian Pediatr.
2007;44:103-21.
13. Olgar S, Yetgin S, Cetin M, Aras T. Can renal
leukemic infiltration cause hypertension in children. J Pediatr Hematol
Oncol. 2006;28:579-84.
14. Hill MR, Szefler SJ, Ball BD, Bartoszek
M, Brenner AM. Monitoring glucocorticoid therapy: A pharmacokinetic
approach. Clin Pharmacol Ther. 1990;48:390-8.
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