Key Points
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Overweight/obesity at diagnosis is associated with inferior EFS in male, but not female, patients aged ≥10 years with ALL.
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Male patients aged ≥10 years with overweight/obesity represent a vulnerable patient group at increased risk of relapse or death.
Visual Abstract
Figure created with biorender.com. Fischer-Posovszky, P. (2026) https://biorender.com/bkuzwjh.
Abstract
Body weight at diagnosis may influence outcomes in childhood acute lymphoblastic leukemia (ALL), although current evidence remains conflicting. Both, underweight and overweight/obesity at diagnosis can negatively affect outcomes. Here, we present data from the ALL-BFM 2000 trial on excess body weight at diagnosis and inferior outcome, especially among male patients aged ≥10 years with ALL. We analyzed 3920 patients with B-cell precursor (BCP)–ALL and 674 patients with T-cell ALL (T-ALL), aged 1 to 17 years. Outcome was assessed by weight category (underweight, normal weight, and overweight/obesity) and sex, age, or risk group. We found that patients aged ≥10 years who were overweight/obese at diagnosis had a significantly worse event-free survival (EFS; BCP-ALL, 63.6%; T-ALL, 65.8%) than patients with normal weight (BCP-ALL, 77.8%; T-ALL, 81.2%) or those who were underweight (BCP-ALL, 77.9%; T-ALL, 83.8%). Interestingly, sex critically determined outcome in patients ≥10 years because especially male patients with overweight/obesity at diagnosis experienced a significantly shorter EFS (BCP-ALL, 54.9%; T-ALL, 62.7%) than patients with normal weight (BCP-ALL, 81.9%; T-ALL, 78.3%) of this age group. Overweight/obesity at diagnosis was identified as independent negative prognostic marker in the group of male (hazard ratio [HR], 2.23) but not female (HR, 1.04) patients ≥10 years with ALL. Male patients ≥10 years with overweight/obesity classified as medium risk or high risk by minimal residual disease showed a higher cumulative incidence of relapse or death, respectively. Our findings suggest that male patients aged ≥10 years with overweight/obesity represent a particularly vulnerable group of patients with ALL who are at increased risk of relapse or death. This trial was registered at www.clinicaltrials.gov as NCT00430118.
Introduction
Over the past decades, cure rates for childhood acute lymphoblastic leukemia (ALL) have progressively improved, with ∼90% of affected children and adolescents achieving long-term survival today. Nevertheless, relapse remains associated with a poorer prognosis. Despite significant advancements in treatment, male patients with pediatric ALL continue to exhibit an increased risk of relapse compared with their female counterparts.1 Efforts to address this disparity, such as extending the duration of maintenance therapy specifically for male patients, have not yielded improvements in event-free survival (EFS).2 Instead, this approach has led to an increased incidence of therapy-related side effects and a greater burden on patients and their families.2
Evidence is accumulating that body weight can influence the prognosis of patients with pediatric ALL, but published data remain conflicting.3, 4, 5, 6, 7, 8, 9, 10, 11 Obesity at diagnosis was identified as an independent predictor of relapse in patients with ALL.4,9 In line with this, patients with ALL and obesity at the time of diagnosis had an increased risk of persistent minimal residual disease (MRD) after induction therapy7 and a worse EFS.7,11 In a Mexican patient population with ALL, overweight and obesity were identified as early predictors of mortality, but not of early relapse.12 In contrast, other studies found no association between obesity at the time of diagnosis and EFS in pediatric patients with ALL,3,6,8 whereas other studies identified pediatric patients with ALL who were underweight at diagnosis had a higher risk of relapse5 and poorer EFS.4 Given these controversies, several meta-analyses were published evaluating the impact of body weight at diagnosis on survival in childhood ALL, which have consistently identified overweight and/or obesity as detrimental to clinical outcome.13, 14, 15, 16
Patients with extreme body weight for much of their therapy, both underweight and obese, presented with poorer EFS,10 further suggesting that weight extremes may negatively affect leukemia cure. Obesity is a growing health problem, especially in the Western world. Children and adolescents with ALL gain weight during therapy, show an increased prevalence of overweight and obesity even after completion of therapy, and are at increased risk of developing signs of metabolic syndrome.17, 18, 19, 20 In previous studies investigating the influence of body weight on the prognosis of patients with childhood ALL, the influence of sex was either not investigated3,5,7, 8, 9, 10, 11, 12 or shown to have no effect.4,6
Data on the impact of body weight at diagnosis on the survival of patients with childhood ALL from Germany, Austria, and Switzerland have not yet been reported. Here, we therefore retrospectively analyzed data from the ALL-BFM 2000 trial and identified male patients aged ≥10 years with overweight/obesity to be a vulnerable group of patients with particularly increased risk of relapse and death.
Methods
Patients and relevant study design of the ALL-BFM 2000 study cohort
The ALL-BFM 2000 trial was registered at www.clinicaltrials.gov (identifier: NCT00430118). The retrospective data analysis included pediatric patients with ALL aged 0 to 17 years at the time of diagnosis treated in one of the participating study centers located in Germany, Austria, or Switzerland within the ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia from 1 July 2000 until June 2006, and the subsequent registry phase until November 2010. The study protocol was approved by the respective ethics committees of the national coordinating centers (Hannover Medical School, Hannover, Germany; St. Anna Children’s Hospital, Vienna, Austria; University Children’s Hospital, Zürich, Switzerland). All patients were registered, and the patients and/or their legal guardians provided written informed consent to the study and agreed to the use of anonymized data for further scientific purposes. Of the 4975 patients who were eligible for the study, 259 were excluded from the analysis because of age <1 year or immunophenotype not known or other than B-cell precursor ALL (BCP-ALL) or T-cell ALL (T-ALL). Furthermore, 122 patients with trisomy 21 were excluded from our analyses because specific growth charts are commonly used for these patients.21 The median follow-up time of the cohort was 11.3 years. The flow diagram can be found in supplemental Figure 1.
BMI percentiles
In adults, overweight or obesity is defined by a body mass index (BMI) of 25 to 29.9 kg/m2 or ≥30 kg/m2, respectively.22 In children and adolescents, the BMI is influenced by age- and sex-specific physiological changes and is therefore expressed in relation to other children of the same age and sex. Age- and sex-adjusted BMI percentiles have been established by the Arbeitsgemeinschaft Adipositas im Kindes- und Jugendalter (https://adipositas-gesellschaft.de/aga/). Here, underweight is defined as a BMI below the 10th percentile, normal weight between the 10th and the 90th percentile, and overweight/obesity as a BMI above the 90th percentile.23 This reference data were used to calculate the respective patients’ BMI percentiles from weight and height at diagnosis. The World Health Organization (WHO) defines the different weight categories from the age of 5 to 19 years as follows: underweight, less than −2 standard deviations (SD); normal weight, −2 SD to +1 SD; and overweight/obese, greater than +1 SD. Reference percentiles by the WHO (https://www.who.int/tools/growth-reference-data-for-5to19-years/indicators/bmi-for-age) were used to group patients into the different WHO weight categories.
Outcomes
EFS, defined as the time from diagnosis to the last follow-up or first event, was the primary outcome of this study. Nonresponse, relapse, secondary neoplasm, or death from any cause were all considered events. Relapse was defined as a recurrence of ≥25% lymphoblasts in the bone marrow or localized leukemic infiltrate at any site. Failure to achieve remission as a result of early death or nonresponse was considered as event at time 0. Secondary outcomes were overall survival (OS), cumulative incidence of relapse or death, and MRD levels at the end of induction and after consolidation. OS was defined as the time from diagnosis to death from any cause or last follow-up.
Further diagnostic studies
Diagnostic studies included cytomorphology, immunophenotyping, early cytomorphologic response assessment, and quantitative assessment of MRD based on immunoglobulin and T-cell receptor gene rearrangements.
Risk stratification by MRD
MRD was determined after induction (time point 1 [TP1], day 33) and consolidation treatment (TP2, day 78). Risk stratification according to MRD in patients of the ALL-BFM 2000 trial was performed as follows. MRD-standard risk (MRD-SR): if MRD was negative on days 33 and 78, with at least 2 markers with a sensitivity of ≤10−4 (MRD-SR), patients were allocated to the MRD-SR group. MRD-medium risk (MRD-MR): patients were assigned to the MRD-MR group if they had a positive MRD on day 33 and/or day 78 but at a level of <5 × 10−4 on day 78. MRD-high risk (MRD-HR): patients were classified as MRD-HR if they had an MRD load of 5 × 10−4 or more on day 78.
Statistical analysis
The Kaplan-Meier method was used to estimate survival rates; differences between groups were compared with the log-rank test. Cumulative incidence functions for competing events were estimated according to Kalbfleisch and Prentice and compared with the Gray test. The Cox proportional hazard model was used for univariate and multivariate analyses. Analyses were performed using SAS 9.4.
Results
A total of 3920 patients with BCP–ALL and 674 patients with T-ALL, aged 1 to 17 years, were included in the analyses (supplemental Figure 1). By using age- and sex-adjusted BMI percentiles,23 we grouped patients into 3 different weight categories: underweight, normal weight, and overweight/obesity. At diagnosis, the weight distribution of the cohort of patient with BCP-ALL largely matched those of the reference population (underweight, 14.4%; normal weight, 76.3%; overweight/obese, 9.3%; Table 1). Within BCP-ALL, no major differences in the proportion of patients who were overweight/obese were observed across genetic subgroups (BCR::ABL1, KMT2A::AFF1, and ETV6::RUNX1) compared with patients lacking these aberrations (data not shown). Similar results were obtained for patients with T-ALL (underweight, 12.8%; normal weight, 75.1%; and overweight/obese, 12.2%; Table 1). Five-year EFS of patients with BCP-ALL did not significantly differ among the 3 weight groups (underweight, 84.7% ± standard error [SE] 1.5%; normal weight, 85.0% ± SE 0.7%; and overweight/obese, 81.5% ± SE 2.0%; Figure 1A; Table 2; see supplemental Table 1 for OS). Obesity at diagnosis has previously been identified as an independent predictor of relapse in children and adolescents aged ≥10 years with ALL.4 Therefore, we analyzed EFS according to weight group in the ALL-BFM study group by grouping patients into 2 different age groups. In line with the results from a US cohort study,4 we found patients aged ≥10 years who were overweight or obese had significantly worse EFS (63.6% ± SE 4.3%) than patients with normal weight (77.8% ± SE 1.7%; P = .0003) or those who were underweight (77.9% ± SE 3.8%; P = .011) within the same age group (Figure 1C). Importantly, this effect was not observed in patients with BCP-ALL aged 1 to 10 years (Figure 1B). Furthermore, patients with T-ALL also showed a significantly worse EFS, predominantly in the age group of ≥10 years, when they were overweight or obese (supplemental Figure 2; Table 2; see supplemental Table 1 for OS).
Table 1.
Weight distribution of the study populations
| Cohort/subgroup | Patients, n (%) | Underweight, n (%) | Normal weight, n (%) | Overweight/obesity, n (%) |
|---|---|---|---|---|
| BCP-ALL | 3920 (100.0) | 564 (14.4) | 2991 (76.3) | 365 (9.3) |
| Aged >1 to <10 y | 3055 (77.9) | 439 (14.4) | 2375 (77.7) | 241 (7.9) |
| Aged ≥10 y | 865 (22.1) | 125 (14.5) | 616 (71.2) | 124 (14.3) |
| Male | 2089 (53.3) | 286 (13.7) | 1599 (76.5) | 204 (9.8) |
| Aged >1 to <10 y | 1617 (77.4) | 222 (13.7) | 1267 (78.4) | 128 (7.9) |
| Aged ≥10 y | 472 (22.6) | 64 (13.6) | 332 (70.3) | 76 (16.1) |
| Female | 1831 (46.7) | 278 (15.2) | 1392 (76.0) | 161 (8.8) |
| Aged >1 to <10 y | 1438 (78.5) | 217 (15.1) | 1108 (77.1) | 113 (7.9) |
| Aged ≥10 y | 393 (21.5) | 61 (15.5) | 284 (72.3) | 48 (12.2) |
| T-ALL | 674 (100.0) | 86 (12.8) | 506 (75.1) | 82 (12.2) |
| Aged >1 to <10 y | 356 (52.8) | 48 (13.5) | 270 (75.8) | 38 (10.7) |
| Aged ≥10 y | 318 (47.9) | 38 (12.0) | 236 (74.2) | 44 (13.8) |
| Male | 477 (70.8) | 61 (12.8) | 356 (74.6) | 60 (12.6) |
| Aged >1 to <10 y | 244 (51.2) | 30 (12.3) | 189 (77.5) | 25 (10.3) |
| Aged ≥10 y | 233 (48.8) | 31 (13.3) | 167 (71.7) | 35 (15.0) |
| Female | 197 (29.2) | 25 (12.7) | 150 (76.1) | 22 (11.2) |
| Aged >1 to <10 y | 112 (56.9) | 18 (16.1) | 81 (72.3) | 13 (11.6) |
| Aged ≥10 y | 85 (43.1) | 7 (8.2) | 69 (81.2) | 9 (10.6) |
Figure 1.
EFS in patients with BCP-ALL according to weight group defined by BMI percentile at diagnosis. (A) EFS in patients aged >1 year. (B) EFS in patients aged >1 to <10 years. (C) EFS in patients aged ≥10 years.
Table 2.
EFS of patients in the different weight categories
| All weight categories |
Underweight |
Normal weight |
Overweight/obesity |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Events | 5-y EFS (SE), % | 10-y EFS (SE), % | n | Events | 5-y EFS (SE), % | n | Events | 5-y EFS (SE), % | n | Events | 5-y EFS (SE), % | |
| BCP-ALL | |||||||||||||
| Aged >1 y | 3920 | 657 | 84.6 (0.6) | 82.7 (0.6) | 564 | 91 | 84.7 (1.5) | 2991 | 494 | 85.0 (0.7) | 365 | 72 | 81.5 (2.0) |
| Aged >1 to <10 y | 3055 | 434 | 87.1 (0.6) | 85.4 (0.6) | 439 | 62 | 86.7 (1.6) | 2375 | 348 | 86.8 (0.7) | 241 | 24 | 90.8 (1.9) |
| Aged ≥10 y | 865 | 223 | 75.7 (1.5) | 72.6 (1.6) | 125 | 29 | 77.9 (3.8) | 616 | 146 | 77.8 (1.7) | 124 | 48 | 63.6 (4.3) |
| Male | |||||||||||||
| Aged >1 y | 2089 | 357 | 84.0 (0.8) | 82.4 (0.9) | 286 | 51 | 82.6 (2.3) | 1599 | 258 | 85.2 (0.9) | 204 | 48 | 76.8 (3.0) |
| Aged >1 to <10 y | 1617 | 239 | 86.4 (0.9) | 84.8 (0.9) | 222 | 33 | 85.9 (2.3) | 1267 | 193 | 86.1 (1.0) | 128 | 13 | 89.7 (2.7) |
| Aged ≥10 y | 472 | 118 | 76.2 (2.8) | 73.4 (2.1) | 64 | 18 | 71.4 (5.7) | 332 | 65 | 81.9 (2.2) | 76 | 35 | 54.9 (5.7) |
| Female | |||||||||||||
| Aged >1 y | 1831 | 300 | 85.2 (0.8) | 83.1 (0.9) | 278 | 40 | 86.9 (2.0) | 1392 | 236 | 84.7 (1.0) | 161 | 24 | 87.5 (2.6) |
| Aged >1 to <10 y | 1438 | 195 | 87.9 (0.9) | 86.1 (0.9) | 217 | 29 | 87.5 (2.3) | 1108 | 155 | 87.6 (1.0) | 113 | 11 | 92.0 (2.6) |
| Aged ≥10 y | 393 | 105 | 75.3 (2.2) | 71.6 (2.4) | 61 | 11 | 84.6 (4.7) | 284 | 81 | 73.0 (2.7) | 48 | 13 | 77.1 (6.1) |
| T-ALL | |||||||||||||
| Aged >1 y | 674 | 141 | 81.8 (1.5) | 77.8 (1.7) | 86 | 15 | 88.2 (3.5) | 506 | 100 | 82.7 (1.7) | 82 | 26 | 69.5 (5.1) |
| Aged >1 to <10 y | 356 | 71 | 83.9 (2.0) | 79.1 (2.2) | 48 | 8 | 91.5 (4.1) | 270 | 53 | 84.0 (2.2) | 38 | 10 | 73.7 (7.1) |
| Aged ≥10 y | 318 | 70 | 79.4 (2.3) | 76.8 (2.5) | 38 | 7 | 83.8 (6.0) | 236 | 47 | 81.2 (2.6) | 44 | 16 | 65.8 (7.2) |
| Male | |||||||||||||
| Aged >1 y | 477 | 106 | 80.8 (1.8) | 76.5 (2.0) | 61 | 13 | 84.9 (4.6) | 356 | 73 | 82.2 (2.0) | 60 | 20 | 68.2 (6.0) |
| Aged >1 to <10 y | 244 | 47 | 85.2 (2.3) | 79.9 (2.6) | 30 | 7 | 89.9 (5.5) | 189 | 34 | 85.7 (2.6) | 25 | 6 | 76.0 (8.5) |
| Aged ≥10 y | 233 | 59 | 76.1 (2.0) | 73.4 (3.0) | 31 | 6 | 80.1 (7.3) | 167 | 39 | 78.3 (3.2) | 35 | 14 | 62.7 (8.2) |
| Female | |||||||||||||
| Aged >1 y | 197 | 35 | 84.2 (2.6) | 81.0 (3.0) | 25 | 2 | 96.0 (3.9) | 150 | 27 | 83.8 (3.0) | 22 | 6 | 72.7 (9.5) |
| Aged >1 to <10 y | 112 | 24 | 81.2 (3.7) | 77.3 (4.2) | 18 | 1 | 94.4 (5.4) | 81 | 19 | 80.1 (4.4) | 13 | 4 | 69.2 (12.8) |
| Aged ≥10 y | 85 | 11 | 88.1 (3.5) | 86.1 (4.0) | 7 | 1 | 100.0 (0.0) | 69 | 8 | 88.2 (3.9) | 9 | 2 | 77.8 (13.9) |
Although EFS did not significantly differ in male vs female patients with ALL (supplemental Figure 3A), the cumulative incidence of relapse was significantly higher in male patients than in female patients (supplemental Figure 3B). This was due to the increased incidence of relapse in male patients with BCP-ALL but not in those with T-ALL (supplemental Figure 3C-D), confirming previous reports.1 Subsequently, we evaluated sex-specific differences in EFS in relation to body weight at the time of diagnosis. Interestingly, although EFS in female patients did not differ among the weight groups (Figure 2A), male patients with overweight or obesity had significantly lower EFS (76.8% ± SE 3.0%) than male patients with normal weight (85.2% ± SE 0.9%; P = .0037) (Figure 2B). This effect was attributable exclusively to the group of male patients aged ≥10 years (Figure 2F; see Figure 2E for the comparison with female patients aged ≥10 years). Patients aged 1 to 10 years did not show any significant differences in EFS according to weight group when further grouped according to sex (Figure 2C-D). Similar data were obtained for patients with T-ALL (supplemental Figure 4). To evaluate whether the choice of BMI reference percentiles influenced these results, we grouped patients with BCP-ALL aged ≥10 years into underweight, normal weight, and overweight/obese according to the WHO criteria. Consistently, male but not female patients aged ≥10 years with overweight/obesity showed inferior EFS (supplemental Figure 5), indicating that this observation is robust and independent of the BMI reference percentile used.
Figure 2.
EFS in patients with BCP-ALL according to weight group, age, and sex assigned at birth. (A) EFS in female patients aged >1 year. (B) EFS in male patients aged >1 year. (C) EFS in female patients aged >1 to <10 years. (D) EFS in male patients aged >1 to <10 years. (E) EFS in female patients aged ≥10 years. (F) EFS in male patients aged ≥10 years.
To our knowledge, the ALL-BFM 2000 study was the first trial in Germany, Austria, and Switzerland in which patients were stratified by MRD using quantitative polymerase chain reaction after induction (TP1, day 33) and consolidation treatment (TP2, day 78) into SR, MR, and HR treatment groups.24 The proportion of MRD-SR and MRD-HR patients was similar among patients with BCP-ALL who were overweight/obese vs those who were not overweight/obese (MRD-SR, 47% vs 43%; MRD-HR, 8% vs 6%). Similar results were observed among patients with T-ALL who were overweight/obese vs those who were not overweight/obese (MRD-SR, 20% vs 17%; MRD-HR, 15% vs 17%). Furthermore, we did not identify male patients with overweight/obesity aged ≥10 years as having an increased risk based on their MRD because patients who were overweight/obese continued to have poorer outcomes within the individual risk groups (Figure 3A-C; Table 3) and were evenly distributed among the MRD-SR, -MR, and -HR groups (Figure 3D). By determining hazard ratios (HR), we identified overweight/obesity at diagnosis as an independent risk factor in patients aged ≥10 years (supplemental Figure 6A; HR, 1.71; P < .001), but not in those aged 1 to 10 years (supplementary Figure 6B; HR, 0.77; P = .183) or those aged >1 year (supplemental Figure 6C; HR, 1.18; P = .168). Importantly, this independent risk was exclusively attributable to male (Figure 3F; HR, 2.23; P < .001), but not female (Figure 3E; HR, 1.04; P = .876), patients aged ≥10 years.
Figure 3.
EFS in male patients aged ≥10 years with ALL according to MRD and weight group. (A) EFS according to weight group and MRD-SR. (B) EFS according to weight group and MRD-MR. (C) EFS according to weight group and MRD-HR. (D) Frequency distribution of weight categories “underweight,” “normal weight,” and “overweight/obesity” according to MRD-SR, -MR, and -HR. (E) Hazard ratio (HR) in the group of female patients with ALL aged ≥10 years. (F) HR in the group of male patients with ALL aged ≥10 years.
Table 3.
Five-year EFS, OS, and cumulative incidence of relapse and death according to MRD risk group and weight category in male patients aged ≥10 years
| Underweight (1) |
P value (1) ↔ (2) | Normal weight (2) |
P value (2) ↔ (3) | Overweight/obesity (3) |
P value (3) ↔ (1) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Events | % (SE) | n | Events | % (SE) | n | Events | % (SE) | ||||
| MRD-SR | ||||||||||||
| EFS | 11 | 0 | 100.0 (0.0) | .32 | 103 | 9 | 95.0 (2.2) | .13 | 25 | 5 | 80.0 (8.0) | .14 |
| OS | 11 | 0 | 100.0 (0.0) | .58 | 103 | 3 | 98.0 (1.4) | .08 | 25 | 3 | 92.0 (5.4) | .28 |
| Cum incidence of relapse | 11 | 0 | 0.0 (0.0) | .37 | 103 | 7 | 3.1 (1.7) | .06 | 25 | 5 | 20.0 (8.2) | .13 |
| Cum incidence of death | 11 | 0 | 0.0 (0.0) | .74 | 103 | 1 | 1.0 (1.0) | .62 | 25 | 0 | 0.0 (0.0) | na |
| MRD-MR | ||||||||||||
| EFS | 45 | 11 | 74.8 (6.6) | .6 | 246 | 53 | 79.2 (2.6) | .0062 | 44 | 18 | 63.0 (7.4) | .13 |
| OS | 45 | 6 | 91.0 (4.3) | .94 | 246 | 33 | 88.0 (2.1) | .25 | 44 | 9 | 83.7 (5.6) | .43 |
| Cum incidence of relapse | 45 | 10 | 23.0 (6.5) | .48 | 246 | 45 | 17.5 (2.5) | .047 | 44 | 14 | 30.1 (7.1) | .35 |
| Cum incidence of death | 45 | 1 | 2.2 (2.2) | .93 | 246 | 5 | 2.0 (0.9) | .32 | 44 | 2 | 4.5 (3.2) | .56 |
| MRD-HR | ||||||||||||
| EFS | 11 | 3 | 72.7 (13.4) | .59 | 59 | 21 | 66.1 (6.2) | .029 | 13 | 9 | 30.8 (12.8) | .06 |
| OS | 11 | 2 | 81.8 (11.6) | .63 | 59 | 16 | 72.8 (5.8) | .0012 | 13 | 9 | 30.8 (12.8) | .029 |
| Cum incidence of relapse | 11 | 2 | 18.2 (12.3) | .65 | 59 | 14 | 23.7 (5.6) | .72 | 13 | 4 | 30.8 (13.8) | .52 |
| Cum incidence of death | 11 | 1 | 9.1 (9.1) | .94 | 59 | 6 | 10.2 (4.0) | .0090 | 13 | 5 | 38.5 (14.4) | .11 |
Cum, cumulative; na, not applicable (0 events in both groups).
Interestingly, although male patients who were overweight/obese in the MRD-MR group had an increased risk of relapse (Figure 4A), patients who were overweight/obese in the MRD-HR group showed an increased incidence of death during the first 2 years of therapy (Figure 4B). The cause of death in these patients was mainly attributable to chemotherapy or hematopoietic stem cell transplantation.
Figure 4.
Obesity is an independent risk factor in male patients aged ≥10 years with ALL. (A) Cumulative incidence of relapse in male patients aged ≥10 years with MRD-MR. (B) Cumulative incidence of death in male patients aged ≥10 years with MRD-HR.
Discussion
Although survival outcomes for children and adolescents with ALL have improved considerably over the past decades, male patients with ALL still experience inferior EFS compared with female patients.1 The inferior outcomes of boys with BCP-ALL have been attributable to higher incidence of relapses, especially involving the central nervous system.1 In this study, we identified overweight/obesity as an independent risk factor in male patients aged ≥10 years in the ALL-BFM 2000 study conducted in study centers in Germany, Austria, and Switzerland. The association between body weight at diagnosis and outcome in pediatric ALL has been investigated previously: some studies did not observe any association between body weight and survival,3,6,8 whereas others detected a significant negative impact of overweight and/or obesity on OS and/or EFS in pediatric ALL.4,7,9,11 In one of the large US cohort studies, obesity at diagnosis was shown to independently predict the likelihood of relapse and cure in patients aged ≥10 years with ALL.4 However, in this study, male sex was not associated with a statistically significant HR in the multivariate analyses.4 We now show that overweight/obesity at diagnosis is associated with an increased relapse and death in male patients with ALL aged ≥10 years.
Previous studies evaluating the impact of body weight on outcomes in childhood ALL have either excluded patients with T-ALL from analysis3,7 or have analyzed BCP-ALL and T-ALL collectively.4, 5, 6,8, 9, 10, 11, 12 We independently analyzed 674 patients with T-ALL and found that overweight/obesity was associated with inferior prognosis, particularly among patients aged ≥10 years, mirroring observations in patients with BCP-ALL in this and previous studies.7
The prevalence of obesity among children and adolescents varies in different geographic regions ranging from 3.79% in Western Europe to 17.17% in Northern America.25 Therefore, the impact of overweight and obesity on the outcome of ALL may be more pronounced in countries with a high obesity prevalence. In Germany, the prevalence of overweight and obesity in children and adolescents has increased from the 1990s to the early 2000s and has since then stabilized at ∼15%.26 It will be interesting to assess the outcome of male patients aged ≥10 years with overweight/obesity in contemporary ALL protocols.
Overweight/obesity may contribute to inferior outcomes through 2 mechanisms: first, chemotherapy resistance potentially increasing relapse risk; and second, higher susceptibility to treatment-related toxicity. Previous meta-analyses predominantly reported higher BMI to be associated with increased mortality rather than relapse in childhood ALL.13,16 Our findings suggest that this may depend on the MRD risk group because male patients aged ≥10 years within the MRD-MR or MRD-HR groups showed a higher incidence of relapse or mortality, respectively. However, the limited number of events precludes definitive conclusions.
The mechanisms underlying the vulnerability of male patients aged ≥10 years with overweight/obesity warrant further investigation. During adolescence, body composition changes, with an increase in body fat mass in both sexes (girls > boys).27 However, male adolescents have been shown to exhibit a higher proportion of visceral adiposity,28 which is linked to a higher risk for metabolic syndrome and chronic inflammation.29,30 In obesity, adipocyte hypertrophy and/or hyperplasia result in the expansion of white adipose tissue leading to local hypoxia, increased adipocyte death, recruitment of immune cells, and production of inflammatory mediators.31 This may lead to the formation of a protumorigenic microenvironment in fat depots.31 Chronic adipose tissue inflammation may be more pronounced in adolescents than in younger children. Clinical trials using dual-energy X-ray absorptiometry scans for patients with ALL have revealed a change in body composition, including increased body fat and reduced lean muscle mass.32 Whether male adolescents with ALL show higher increase in visceral fat than female adolescents over the course of intense chemotherapy remains to be determined.
Obesity-related,33 age-dependent,34 and potentially sex-dependent35 alterations in drug distribution and clearance may result in a less favorable balance between treatment efficacy and tolerability in male adolescents who are overweight/obese. Chemotherapy dosing based on body surface area (BSA) results in a relatively lower drug dose per kilogram of body weight in adolescents than in younger children, which could contribute to the poorer outcome observed in older patients. This effect may be further amplified by routine vincristine dose capping at a BSA of >1.33 m2, which affected significantly more male patients than female patients (20.8% vs 17.4%; P(χ2) = .00328). Additional individual physician-directed dose capping for patients with a BSA of >2 m2, more closely linked to obesity, was not systematically recorded. However, excluding patients with a BSA of >2 m2 only marginally affected the inferior EFS in male patients aged ≥10 years with ALL (5-year EFS, 54.9% ± SE 5.7% vs 59.9% ± SE 6.9% after exclusion). Patients with ALL commonly gain weight during therapy.36,37 Therefore, the proportion of patients affected by dose capping is likely to increase during treatment. Because longitudinal anthropometric data were not available, sex-specific differences in treatment-associated weight gain could not be assessed in this study. Considering that weight extremes during therapy have been associated with inferior survival,10 we propose integrating standardized BMI assessments into ALL study protocols. Furthermore, increased androgen levels during puberty may modulate chemotherapy sensitivity in male patients vs female patients,38,39 although data remain limited and body weight itself influences testosterone levels.40 Therefore, to determine how sex-specific hormones influence outcome in patients with ALL, androgen levels could be determined in adolescent patients with ALL under therapy.
Diets are increasingly incorporated into conventional chemotherapeutic regimens. For example, fasting-mimicking diets induce systemic metabolic changes and activate antitumor immune programs during chemotherapy.41 Dietary interventions are currently being evaluated in ALL,42, 43, 44 demonstrating the feasibility of the diet and the potential to prevent weight gain43 or at least reduce gain in fat mass in patients who are overweight/obese.44 These dietary regimens may also help to avoid long-term consequences of therapy-induced metabolic syndrome observed in long-term survivors of ALL.45 Successful dietary interventions require a thorough understanding of the relationship between body weight and survival in pediatric ALL and the identification of patients most likely to benefit. Our data suggest that male patients with ALL aged ≥10 years represent a particularly vulnerable group that may profit the most from such dietary interventions during therapy.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Declaration of generative AI and AI-assisted technologies in the writing process: During the preparation of this work, the authors used ChatGPT (GPT-5, Open AI) for wording suggestions during the writing process. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Acknowledgments
The authors thank the patients and their legal guardians for participation in this study.
The conduct of the study was supported by Deutsche Krebshilfe e.V., Bonn, Germany (grants 50-2698 Schr1 and 50-2410 Ba7), Oncosuisse/Krebsforschung Schweiz (grant OCS 1230-02-2002), and St. Anna Kinderkrebsforschung Austria. J.Z. received funding from the German Research Foundation (project number 520584003) and has been a fellow of the Margarete von Wrangell Habilitation program supported by the State of Baden-Wuerttemberg and the European Social Fund.
Authorship
Contribution: J.Z. and P.F.-P. contributed to the conceptualization; M.Z. contributed to the data curation and formal analysis; J.Z. contributed to the funding acquisition and writing of the original draft; M.Z., C.D., A.M., and J.Z. contributed to the investigation; M.Z. and A.B. contributed to the methodology; M.Z., A.M., J.A., A.A., N.B., G.C., M.S., K.-M.D., and P.-F.P. contributed to the project administration; A.M., J.A., A.A., N.B., G.C., M.S., K.-M.D., and P.F.-P. contributed to the resources; K.-M.D. and P.-F.P. contributed to the supervision; M.Z. and J.Z. contributed to the visualization; and all authors contributed to the review and editing of the manuscript.
Footnotes
Deidentified data are available to qualified researchers who submit an in-scope proposal. The data will be available from the authors of the publication (Zimmermann.Martin@mh-hannover.de) to ensure that data are used in accordance with the informed consent. Data are provided for the sole use of the approved request (tertiary dissemination will not be permitted). To gain access, data requesters will need to sign a data sharing agreement.
The full-text version of this article contains a data supplement.
Supplementary Material
References
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