Investigating the relationship between age and body weight on toxicity and survival in pediatric AML: results from NOPHO-AML 2004

Finding optimal treatment strategies for pediatric patients with Acute Myeloid Leukemia (AML) is still a top priority, as approximately 30%–35% of patients die from resistant disease, relapse, or treatment-related toxicity.

Age and body weight are critical factors affecting patients’ outcomes; Ditte J.A. Løhmann et al. report that there was a link between being at an older age, being overweight at diagnosis, and inferior survival.¹ Older age has previously been associated with treatment related mortality (TRM). The situation for infants, in addition to older children, treated for AML is also of concern as they are reported to develop more serious infections.

Despite these observations the exact correlation between Body Mass Index (BMI), age, toxicity and survival is still to be determined. Consequently Ditte J.A. Løhmann from Aarhus University Hospital, Denmark, and colleagues investigated the effect of age and BMI on toxicity and survival in pediatric AML patients. With a median age of 6.4 years, 318 children were treated according to the NOPHO-AML 2004 protocol² for a length of 10 years; grade 3–4 toxicities were documented. Their study was published in Haematologica in July 2016.

The key published results

• The incidence of sepsis with hypotension was higher in children aged 10–17 compared to those aged 2–9 years.
• Older children (10–17 years old) demonstrated an increased risk of many different toxicities, examples include severe abdominal pain and admission to intensive care.
• The risk of developing grade 3–4 adverse events was higher is children aged 10–17 years and overweight children.
• The risk of experiencing toxicities during chemotherapy was very low among infants.
• Being overweight (BMI> +1 SD for age) at diagnosis did not seem to influence prognosis in children between 2 and 9 years of age.
• In children aged 10–17, 5-year EFS was 59% and 40% (adjusted HR 0.6, 95%CI: 0.3–1.1) and 5-year OS was 78% and 56% (adjusted HR 0.5 95%CI: 0.2–1.0) in overweight versus healthy cases, respectively.

In summary, the authors concluded that, when treated with the NOPHO-AML 2004 protocol, older children aged between 10 and 17 years experienced an increased risk of adverse events and were more likely to have inferior survival, in agreement with previously reported findings. However, an unexpected result of this analysis was that overweight children in the 10–17 age group were more likely to have increased survival compared to healthy children. The authors attribute this finding to the different pharmacokinetics of chemotherapeutic regimens in adolescents and this should be investigated in future studies. In addition, the results for infants were more encouraging; high doses of cytarabine administered to this patient group did not result in any significant adverse events.

Abstract

Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear.

We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n=318). Toxicity following induction and consolidation courses (n=6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (>1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0-3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 29 (64% vs. 76%; P=0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P=0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P=0.09) and 5-year overall survival 78% vs. 56% (P=0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.