Introduction
Methodology of the Review
Epidemiologic Evidence Linking Obesity to Leukemia
Evidence from Epidemiologic Studies and Meta-Analyses
Author/year | Study/population | Findings of the study | Comments |
---|---|---|---|
Ahmed et al. 2023 [39] | 290,888 Participants 21,972 Cases of cancer A population-based study, UK | ✓ ↑ Risk for hematologic malignancies [e.g., lymphoid leukemia: HR = 1.83, 95% CI = 1.44 to 2.33] and higher BMI was reported. ✓ Patients’ metabolic profile associated with leukemia risk included ↑ BMI, ↑ serum CRP, and ↑ cystatin C levels. | ✓ ↑ BMI, ↑ serum CRP and ↑ cystatin C levels were associated with ↑ risk of leukemia, especially lymphoid leukemia. |
Yi et al. 2020 [37] | Estimates from the Global Burden of Disease Study, in 195 countries/territories between 1990 and 2017, 2017 | ✓ ↑ Risk for AML was reported in association with a higher BMI. | ✓ The burden of AML has ↑ during the last years in association with an ↑ in obesity. |
Amankwah et al. 2016 [41] | 13,921 Cases were included. A meta-analysis study, including 11 studies | ✓ ↑ Risk of mortality with ↑ BMI at diagnosis was reported (OS: HR = 1.30, 95% CI = 1.16–1.46 and EFS: HR = 1.46, 95% CI = 1.29–1.64). | ✓ ↑ BMI at diagnosis was associated with a poor OS and EFS among children with acute leukemia. |
Bhaskaran et al. 2014 [36] | 5,240,000 UK adults, among whom 166,955 developed cancer. A population-based cohort study, UK | ✓ Each 5 kg/m2 increase in BMI was linearly related to the risk of leukemia (1.09, 1.05–1.13; p ≤ 0·0001). | ✓ ↑ BMI was related to ↑ risk of leukemia, among other cancers. |
Jeddi et al. 2010 [42] | 39 Patients with APL A study in a Tynisian hospital. | ✓ 11 of the 36 patients evaluated for DS (30.5%) developed DS (severe in 7 cases, moderate in 4, and fatal in 3 cases) within a median of 12 days of treatment with ATRA. Six of the 9 (66.6%) patients with BMI ≥ 30 developed DS vs. 5 of 27 (18.5%) with BMI < 30 (p = 0.012). | ✓ BMI ≥ 30 was a significant predictor of developing DS in APL. |
Strom et al. 2009 [43] | 253 Cases 270 Controls A hospital based case-control study in Texas, USA | ✓ Cases were obese during adulthood, when compared with controls at age 25 [OR = 4.29; 95% CI, 1.63–11.3], at age 40 (OR = 5.12; 95% CI, 1.92–13.6), and at diagnosis (OR = 3.09; 95% CI, 1.56–6.13). | Obesity and weight gain in adulthood are significant risk factors for developing CML. |
Wong et al. 2009 [44] | 722 Cases of AML 1444 Controls A case-control study in Shanghai, China | ✓ An inverse relationship between BMI and overall AML or the sub-category “AML not otherwise categorized,” was reported, whereas a positive association between BMI and the subtype APL was noted. | ✓ Categorization by WHO subtypes may not be so significant regarding risk factors for AML. |
Larsson et al. 2008 [31] | 7,780,338 Participants among whom 17,349 patients with leukemia A meta-analysis of 9 cohort studies | ✓ A 5 kg/m2 ↑ in BMI was related to a 13% ↑ risk of leukemia (RR, 1.13; 95% CI, 1.07–1.19). ✓ In a meta-analysis of 4 studies, the RRs related to obesity were 1.25 (95% CI, 1.11–1.41) for CLL, 1.65 (95% CI, 1.16–2.35) for ALL, 1.52 (95% CI, 1.19–1.95) for AML and 1.26 (95% CI, 1.09–1.46) for CML. | ✓ This meta-analysis supports that ↑ BMI is associated with ↑ risk of leukemia, either acute or chronic forms. |
Chiu et al. 2006 [45] | 35,420 Participants A cohort study in Chicago, USA | ✓ For women, there was a trend for ↑ mortality from leukemia with ↑ BMI (HR, 2.47; 95% CI, 0.96–6.36; p = 0.02). | ✓ A trend for an association between ↑ BMI and ↑ mortality from leukemia was noted only in women. |
Kasim et al. 2005 [46] | 1068 Cases 5039 Controls A population-based cohort study in Canada | ✓ The authors reported a relationship between the highest BMI for AML, CML, and CLL, with a dose-response association. | ✓ The highest BMI was associated with ↑ risk for AML, CML and CLL. |
Ross et al. 2004 [47] | Over 40,000 Iowa women, by questionnaire. 200 Women developed leukemia: 74 AML and 88 CML. During follow-up. Minneapolis, USA | ✓ The risk of AML was ↑ among women, who had reported an ↑ BMI (RR for overweight, 1.9; 95% CI, 1.0–3.4; RR for obese, 2.4; 95% CI, 1.3–4.5; p = 0.006), when compared with women of normal BMI. | ✓ A trend between ↑ BMI and ↑ risk for AML and CLL was reported. |
Estey et al. 1997 [48] | 1245 Patients with AML whom 120 had APL. A hospital-based cohort study in Texas, USA | ✓ ↑ BMI has a positive relationship with diagnosis of APL (p = 0.0003). | ✓ The authors reported a strong association between ↑ BMI and ↑ risk for APL. |
Birth Weight and Childhood Leukemia
Author/year | Study population | Findings of the study | Remarks |
---|---|---|---|
Stacy et al. 2019 [57] | 1,827,875 Infants with 747 children being diagnosed with leukemia before the age of 14 y.o. A prospective cohort analysis. | ✓ Children born to mothers with a BMI ≥ 40 had a 57% (95% CI: 12, 120) higher risk for childhood leukemia. ✓ Newborn size of ≥ 30% higher than expected related to a 1.8-fold HR for leukemia, when compared to those with the expected size. | ✓ Maternal obesity and increased newborn size may be involved in an ↑ risk for developing childhood leukemia. ✓ Increased insulin and IGFs may underlie these findings. |
Jimenez-Hernadez et al. 2018 [58••] | 1455 Children with leukemia. 1455 controls. 0–18 y.o. A case-control study | ✓ A significant relationship between ALL and child’s birthweight ≥ 2500 g was reported (aOR 2.06; 95% CI: 1.59, 2.66). ✓ This association was observed in those with birthweight ≥ 3500 g as well (aOR 1.19; 95% CI: 1.00, 1.41) | ✓ BW ≥ 3500 g was related to ALL and AML. ✓ There was a relationship between ↑ BW and ↑ risk of acute leukemia. |
Tran et al. 2017 [59] | 124 Children with leukemia 822 Controls A case-control study | ✓ ORs of leukemia risk for children with low and high BWs were 0.8 (95% CI: 0.2, 3.0) and 1.4 (95% CI: 0.7, 2.6), respectively. | ✓ No statistically significant relationship between BW and childhood leukemia was noted. ✓ However, this study was performed mainly to estimate the risk for CNS tumors among different BW. |
Sprehe et al. 2010 [56] | 2254 Children with cancer aged < 5 y.o. at cancer diagnosis 11,734 Controls, matched for age A total of 13,988 children A retrospective chart review | ✓ Children with BW LGA at birth had a 1.66 (95% CI 1.32–2.10) higher odds of ALL, compared to children with BW AGA. ✓ Children with a BW ≥ 4000 g had a 1.5 (95% CI 1.18–1.89) higher odds for ALL, compared to children who had BW > 2500 and < 4000 g. ✓ ORs were similar for LGA children who were < 4000 g and LGA children who were ≥ 4000 g (OR: 1.5, 95% CI 0.97–2.5 and OR: 1.67, 95% CI 1.29–2.16, respectively) | BW, especially when corrected for gestational age was a better predictive factor of BW alone for the development of ALL. |
Milne et al. 2009 [52] | 347 Children with cancer aged 0–14 y.o. 762 Controls aged 0–14 y.o. A case-control study | ✓ Risk of ALL was related to proportion of optimal BW; the OR for a 1 standard deviation ↑ in proportion of optimal BW was 1.18 (95% confidence interval: 1.04, 1.35) after adjustment for matching variables and various confounders. | ✓ Accelerated growth at birth, even more than BW per se, was related to ↑ risk for ALL. ✓ A potential implication for IGFs may underlie the abovementioned findings. |
Caughey et al. 2009 [53] | 16,501 Children with leukemia, aged ≤ 30 y.o. In particular: 10,974 Children with ALL. 1832 Children with AML. A meta-analysis of 32 studies. | ✓ OR for the relationship between high BW and ALL and AML were 1.23 (95% CI: 1.15, 1.32) and 1.40 (95% CI: 1.11, 1.76), respectively, when compared to normal BW. ✓ ↑ BW was not related to overall and ALL leukemia, but only to AML (OR = 1.50; 95% CI: 1.05, 2.13). | ✓ This meta-analysis reported an ↑ risk for overall cases of leukemia as well as ALL with regards to ↑ BW. |
Hjalgrim et al. 2003 [60] | 10,282 Children with leukemia. A meta-analysis of 18 epidemiological studies | ✓ Children with BW ≥ 4000 g have an ↑ risk of ALL, when compared with children with ↓ BW (OR = 1.26, 95% CI: 1.17, 1.37) | A dose-response-like effect for the association between BW and ALL. |
Limitations of Epidemiologic Studies and Meta-Analyses
Obesity and Childhood ALL Survivors
Weight Gain Among Survivors of Childhood
Relationship Between Excess Body Weight and Risk of Relapse and Mortality
Research/year | Population/type of study | Main findings | Remarks |
---|---|---|---|
Baillargeon et al. 2006 [86] | 322 Pediatric patients with B-precursor ALL, aged 2–18 y.o. Retrospective cohort study | Obesity at diagnosis was not related to ↓ OS (HR: 1.40, 95% CI: 0.69–2.87) or ↓ EFS (HR: 1.08, 95% CI: 0.65–1.82) in the overall study or in either of the age subgroups: 2–9 y.o. and 10–18 y.o. | ✓ Patients were mainly of Hispanic white origin. ✓ No association between obesity and OS/EFS was noted. |
Ethier et al. 2012 [87] | 238 Patients with ALL aged 2–18 y.o. Retrospective chart review | Patients with ↑ BMI had ↓ 5-year EFS (62.2 ± 12.1% vs. 83.6 ± 2.6%; p = 0.02) and OS (80.7 ± 8.7% vs. 92. ± 1.9%; p = 0.005). | ✓ Obese patients with childhood ALL have ↓ OS. |
Aldhafiri et al. 2014 [88] | 1033 Patients with ALL aged 2–18 y.o. National cohort study (UK) | No evidence that weight at diagnosis was associated with risk of relapse: log-rank test (p = 0.90) with overweight and obesity as the exposure (n = 917); individual (p = 0.42) and stepwise (p = 0.96) proportional hazard models. | ✓ Overweight/obesity does not change the prognosis of childhood ALL. |
Orgel et al. 2016 [89] | 8680 Patients with ALL aged 0–21 y.o. Meta-analysis from 11 studies | ↓ EFS in patients with an ↑ BMI (RR: 1.35; 95% CI: 1.20-1.51) compared to those with ↓ BMI. There was a statistically non-significant trend towards ↑ risk of relapse (RR: 1.17; 95% CI: 0.99-1.38) in patients with ↑ BMI. | ✓ An ↑ BMI at diagnosis was related to ↑ mortality in ALL patients (RR: 1.31; 95% CI: 1.09-1.58). |
Amankwah et al. 2016 [41] | 13,921 Patients aged < 21 y.o. Meta-analysis from 11 studies | ↑ Risk of mortality with ↑ BMI (OS: HR: 1.30, 95% CI: 1.16–1.46 and EFS: HR: 1.46, 95% CI: 1.29–1.64). | ✓ Targeting obesity in pediatric ALL patients may improve OS. |
Saenz et al. 2018 [90] | 181 Pediatric leukemia patients aged 2–17 y.o. Retrospective cohort study and meta-analysis | The present study did not show a significant relationship between obesity and mortality from ALL. Pooled analysis showed a relationship between overweight/obesity and ↑↑ mortality in ALL (HR: 1.39, 95% CI: 1.16–1.46). In children > 10 y.o., a relationship between obesity and relapse was observed. | Small sample size ✓ ↑ Risk of mortality among children with overweight/obesity in the meta-analysis. |
Nunez-Enriquez et al. 2019 [75] | 1070 Children with ALL aged < 15 y.o. Multicenter cohort study | Overweight/obesity at diagnosis was a predictive factor of early mortality (WHO: HR: 1.4, 95%, CI: 1.0–2.0; CDC: HR: 1.6, 95% CI: 1.1–2.3). No relationship between overweight (WHO: HR: 1.5, 95% CI: 0.9–2.5; CDC: HR: 1.0; 95% CI: 0.6–1.6) and obesity (WHO: HR: 1.5, 95% CI: 0.7–3.2; CDC: HR: 1.4; 95% CI: 0.9–2.3) with early relapse was noted. | ✓ Overweight and obesity either according to WHO or CDC criteria were associated with early mortality in childhood ALL. ✓ However, overweight/obesity was not related to early relapses. |
Biological Mechanisms Associating Obesity with Leukemia
Insulin, Insulin Resistance, and the IGF-1 Axis
Dyslipidemia and Lipid Signaling
Sex Hormones
Chronic Inflammation and Oxidative Stress
Dysregulation of Cytokines and Adipokines
Bone Marrow Adiposity and Bone Marrow Microenvironment
Metabolic Characteristics of Bone Marrow Adipose Tissue and Leukemia
The Role of Adipose-Derived Stem Cells
Other Emerging Mechanisms
Preventive and Therapeutic Perspectives
Preventive Measures (Diet, Bariatric Surgery, Physical Exercise)
Biomarkers
Candidate Therapeutic Agents Targeting Oncogenic Pathways of Obesity and Insulin Resistance in Leukemia
Agent | Target | Study | Main findings |
---|---|---|---|
Metformin | AMPK activation and downstream inhibition of mTOR activity | Scotland et al. 2010 [329] | • Concentration-dependent decrease in oxygen consumption in AML cell lines in vitro • Apoptosis induction-dependent on cell line (MOLM14) |
Green et al. 2010 [330] | • Reduction of synthesis of oncogenic proteins in AML cells • Proliferation inhibition and reduced survival of AML cells ex vivo • Inhibition of human AML cell growth in mouse xenograft models in vivo | ||
Rosilio et al. 2013 [331] | • Proliferation inhibition induction of apoptosis in human T-ALL cells in vitro | ||
Valkana et al. 2013 [332] | • Metformin suppresses CML leukemic precursors and Ph+ ALL cells | ||
Martinez Marignac et al. 2013 [333] | • Metformin is cytotoxic against Dasatinib-sensitive CLL cells in vitro | ||
Bruno et al. 2015 [334] | • Exposure of CLL cells to metformin reduces expression of proteins associated with survival and proliferation • Metformin induces CLL cell apoptosis and inhibits of cell cycle entry after CD40-CD40L ligation stimulus | ||
Adekola et al. 2015 [335] | • Metformin sensitizes CLL cells to Ritonavir in vitro | ||
Tseng 2020 [336] | • Neutral effect of metformin treatment on leukemia incidence among 610,089 type 2 DM patients | ||
Glitazones | PPAR-γ binding/activation | Sugimura et al. 1999 [337] | • Troglitazone reduces cell growth in human eosinophilic, myelomonocytic, and myelomonoblastic leukemia cell lines via induction of a p21 cyclin-dependent kinase inhibitor. |
Hirase et al. 1999 [338] | • Rosiglitazone and Troglitazone induce apoptosis and monocytic differentiation on a HL60 promyelocytic leukemia cell line. | ||
Konopleva et al. 2004 [339] | • Rosiglitazone and Troglitazone induce apoptosis and differentiation in leukemic cells in synergism with retinoid X receptor ligands | ||
Liu et al. 2005 [340] | • Troglitazone exerts anti-proliferative and apoptosis-inducing effects on human AML K562 and HL-60 cell lines, through upregulation of bax and downregulation of survivin and bcl-2 expression | ||
Takenokuchi et al. 2006 [341] | • Troglitazone dose-dependently inhibits cell growth and induces apoptosis human B-ALL cell lines with t(14;18) translocation. | ||
Saiki et al. 2006 [342] | • Pioglitazone dose-dependently inhibits colony formation in human leukemia cell lines (20–71%) and primary leukemia cells (1–25%) without considerably affecting healthy HSCs | ||
Prost et al. 2015 [343] | • Pioglitazone exhibits synergism with Imatinib on inhibition of CML cells in vitro. • Pioglitazone eradicates non-cycling, Imatinib-resistant CML stem cells in vitro. • Pioglitazone administration to Imatinib-treated CML patients in chronic residual disease results in complete molecular response prsisting up to 4.7 years after withdrawal. | ||
Fibrates | PPAR-α binding/activation | Scatena et al. 1999 [344] | • Bezafibrate, gemfibrozil, and clofibric acid inhibit proliferation and induce differentiation of human AML cell lines in vitro. |
Liu et al. 2006 [345] | • TZD18, a dual PPAR-α/-γ agonist inhibits growth of Ph(+) B-ALL cell lines in vitro to a greater degree than pioglitazone. | ||
Statins | HMG-CoA-reductase | Friedman et al. 2010 [346] | • Among 254 patients with CLL, statin therapy at the time of diagnosis did not affect overall and treatment-free survival, but was associated with reduced need for therapy in a subset of patient with short follow-up. |
Shanafelt et al. 2010 [347] | • Among 686 newly diagnosed CLL patients with Rai stage 0 disease, neither baseline statin therapy nor NSAIDs use had an impact on time to initial therapy, irrespective. • Among those treated with Rituximab-containing schemes, statin therapy had no effect on time to salvage therapy | ||
Podhorecka et al. 2010 [348] | • Simvastatin promotes CLL cell apoptosis via a reduction of BCL-2/BAX ratio, without affecting healthy lymphocytes • Simvastatin and fludarabine/cladribine exert synergistic cytotoxic effects on CLL cells | ||
Yavasoglu 2013 [349] | • Atorvastatin and rosiglitazone promote apoptosis of CLL lymphocytes in vitro. | ||
Chae 2014 [350] | • Concomitant intake of statin and aspirin was associated with longer progression-free and overall survival among 280 patients with refractory/relapsed CLL treated with Fludarabine, Cyclophosphamide, and Rituximab compared to each agent alone or no therapy. | ||
Chow et al. 2016 [351] | • Among 231 patients with CLL statin therapy was associated with a longer time to first treatment (57.5 vs. 36.0 months, p < 0.02) after excluding those with 17p deletion. | ||
Henslee 2018 [352] | • Fluvastatin and atorvastatin inhibit proliferation of natural killer leukemic cells and enhance the cytotoxic effects of chemotherapy. • The effects are likely mediated by inhibition of the mevalonate pathway downstream of HMG-CoA-reductase | ||
Gimenez et al. 2018 [353] | • Simvastatin decreases CLL cell survival and enhances the effectiveness of venetoclax and ibrutinib on an in silico model validated in vitro. | ||
Righolt et al. 2019 [354] | • In a case-control study (n = 1385 and 6841, respectively) the use of low-potency lipophilic statins (Fluvastatin/Lovastatin) was associated with a lower risk of CLL (OR vs. non-users 0.64, 95% CI 0.45–0.92) | ||
Jang et al. 2021 [355] | • Concomitant statin use increases the rate of deep molecular response in patients with CML under TKI therapy (55.8% vs. 41.0% at 5 years for n = 88 statin users vs. n = 320 non-users) | ||
Brånvall et al. 2021 [356] | • Among 3279 CLL patients, statin use at any time or follow-up (n = 753) was associated with lower disease-specific mortality. | ||
Aspirin | Cyclooxygenase-1/-2 | Bellosilo et al. 1998 [357] | • Aspirin and salicylate but not other NSAIDs induce a dose- and time-dependent apoptotic effect on CLL cells in vitro, through activation of the caspase pathway |
Weiss 2006 [358] | • In this case-control study of 169 adults with acute leukemia and 676 matched controls, aspirin used was associated with lower leukemia risk (aOR 0.84; 95% CI 0.59–1.21) | ||
Iglesias-Serret et al. 2010 [359] | • Aspirin induces apoptosis in various human leukemia cell lines in vitro by modulating the Mcl-1/Noxa balance. | ||
Ross 2012 [360] | • In this case-control study of 670 newly diagnosed myeloid leukemia cases (420 AML, 186 CML) and 701 controls, aspirin use was associated with lower risk of leukemia among women (OR 1.60; 95% CI 1.04–2.47) but not in men, | ||
Liang 2021 [361] | • Aspirin in combination with chidamide exert anti-proliferative effects on MDS-derived AML cells, likely through inhibition of the PI3K/Akt pathway. |