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Metabolic syndrome in childhood leukemia survivors
reason why in this study we selected only patients with a metabolic syndrome from the LEA and IPC cohorts (Figures 1 and 2).
When assessing the metabolic syndrome patients in both groups (n=106 in the LEA group, n=145 in the control group), metabolic profile differed between the two groups of patients. In the LEA group with metabolic syndrome, patients had significantly higher levels of triglycerides [mean triglyceride level: 2.74±0.4 mmol/L (LEA patients) vs. 1.5±0.1 mmol/L (IPC patients); P=0.001] and elevated systolic and diastolic blood pressure (mean systolic blood pressure: 137.1±1.3 (LEA) and 132.8±1.1 mmHg (IPC); P=0.005; mean diastolic blood pressure: 81.7±1.1 (LEA) vs. 78.5±0.8 mmHg (IPC); P=0.01 (Figures 1 and 2).
Patients with metabolic syndrome from the LEA group who received TBI had a particular metabolic profile: in spite of a smaller mean abdominal circumference [91±2 (LEA) vs. 99.6±1.5 cm (IPC); P=0.01], these patients dis- played higher mean triglyceride levels (3.99±1.06 vs. 1.5±0.07 mmol/L, respectively; P<0.001), higher mean blood pressure (systolic blood pressure: 137.9±2.2 mmHg vs. 132.8±1.1, respectively; P=0.005) and higher mean fast- ing glucose levels (6.2±0.3 vs. 5.6±0.1 mmol/L, respective- ly; P=0.049) than patients with metabolic syndrome from the control group. By contrast, metabolic syndrome patients from the LEA group who received CNS irradia- tion without TBI also displayed higher triglyceride levels (mean: 2.17±0.25 mmol/L vs. 1.5±0.07, respectively; P=0.002) but had a larger waist circumference (109±4.5 cm vs. 99.6±1.5 cm, respectively; P=0.007) compared with metabolic syndrome patients in the control group.
Metabolic syndrome patients who received HSCT without TBI in the LEA cohort showed higher systolic blood pressure levels (mean: 140.6±8.1 mmHg vs. 132.8±1.1 mmHg, respectively; P=0.039) but lower fasting glucose levels (mean: 4.4±0.6 mmol/L vs. 5.6±0.1 mmol/L; P=0.049) compared with metabolic syndrome controls. Lastly, LEA patients with metabolic syndrome who were treated with chemotherapy only displayed higher triglyc- eride levels (1.94±0.17 vs. 1.5±0.07 mmol/L, respectively; P=0.008) and higher systolic blood pressure (138.6±1.5 vs. 132.8±1.1; P=0.02) compared with metabolic syndrome controls.
Discussion
Here we report on one of the largest comparative stud- ies on metabolic syndrome prevalence among adults treat-
ed for AL during childhood or adolescence. We found that patients from the LEA cohort were at greater risk of devel- oping metabolic syndrome (OR=2.49, 95%CI: 1.91-3.25) compared to controls, regardless of the treatment they received.
Furthermore, the risk was significantly higher for patients treated exclusively with chemotherapy compared to controls (OR= 1.68, 95%CI: 1.17-2.41; P=0.005), a fact which has never been shown before, even though it had been suspected. The results presented in previous meta- analyses or comparative studies have so far remained unconfirmed, probably due to the relatively low number of patients receiving chemotherapy only11,29-31 or the lack of proper controls.32,33 The Saint Jude study published by Nottage et al.11 reported a higher risk of metabolic syn- drome in 784 AL survivor patients as compared to con- trols, but 64.6% of them had received cranial irradiation. In the subgroup of patients treated exclusively with chemotherapy, no significant increase in the risk of devel- oping metabolic syndrome could be shown, probably due to the small number of patients who received chemother- apy only (n=277). By contrast, the LEA patients included in this study were mainly treated with chemotherapy only (n=637, 62.2%). So, we demonstrate here that, even in the case of treatment with chemotherapy only, the metabolic syndrome risk is higher among long-term AL survivors than in the control population. This is important since nowadays, the majority of children treated for an AL will receive only chemotherapy, without any irradiation or HSCT. Several mechanisms have been discussed to explain how metabolic syndrome develops after chemotherapy treatment. Alkylating agents are known to induce mitochondrial dysfunction and endothelial cyto- toxicity, which can lead to insulin resistance, steatosis and hypertension. Anthracyclins and antimetabolites can also cause mitochondrial and endothelial dysfunction. Steroids can induce hyperglycemia and dyslipidemia. Vinca alka- loids induce endothelial toxicity and can cause hyper- glycemia by inhibition of GLUT2/4 vesicle translocation.34 Lastly, iron overload, a frequent complication after multi- ple transfusions in patients treated for acute leukemia, could also increase the risk for metabolic syndrome through hepatic toxicity. As a consequence, the notable metabolic syndrome risk in patients treated exclusively with chemotherapy, who represent the majority of future AL survivors, should be taken into careful consideration throughout their long-term follow up.
This high risk among LEA patients is striking given that the LEA patients were found to benefit from more favor-
Table 3. Metabolic syndrome prevalence among Leukemia in Children and Adolescents (LEA) patients according to treatment modality. Comparison with the Investigation and Clinical Prevention) (IPC) group (sex- and age-matched controls).
IPC patients
LEA patients
Chemotherapy alone, no CNS irradiation Chemotherapy+CNS irradiation
HSCT without TBI
HSCT after TBI conditioning
N
3203
1025
637 / 1025 (62.2%) 143 / 1025 (13.9%) 77 / 1025 (7.5%) 168 / 1025 (16.4%)
Metabolic syndrome n (%)
145 (4.5%)
106 (10.3%) 42 (6.6%) 18 (12.6%) 7 (9.1%) 39 (23.2%)
OR (95% CI)
-
2.49 (1.91 – 3.25) 1.68 (1.17 – 2.41) 2.32 (1.36 – 3.97) 2.18 (0.97 – 4.86) 6.26 (4.17 – 9.36)
P
-
<10-3
0.005
0.002
0.057
<10-3
N/n: number; OR: Odds Ratio; CI: Confidence Interval; CNS: central nervous system; HSCT: hematopoietic stem cell transplantation; TBI: total body irradiation. Significant val- ues are in bold.
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