Introduction
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, accounting for approximately 25–30% of all pediatric cancers worldwide with survival rates now exceeding 85–90% in many centers[1]. However, this therapeutic success has simultaneously shifted attention toward treatment-related complications. While induction chemotherapy aims to achieve rapid cytoreduction and complete hematological remission, it exerts significant systemic effects that can predispose children to metabolic, renal and cardiovascular complications. Among these, arterial hypertension has emerged as a clinically significant and increasingly recognized adverse event during induction chemotherapy. Recent studies report that 15–40% of previously normotensive pediatric ALL patients develop elevated blood pressure requiring monitoring or pharmacologic intervention during induction chemotherapy [2]. Multiple mechanisms including high-dose corticosteroids induced increase in systemic vascular resistance, L-asparaginase–associated endothelial dysfunction and hypoalbuminemia exacerbating intravascular volume changes, tumor lysis syndrome (TLS), renal leukemic infiltration and sepsis can contribute to secondary hypertension during induction chemotherapy [3,4]. Acute severe hypertension may precipitate posterior reversible encephalopathy syndrome (PRES) and acute cardiac or renal dysfunction [5,6]. Importantly, childhood hypertension is a recognized predictor of adult hypertension and early vascular disease, raising concerns regarding long-term cardiovascular morbidity among survivors of pediatric ALL [7,8]. Demographic and baseline clinical characteristics such as age, body mass index, family history of hypertension, sex, constipation, coagulopathy, tumor lysis syndrome and bulky kidneys on ultrasound have been reported as predictors of hypertension during induction chemotherapy in pediatric ALL patients [911]. However, data from low- and middle-income countries remain limited and such data are particularly relevant in tertiary care centers in North-Eastern India, where regional epidemiologic characteristics may differ from Western cohorts. Therefore, the present study aims to evaluate the incidence of new-onset arterial hypertension in pediatric ALL patients during induction chemotherapy and to identify demographic as well as clinical factors associated with its development. By systematically evaluating blood pressure patterns during this critical treatment phase, the study seeks to contribute evidence that may improve early detection, guide management strategies and enhance overall treatment safety in pediatric ALL.
Material and Methods
Study Design and Setting
This retrospective and observational study was conducted at Dr. B. Borooah Cancer Institute, Guwahati, a tertiary care oncology center in North-Eastern India. The study period extended over 24 months, from July 2022 to July 2024.
Study population
Pediatric patients aged 1 to 19 years with newly diagnosed ALL who received induction chemotherapy at the Pediatric Oncology Unit of the institute during the study period were included. Only patients who were normotensive at baseline prior to initiation of chemotherapy were considered eligible. Patients with documented pre-existing hypertension and those with relapsed ALL were excluded from the analysis.
Sample Size
The sample size was calculated based on a previously reported prevalence of hypertension of 14.7% among pediatric ALL patients during induction therapy. With a confidence interval of 95% and a margin of error of 5%, the required sample size was estimated using the formula n = Z²pq/d². Substituting Z = 1.96, p = 0.147, q = 0.853, and d = 0.05, the calculated sample size was 194.65, which was rounded off to 195 participants. Accordingly, a total of 195 eligible patients were included in the study.
Treatment Protocol and Data Collection
All patients received induction chemotherapy as per the modified BFM 2002 protocol. Data were retrieved from medical records and documented in a structured data collection sheet prepared for the study. Baseline demographic details including age, sex, body mass index (BMI), and family history of hypertension along with clinical parameters such as immunophenotype, central nervous system(CNS)status, risk stratification category and treatment details were documented. Additional variables including presence of TLS and bulky kidneys on imaging were also recorded. For patients who developed hypertension, details regarding antihypertensive therapy, including the type of medication initiated, dose, need for additional agents, and duration of treatment, were documented.
Blood pressure measurement and Definition
Blood pressure measurements were recorded at baseline and during induction chemotherapy on days 1, 8, 15, and 30. Blood pressure was measured using an appropriately sized cuff covering approximately 80% of the arm circumference and 40% of the arm length. Measurements were obtained in the right arm with the child in a resting seated position. Oscillometric readings were confirmed by auscultatory measurement to ensure accuracy. Hypertension was defined according to the 2017 American Academy of Pediatrics Clinical Practice Guideline. For children younger than 13 years, blood pressure values at or above the 95th percentile for age, sex, and height were considered hypertensive. For adolescents aged 13 years or older, blood pressure of 130/80 mmHg or higher was classified as hypertension. Diagnosis required elevated readings on two separate occasions on the same day.
Outcome Measures
The primary outcome was the development of hypertension during induction chemotherapy. Secondary outcomes included timing of hypertension onset, associated clinical factors, antihypertensive therapy used, and occurrence of complications such as posterior reversible encephalopathy syndrome (PRES).
Statistical Analysis
Data were analyzed using SPSS version 29.0. Descriptive statistics were applied to summarize demographic and clinical characteristics. Continuous variables were expressed using mean and standard deviation, while categorical variables were presented as frequencies and percentages. Logistic regression analysis was performed to identify factors associated with development of hypertension during induction chemotherapy. Associations between categorical variables were assessed using the chi-square test, with statistical significance determined at a p-value of less than 0.05.
Ethical Considerations
The study protocol was reviewed and approved by the Institutional Ethics Committee of Dr. B. Borooah Cancer Institute prior to commencement of data collection.
Results
A total of 195 pediatric patients with newly diagnosed ALL who were normotensive at baseline and received induction chemotherapy were included in the analysis.
Baseline Characteristics
The baseline demographic and clinical characteristics of the study population (N = 195) are summarized in Table-1.
| Variable | Frequency (N=195) | Percentage (%) |
| Age Group | ||
| 1–12 years | 142 | 72.8 |
| 13–14 years | 19 | 9.7 |
| 15–16 years | 20 | 10.3 |
| 17–19 years | 14 | 7.2 |
| Gender | ||
| Male | 108 | 55.4 |
| Female | 87 | 44.6 |
| Body Mass Index (BMI) | ||
| Normal | 124 | 63.6 |
| Overweight/Obese | 71 | 36.4 |
| Family History of Hypertension | ||
| Present | 49 | 25.1 |
| Absent | 146 | 74.9 |
| ALL Phenotype | ||
| B-cell ALL | 156 | 80.0 |
| T-cell ALL | 39 | 20.0 |
| Risk Group of ALL | ||
| Standard Risk | 92 | 47.2 |
| Intermediate Risk | 71 | 36.4 |
| High Risk | 32 | 16.4 |
| CNS Status at Diagnosis | ||
| CNS 1 | 161 | 82.6 |
| CNS 2 | 22 | 11.3 |
| CNS 3 | 12 | 6.1 |
Incidence of Hypertension During Induction Chemotherapy
During the induction phase, 64 of 195 patients developed hypertension, corresponding to an overall incidence of 32.8% (95% CI: 26.2%–39.4%). Thus, approximately one in three pediatric patients experienced new-onset hypertension during induction chemotherapy.
Figure 1Incidence of hypertension among pediatric patients with acute lymphoblastic leukemia during induction chemotherapy.
Blood Pressure Trends During Induction Chemotherapy
The mean systolic blood pressure increased progressively from 103.20 ± 13.30 mmHg on Day 1 to 121.55 ± 18.84 mmHg on Day 8 and reached the highest value of 124.92 ± 11.33 mmHg on Day 15, before declining to 114.53 ± 11.26 mmHg by Day 30. A similar trend was observed in diastolic blood pressure, which increased from 67.42 ± 8.64 mmHg on Day 1 to 79.63 ± 10.92 mmHg on Day 8 and peaked at 82.14 ± 9.75 mmHg on Day 15, before decreasing to 74.80 ± 8.91 mmHg by Day 30. These findings demonstrate that blood pressure elevation was most pronounced during the first two weeks of induction chemotherapy, particularly around Day 15.
Figure 2Trend in mean systolic and diastolic blood pressure among hypertensive patients (N=64) during induction chemotherapy, demonstrating peak blood pressure around Day 15.
Timing of Hypertension Development
The majority of cases developed hypertension during the second week of induction therapy. Hypertension was first detected between Day 8 and Day 14 in 28 patients (43.8%), representing the highest proportion of cases. In contrast, 12 patients (18.8%) developed hypertension during the first week (Day 1–7), 16 patients (25.0%) between Day 15-21, and 8 patients (12.5%) during Day 22-30.
Figure 3 Kaplan–Meier analysis demonstrated a progressive decline in the probability of remaining normotensive during the early induction period, with the steepest decline observed between Day 8 and Day 15, indicating that most hypertension events occurred during this interval.
Comparison Between Hypertensive and Non-Hypertensive Patients
| Variable | Hypertensive (N = 64) | Non-Hypertensive (N = 131) | p value |
| Age Group | 0.48 | ||
| 1–12 years | 45 (70.3%) | 97 (74.0%) | |
| 13–14 years | 6 (9.4%) | 13 (9.9%) | |
| 15–16 years | 8 (12.5%) | 12 (9.2%) | |
| 17–19 years | 5 (7.8%) | 9 (6.9%) | |
| Gender | 0.41 | ||
| Male | 38 (59.4%) | 70 (53.4%) | |
| Female | 26 (40.6%) | 61 (46.6%) | |
| ALL Phenotype | 0.67 | ||
| B-cell ALL | 50 (78.1%) | 106 (80.9%) | |
| T-cell ALL | 14 (21.9%) | 25 (19.1%) | |
| Risk Group | 0.29 | ||
| Standard Risk | 27 (42.2%) | 65 (49.6%) | |
| Intermediate Risk | 23 (35.9%) | 48 (36.6%) | |
| High Risk | 14 (21.9%) | 18 (13.7%) |
Risk Factors Associated with Hypertension
Several clinical and laboratory variables were evaluated including body mass index, family history of hypertension, tumor lysis syndrome, CNS status, headache, initial white blood cell count, bulky kidneys on ultrasonography, febrile neutropenia, constipation, coagulopathy, sepsis, and convulsions. In the univariate logistic regression analysis, tumor lysis syndrome, bulky kidneys on ultrasonography, and febrile neutropenia showed increased odds of developing hypertension. Tumor lysis syndrome demonstrated a statistically significant association with hypertension (OR = 2.31, 95% CI: 1.24–4.29, p = 0.008). Similarly, bulky kidneys on ultrasonography were strongly associated with hypertension (OR = 2.76, 95% CI: 1.39–5.49, p = 0.003). Febrile neutropenia also showed a statistically significant association (OR = 2.12, 95% CI: 1.14–3.95, p = 0.01). After adjustment for potential confounding variables in the multivariate logistic regression model, tumor lysis syndrome and bulky kidneys on ultrasonography remained independent predictors of hypertension. Patients with tumor lysis syndrome had 2.41 times higher odds of developing hypertension (95% CI: 1.18–4.93, p = 0.015), while patients with bulky kidneys had 2.67 times higher odds (95% CI: 1.29–5.54, p = 0.008). Febrile neutropenia, BMI category, and headache did not retain statistical significance after adjustment.
| Variable | Univariate OR | 95% CI | p value | Adjusted OR | 95% CI | p value |
| BMI (Overweight/Obese vs Normal/Underweight) | 1.62 | 0.91–2.87 | 0.09 | 1.33 | 0.72–2.45 | 0.35 |
| Family history of hypertension (Yes vs No) | 1.44 | 0.78–2.66 | 0.23 | — | — | — |
| Tumor lysis syndrome (Yes vs No) | 2.31 | 1.24–4.29 | 0.008 | 2.41 | 1.18–4.93 | 0.015 |
| CNS status (CNS 2/3 vs CNS 1) | 1.53 | 0.79–2.97 | 0.20 | — | — | — |
| Headache (Yes vs No) | 1.66 | 0.92–3.00 | 0.08 | 1.42 | 0.74–2.73 | 0.28 |
| Initial WBC count (>1 lakh vs <1 lakh) | 1.48 | 0.79–2.75 | 0.21 | — | — | — |
| USG bulky kidneys (Yes vs No) | 2.76 | 1.39–5.49 | 0.003 | 2.67 | 1.29–5.54 | 0.008 |
| Febrile neutropenia (Yes vs No) | 2.12 | 1.14–3.95 | 0.01 | 1.58 | 0.82–3.03 | 0.16 |
| Constipation (Yes vs No) | 1.27 | 0.68–2.36 | 0.44 | — | — | — |
| Coagulopathy (Yes vs No) | 1.33 | 0.71–2.49 | 0.36 | — | — | — |
| Sepsis (Yes vs No) | 1.52 | 0.79–2.92 | 0.20 | — | — | — |
| Convulsions (Yes vs No) | 1.74 | 0.76–3.99 | 0.19 | — | — | — |
Figure 4Forest plot showing the association between clinical variables and development of hypertension during induction chemotherapy based on logistic regression analysis.
Neurological Complications
Among the 64 hypertensive patients, PRES was observed in 2 patients (3.1%), while 58 patients (96.8%) did not develop PRES. These findings indicate that although PRES was relatively uncommon, it occurred in a small proportion of hypertensive patients during induction therapy. The development of PRES in these patients may be related to sudden elevation of blood pressure and endothelial dysfunction associated with chemotherapy and metabolic disturbances. Early identification and prompt management of hypertension are therefore important to prevent neurological complications such as PRES during induction chemotherapy.
Management of Hypertension
The majority of hypertensive patients were managed with single-agent antihypertensive therapy. Amlodipine alone was sufficient in 46 patients (71.9%), while 18 patients (28.1%) required combination therapy with Amlodipine and Enalapril for adequate blood pressure control. These findings suggest that hypertension occurring during induction therapy was generally manageable with single drug therapy, while a smaller proportion of patients required combination treatment.
Clinical Outcomes
Despite the occurrence of hypertension and neurological complications such as PRES, no mortality related to hypertensive emergencies or PRES was observed during the study period. All patients were successfully managed with timely antihypertensive therapy and supportive care.
Discussion
Hypertension during induction chemotherapy in children with ALL has increasingly been recognized as an important treatment-related complication with potential implications for acute neurological and cardiovascular morbidity. In the present study, 32.8% of pediatric ALL patients developed hypertension during induction chemotherapy, reinforcing that elevated blood pressure is a common yet underappreciated adverse effect during this critical treatment phase. This incidence is consistent with previously reported rates from both Indian and international cohorts, which range from 12 to 45%, thereby supporting the external validity of our findings [2,9].
Our results closely parallel those reported by Payal Malhotra et al, who documented a 29% incidence of hypertension in children treated with BFM-based protocols [9]. Notably, Yamini Karanam et al. demonstrated a substantially higher incidence (58.7%) in a prospectively monitored cohort compared with 12.5% in retrospective analysis, underscoring the critical influence of systematic blood pressure surveillance on detection rates [11]. This discrepancy highlights a key issue in pediatric oncology practice—hypertension during induction is likely underdiagnosed in settings where routine monitoring is inconsistent. Our findings, therefore, further emphasize the need for standardized blood pressure monitoring protocols during ALL therapy.
A notable observation in our cohort was the early onset of hypertension, with peak systolic and diastolic pressures occurring around Day 15 of induction. This temporal pattern is in agreement with prior studies, including that of Malhotra et al., who reported a median onset around Day 10. The early emergence of hypertension is likely attributable to the cumulative effects of induction-phase therapies [9].
Importantly, our study identified TLS and bulky kidneys on ultrasonography as independent predictors of hypertension, with 2.4-fold and 2.67-fold increased risks, respectively. These findings are biologically plausible and align with existing literature suggesting that TLS-related electrolyte disturbances and renal dysfunction contribute to blood pressure elevation. Similarly, renal enlargement likely reflects leukemic infiltration, which may impair renal perfusion and activate the renin–angiotensin–aldosterone system, thereby promoting secondary hypertension. These observations strengthen the concept that hypertension during induction is not solely treatment-induced but reflects a complex interplay between disease burden and therapy-related physiological stress [12,16].
Previous studies further support this multifactorial etiology. Malhotra et al. identified younger age and constipation as independent predictors [9], while Saha et al. demonstrated significant associations with TLS and coagulopathy [10]. Additionally, comprehensive reviews have highlighted the contribution of patient-related factors such as obesity, family history, sex, and ethnicity, alongside treatment-related variables including acute kidney injury and endothelial injury [2,12]. Taken together, these findings suggest that risk stratification for hypertension in pediatric ALL should incorporate both baseline characteristics and dynamic treatment-related factors. The association between bulky kidneys and hypertension observed in our study may therefore reflect underlying leukemic infiltration or renal parenchymal involvement at diagnosis.
Neurological complications, particularly posterior reversible encephalopathy syndrome (PRES), represent one of the most serious consequences of uncontrolled hypertension in this population. In our study, PRES occurred in 3.1% of hypertensive patients, which is comparable to the 2–8% incidence reported in pediatric ALL cohorts [5,13]. The pathogenesis of PRES is closely linked to acute hypertension, endothelial dysfunction, and cytotoxic therapy. Importantly, no mortality was observed in our cohort, and all affected patients demonstrated clinical recovery, consistent with literature indicating that PRES is typically reversible with timely recognition and aggressive blood pressure control [14,15]. These findings underscore the importance of early detection and prompt management of hypertension to prevent irreversible neurological injury.
From a therapeutic perspective, hypertension in our cohort was effectively managed in the majority of patients with single-agent therapy, most commonly amlodipine, while a minority required combination treatment. This is consistent with existing pediatric oncology practice, where calcium channel blockers are widely used as first-line agents for steroid-induced hypertension.
Conclusion
Hypertension is a relatively common complication during induction chemotherapy in children with acute lymphoblastic leukemia. The present study demonstrates that a significant proportion of patients develop hypertension during the early phase of treatment, emphasizing the importance of regular blood pressure monitoring during induction therapy. Although hypertension may lead to neurological complications such as PRES, prompt detection and appropriate management can effectively prevent fatal outcomes. Routine screening and early intervention strategies should therefore be incorporated into standard clinical protocols for pediatric leukemia management to reduce morbidity associated with treatment-related hypertension.
Declarations
Ethical Approval and Consent to Participate
Ethical approval was obtained from the Ethics Committee.
Availability of Supporting Data
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.