High body mass index (BMI) is associated with relapse of certain adult cancers, but limited knowledge exists on its association with pediatric leukemia relapse. We evaluated the association between overweight/obesity (BMI ≥ 85th percentile) at pediatric leukemia diagnosis and relapse or mortality. A meta-analysis combining our findings with those of previous studies was also performed. The study included 181 pediatric leukemia patients. Sporadic missing data were multiply imputed, and hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazard. Age- and sex-adjusted analysis for patients ≥10 years showed a trend towards increased risk of relapse for overweight/obese patients (HR = 2.89, 95% CI = 0.89–9.36,
Leukemia is the most prevalent pediatric malignancy and the leading cause of cancer-related death among youth [
Obesity has been associated with relapse of certain adult cancers [
The purpose of this study was to evaluate the association between body mass index (BMI) at diagnosis and pediatric (<21 years) leukemia relapse by comparing the risk for non-overweight to overweight/obese patients. We hypothesized that pediatric leukemia patients with a higher BMI at diagnosis are more likely to relapse than pediatric leukemia patients with a normal or lower BMI at diagnosis. We also evaluated the association between BMI at diagnosis and overall mortality.
We conducted a retrospective analysis on children diagnosed with leukemia at Johns Hopkins All Children’s Hospital (JHACH, St. Petersburg, FL). JHACH is a tertiary children’s hospital with an established Cancer and Blood Disorders Institute that serves as the largest pediatric cancer center in West Florida. The study was approved by JHACH Institutional Review Board, with waiver of informed consent granted.
All patients with leukemia treated at JHACH were considered eligible for the study. However, the analysis was limited to patients diagnosed between April 2005 and December 2014 and followed through June 2016, because BMI was not consistently collected in our database before this period. Participants were identified via an electronic health record-derived data warehouse using the first recorded International Classification of Diseases, Ninth Revision (ICD-9) codes 204.00–205.92. Diagnoses included ALL, AML, and chronic myeloid leukemia (CML). We reviewed the records of 194 patients with leukemia treated with AALL0932, AALL0434, AALL1131, and AALL0631 for ALL and AAML0531 and AAML1031 for AML. We excluded patients diagnosed at an age younger than 2 years (
Diagram of eligible and included leukemia patients.
BMI at diagnosis was calculated as weight (kilograms) divided by the square of height (meters). BMI percentiles were determined using the 2000 Centers for Disease Control and Prevention (CDC) BMI for age growth charts for children between 2 and 20 years of age [
Demographic and clinical characteristics were summarized by obesity status using median and range for continuous variables and counts and percentages for categorical variables. Duration of relapse-free survival (RFS) was defined as the time from diagnosis date to the first documentation of any relapse. Duration of overall survival (OS) was defined as the time from diagnosis date to the date of death. Patients who were lost to follow-up or who did not experience an event were censored at the date of last contact.
A complete set analysis and an analysis after multiple imputation of missing values for both response (relapse,
The number of eligible patients treated at our institution during the study period (
Descriptive statistics were performed using SAS version 9.4 and multiple imputation, Cox analyses and meta-analyses were performed using Stata v 15. All statistical tests were two-sided with a
Characteristics of patients with unimputed information on obesity status are shown in Table
Characteristics at diagnosis for pediatric leukemia patients by obesity status.
All | Obesity | |||||
---|---|---|---|---|---|---|
Non-overweight ( |
Overweight/obese ( |
|||||
|
% |
|
% |
|
% | |
Gender | ||||||
Female | 73 | 46.79 | 51 | 45.95 | 22 | 48.89 |
Male | 83 | 53.21 | 60 | 54.05 | 23 | 51.11 |
Age at diagnosis (yrs), median (range) | 156 | 7 (2–20) | 111 | 6 (2–19) | 45 | 13 (2–20) |
<10 | 102 | 65.38 | 84 | 75.68 | 18 | 40 |
≥10 | 54 | 34.62 | 27 | 24.32 | 27 | 60 |
Race/ethnicity | ||||||
Asian | 6 | 3.85 | 4 | 3.6 | 2 | 4.44 |
Black | 11 | 7.05 | 7 | 6.31 | 4 | 8.89 |
Caucasian | 98 | 62.82 | 76 | 68.47 | 22 | 48.89 |
White Hispanic | 34 | 21.79 | 19 | 17.12 | 15 | 33.33 |
Other | 7 | 4.49 | 5 | 4.5 | 2 | 4.44 |
Insurance type | ||||||
Private | 80 | 51.28 | 62 | 55.86 | 18 | 40 |
Public | 73 | 46.79 | 49 | 44.14 | 24 | 53.33 |
Missing | 3 | 1.92 | 0 | 0 | 3 | 6.67 |
Type of leukemia | ||||||
ALL | 123 | 78.85 | 93 | 83.78 | 30 | 66.67 |
AML | 25 | 16.03 | 14 | 12.61 | 11 | 24.44 |
|
8 | 5.13 | 4 | 3.6 | 4 | 8.89 |
WBC, median (range) | 9.46 | (0.21–744.0) | 7.45 | (0.72–402.6) | 11.86 | (0.21–744.0) |
<50 × 103/L | 118 | 75.64 | 87 | 78.38 | 31 | 68.89 |
≥50 × 103/L | 25 | 16.03 | 13 | 11.71 | 12 | 26.67 |
Missing | 13 | 8.33 | 11 | 9.91 | 2 | 4.44 |
Follow-up time (months), median (range) | 57.04 | (0.42–260.75) | 45.42 | (0.92–250.5) | 61.67 | (0.42–260.75) |
Hazard ratios for the association between obesity status and relapse-free survival.
Imputed | Complete set | |||||||
---|---|---|---|---|---|---|---|---|
Variables | HR |
Lower 95% CI | Upper 95% CI |
|
HR |
Lower 95% CI | Upper 95% CI |
|
Unadjusted | ||||||||
All | ||||||||
Overweight/obese vs non-overweight | 1.77 | 0.91 | 3.46 | 0.09 | 1.75 | 0.85 | 3.40 | 0.13 |
<10 years | ||||||||
Overweight/obese vs non-overweight | 0.52 | 0.08 | 3.39 | 0.48 | 0.33 | 0.04 | 2.56 | 0.29 |
≥10 years | ||||||||
Overweight/obese vs non-overweight | 2.39 | 0.79 | 7.26 | 0.12 | 2.17 | 0.78 | 6.01 | 0.14 |
|
||||||||
Sex and/or age adjusted | ||||||||
All | ||||||||
Overweight/obese vs non-overweight | 1.57 | 0.71 | 3.45 | 0.26 | 1.45 | 0.67 | 3.14 | 0.34 |
Female vs male | 0.56 | 0.29 | 1.08 | 0.08 | 0.46 | 0.22 | 0.99 | 0.046 |
Age at diagnosis | 1.07 | 1.02 | 1.13 | 0.012 | 1.11 | 1.04 | 1.18 | 0.002 |
<10 years | ||||||||
Overweight/obese vs non-overweight | 0.52 | 0.08 | 3.54 | 0.49 | 0.31 | 0.04 | 2.46 | 0.27 |
Female vs male | 1.01 | 0.42 | 2.43 | 0.99 | 1.23 | 0.44 | 3.46 | 0.70 |
≥10 years | ||||||||
Overweight/obese vs non-.overweight | 2.89 | 0.89 | 9.36 | 0.08 | 2.46 | 0.96 | 7.27 | 0.06 |
Female vs male | 0.31 | 0.11 | 0.90 | 0.031 | 0.19 | 0.05 | 0.67 | 0.009 |
Hazard ratios for the association between obesity status and overall survival.
Imputed | Complete set | |||||||
---|---|---|---|---|---|---|---|---|
Variables | HR |
Lower 95% CI | Upper 95% CI |
|
HR |
Lower 95% CI | Upper 95% CI |
|
Unadjusted | ||||||||
All | ||||||||
Overweight/obese vs non-overweight | 2.54 | 1.15 | 5.60 | 0.021 | 2.72 | 1.26 | 5.91 | 0.011 |
<10 years | ||||||||
Overweight/obese vs non-overweight | 0.93 | 0.10 | 8.57 | 0.94 | 1.07 | 0.12 | 9.59 | 0.95 |
≥10 years | ||||||||
Overweight/obese vs non-overweight | 1.74 | 0.67 | 4.56 | 0.25 | 1.75 | 0.70 | 4.36 | 0.23 |
|
||||||||
Sex and/or age adjusted | ||||||||
All | ||||||||
Overweight/obese vs non-overweight | 1.60 | 0.62 | 4.12 | 0.32 | 1.72 | 0.75 | 3.93 | 0.20 |
Female vs male | 0.48 | 0.22 | 1.08 | 0.08 | 0.40 | 0.16 | 0.95 | 0.039 |
Age at diagnosis | 1.18 | 1.09 | 1.27 | <0.001 | 1.20 | 1.10 | 1.30 | <0.001 |
<10 years | ||||||||
Overweight/obese vs non-overweight | 0.89 | 0.09 | 8.62 | 0.92 | 1.05 | 0.17 | 9.39 | 0.97 |
Female vs male | 1.63 | 0.36 | 7.32 | 0.53 | 1.61 | 0.27 | 9.65 | 0.60 |
≥10 years | ||||||||
Overweight/obese vs non-overweight | 2.13 | 0.77 | 5.88 | 0.14 | 2.22 | 0.89 | 5.51 | 0.09 |
Female vs male | 0.29 | 0.10 | 0.80 | 0.017 | 0.22 | 0.07 | 0.66 | 0.007 |
Association between obesity and relapse or mortality among pediatric ALL patients.
Imputed | Complete set | |||||||
---|---|---|---|---|---|---|---|---|
Variables | HR |
Lower 95% CI | Upper 95% CI |
|
HR |
Lower 95% CI | Upper 95% CI |
|
Relapse | ||||||||
Unadjusted | ||||||||
Overweight/obese vs non-overweight | 1.09 | 0.43 | 2.76 | 0.86 | 0.99 | 0.36 | 2.67 | 0.98 |
|
||||||||
Sex and age adjusted | ||||||||
Overweight/obese vs non-overweight | 1.00 | 0.35 | 2.84 | 0.99 | 0.88 | 0.31 | 2.48 | 0.81 |
Female vs male | 0.79 | 0.37 | 1.69 | 0.55 | 0.65 | 0.27 | 1.55 | 0.33 |
Age at diagnosis | 1.05 | 0.98 | 1.12 | 0.17 | 1.09 | 1.00 | 1.17 | 0.04 |
|
||||||||
Multivariable adjusted | ||||||||
Overweight/obese vs non-overweight | 0.95 | 0.32 | 2.84 | 0.93 | 0.74 | 0.22 | 2.46 | 0.62 |
Female vs male | 0.71 | 0.33 | 1.53 | 0.38 | 0.65 | 0.25 | 1.68 | 0.37 |
Age at diagnosis | 1.07 | 0.99 | 1.16 | 0.08 | 1.13 | 1.03 | 1.25 | 0.011 |
Public vs private | 1.87 | 0.80 | 4.38 | 0.15 | 2.20 | 0.79 | 6.15 | 0.13 |
WBC at diagnosis | 0.97 | 0.73 | 1.28 | 0.81 | 0.92 | 0.68 | 1.26 | 0.61 |
|
||||||||
Mortality | ||||||||
Unadjusted | ||||||||
Overweight/obese vs non-overweight | 2.58 | 0.84 | 7.92 | 0.10 | 2.83 | 0.95 | 8.46 | 0.06 |
Sex and age adjusted | ||||||||
Overweight/obese vs non-overweight | 1.61 | 0.43 | 6.33 | 0.47 | 1.89 | 0.60 | 6.00 | 0.28 |
Female vs male | 0.77 | 0.27 | 2.20 | 0.63 | 0.52 | 0.16 | 1.74 | 0.29 |
Age at diagnosis | 1.20 | 1.09 | 1.33 | <0.001 | 1.25 | 1.10 | 1.42 | <0.001 |
Multivariable adjusted | ||||||||
Overweight/obese vs non-overweight | 1.52 | 0.38 | 6.10 | 0.54 | 2.00 | 0.50 | 8.12 | 0.33 |
Female vs male | 0.63 | 0.21 | 1.88 | 0.41 | 0.35 | 0.08 | 1.46 | 0.15 |
Age at diagnosis | 1.21 | 1.09 | 1.34 | <0.001 | 1.30 | 1.12 | 1.52 | 0.001 |
Government vs commercial | 2.24 | 0.70 | 7.13 | 0.17 | 1.98 | 0.51 | 7.62 | 0.32 |
WBC at diagnosis | 1.24 | 0.93 | 1.64 | 0.14 | 1.21 | 0.87 | 1.68 | 0.26 |
A meta-analysis combining our HRs from the multivariable models with those of previous studies showed associations between obesity and increased risk for mortality (HR = 1.79, 95% CI = 1.03–3.10) and relapse (HR = 1.28, 95% CI = 1.04–1.57) for ALL, albeit the analysis for relapse included only two studies (Figure
Meta-analyses combining the results of relapse (a) and overall survival (b) for ALL from this study with previous studies.
Meta-analyses combining the results of overall survival for AML from this study with previous studies.
In the present study, we evaluated the association between obesity status and pediatric leukemia relapse and mortality. We observed a trend towards an increased risk of relapse associated with overweight/obesity in age- and sex-adjusted model among children ≥10 years, but the trend disappeared after additional adjustment for insurance type and WBC at diagnosis. We observed an association between overweight/obesity and mortality in unadjusted models, but the association disappeared in multivariable models that adjusted for factors including insurance type. However, the results of a meta-analysis that combined our findings with previous studies revealed an increased risk of mortality for overweight/obesity.
The relationship between obesity and cancer relapse is biologically plausible as obesity may affect molecular pathways that are relevant to cancer progression [
However, other studies have reported an increased risk of pediatric leukemia relapse with obesity. A large retrospective cohort study of 4,260 US patients with ALL found obesity at time of diagnosis to be an independent predictor of relapse in patients ≥10 years of age [
Evidence from these previous studies suggest that the inconsistency in study findings may not be attributed to sample size, since an association or lack of an association is observed in both large and small studies. Our findings suggested a trend towards an increased risk of relapse for overweight/obese patients among children ≥10 years old. The association may be limited to a certain pediatric age group and thus not evident in studies that do not stratify on age. Therefore, future larger multicenter studies that will stratify analyses on age are warranted to provide further insights into the relationship between obesity at diagnosis and pediatric leukemia relapse. Existing evidence suggests that White Hispanics have a higher risk of relapse and mortality compared to other racial/ethnic groups [
Our meta-analyses findings suggested an increased risk of mortality for overweight/obese patients that is consistent with the result of a recent meta-analysis [
Potential strengths of this study include the restriction of analyses to patients with leukemia (as some of the prior studies included patients with various forms of hematologic conditions [
The main limitation of our study is the small sample size, which limited the analysis for each leukemia subtype. Lumping all forms of leukemias together could potentially distort associations with specific leukemias. We performed analyses limited to ALL, the most common type of leukemia. Though the effect estimates of these analyses did not vary appreciably from that of all leukemias combined, none of the associations were statistically significant possibly due to the small sample size. Another limitation is the grouping of overweight and obesity together. This grouping may represent a more heterogeneous adiposity profile, which could potentially mask an association between obesity and relapse or mortality. We could not also adjust for several important potential confounding factors such as cytogenetic-defined risk groups, T phenotype, B-precursor subgroup, immunophenotype, and minimal residual disease. In addition, the study was a secondary analysis of administrative data that were not collected for research purposes and more specifically, to investigate the relationship between obesity and pediatric leukemia relapse. As a result, we were limited in the scope of analysis that could be performed. We also used BMI as a measure of obesity. It is important to note that reliance on BMI as an anthropomorphic measure of obesity does not elucidate fat and lean muscle mass content. While BMI is a universally accepted method to approximate body composition, future studies would benefit from coupling it with other measures of body composition such as Dual energy X-ray absorptiometry (DEXA) scans and bioimpedance. Another limitation is the use of insurance type as a proxy for socioeconomic status (SES). We did not have information on parental educational level, occupation, and/or income, which may be better measures of SES. However, insurance status has been associated with income whereby public insurance is associated with low SES [
Obesity represents a rare opportunity for preventive intervention that could improve outcomes; therefore, understanding the prognostic impact of obesity on pediatric cancer outcomes has both clinical and public health implications. Although our study did not find statistically significant associations between overweight/obesity and relapse or mortality due to the small sample size, the findings from meta-analyses revealed an increased risk of mortality for overweight/obese patients. In addition, our findings may suggest a potential association between obesity and relapse that may be limited to children ≥10 years. However, our study was based on a small sample size from a single institution, and this association needs to be further investigated in larger, multicenter studies.
The authors declare that they have no conflicts of interest.
Supplementary Table 1: multivariable adjusted models for the association between obesity and relapse or mortality among pediatric leukemia patients.