Obesity Has Early and Lasting Effects on Children with ALL

For children with B-precursor acute lymphocytic leukemia (BP-ALL), having a BMI ≥30 kg/m2 at the time of treatment initiation more than doubled the likelihood of having persistent leukemia, according to results from a study recently published in Blood. Obesity was actually one of the strongest predictors of treatment outcome, along with established predictors such as white blood cell count and cytogenetics.

The response to initial induction chemotherapy is traditionally measured by whether a patient has achieved a complete remission, determined by the absence of leukemia cells in the bone marrow in the setting of recovered blood counts. Minimal residual disease (MRD) takes this assessment a step further, in identifying remaining leukemia cells using more sensitive technology, such as flow cytometry.  According to the authors, led by Steven D. Mittelman, MD, PhD, and Hisham Abdel-Azim, MD, of the Children’s Hospital Los Angeles, MRD is among the strongest predictors of long-term survival and disease recurrence. However, they noted, “Whether obesity poses a uniform risk during this period or whether it contributes greater influence during certain phases of treatment has yet to be investigated.”

The investigators hypothesized that obesity during remission induction therapy is associated with persistent leukemia – as seen on end-of-induction MRD positivity– due in part to the “active” nature of adipocytes (fat cells) in the regulation of chemotherapy response in patients with ALL cell lines.

To test that hypothesis, the investigators analyzed a cohort of 198 pediatric patients who were diagnosed with BP-ALL between the ages of 1 and 21. All patients were treated with Children’s Oncology Group induction chemotherapy regimens for one month, either as a three-drug or four-drug regimen, depending on the patient’s risk level. Investigators assessed the influence of body mass index (BMI) on risk of MRD in the bone marrow; MRD was determined from flow cytometry analysis of bone marrow specimens collected at the end of induction therapy.

Approximately one-third of the cohort was classified as overweight (n=30; 15.2%) or obese (n=41; 20.7%) at the time of diagnosis. More than half of the cohort gained weight during the induction, the authors noted, with 22.7 percent of the “lean” group gaining enough weight to be classified as “overweight” or “obese” at the end of induction.

Twenty-three percent of lean patients had MRD (defined as ≥0.1% leukemia cells) after induction therapy, compared with 27 percent of overweight and 44 percent of obese patients.

On univariate analysis, obese children with BP-ALL were more than two-and-a-half times more likely to have residual leukemia as measured by MRD (odds ratio [OR] = 2.62 [95% CI 1.24-5.50; p=0.042]). This association held true when the authors conducted two separate multivariate analyses that took into account patients’ age, sex, ethnicity, white blood cell count, BMI, and cytogenetics.

Event-free survival up to five years was also significantly longer for children who were lean at the time of diagnosis. Additionally, the presence of MRD after induction therapy increased a patient’s risk of an event (hazard ratio = 3.48; 95% CI 1.00 -12.12; p=0.45). “Overweight or obesity may thus continue to exert an adverse impact on event-free survival even following the induction phase,” the authors wrote.

The effects of adiposity on survival in pediatric ALL, therefore, start early – already present and significant at the time of diagnosis – and endure through the next treatment phase. According to study author Etan Orgel, MD, of the Children’s Hospital Los Angeles, and colleagues, this raises the question of “whether obese patients should be considered as a higher risk group from time of diagnosis, analogous to adolescents, who could potentially benefit from more intensive therapy during induction.”

What explains this relationship between obesity and poorer outcomes with BP-ALL? While the mechanism has yet to be fully elucidated, the authors suggest that adipocyte-leukemia interactions may mediate the adverse impact of obesity noted in pediatric ALL.


Reference

Orgel E, Tucci J, Alhushki W, et al. Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia. Blood. 2014 October 27. [Epub ahead of print]

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