Clinical Challenges: Pediatric ALL in Children With Obesity

For almost 40 years, the incidence of pediatric B-cell acute lymphoblastic leukemia (B-ALL), the most common malignancy seen in children and adolescents and young adults (AYAs), has risen steadily, accompanied by explosive growth in the prevalence of childhood obesity.

Although obesity has been strongly linked to 13 cancers in adults, and is suspected as a risk factor in many hematologic malignancies, the relationship between obesity and childhood cancer is less clear. Experts agree that managing outcomes in young patients with leukemia who are overweight or obese remains a significant clinical challenge.

“Obesity is a real problem when it comes to childhood and adolescent B-ALL outcomes,” Lucie M. Turcotte, MD, of the University of Minnesota School of Medicine in Minneapolis, told MedPage Today. “Multiple studies have shown that obesity is associated with inferior post-induction MRD [minimal residual disease] outcomes, along with worse event-free survival. Additionally, obesity is associated with increased rates of morbidity, which can make these children challenging to treat.”

“Malnutrition, including both overweight and underweight, is an independent modifiable prognostic factor in children with leukemia,” Paul C. Rogers, MD, of the University of British Columbia and BC Children’s Hospital in Vancouver, Canada, told MedPage Today.

“Despite growing evidence, nutrition supportive care during therapy is not a priority for clinicians,” emphasized Rogers, who is former chairman of the nutritional committee of the Children’s Oncology Group (COG). “Nutritional assessment should be undertaken from time of diagnosis and continue through therapy.”

Two recent studies provide novel evidence of the association between obesity and increased risk of high-risk B-ALL and the effectiveness of a non-pharmacologic intervention for reducing MRD risk.

In the first, the authors of a COG study point to an analysis of data from 4,726 children and AYAs with high-risk B-ALL who participated in five COG frontline treatment studies. Associations between prognostic B-ALL characteristics and body mass index (BMI) categories were compared with data from the National Health and Nutrition Examination Survey.

The results, reported by Turcotte and colleagues in 2020 in Cancer Medicine, showed that obesity was associated with B-ALL among boys (OR 1.57, 95% CI 1.30-1.91) and children of Hispanic descent, particularly during adolescence (OR 1.78, 95% CI 1.39-2.29).

There was also an association between obesity and risk for ALL central nervous system (CNS) involvement. Obesity was associated with higher rates of CNS 1-2 status in boys but not in girls, and in participants who were Hispanic. In addition, the findings confirmed an association between underweight status and ALL.

These findings have important implications for the prevention and treatment of obesity in children and adolescents to reduce cancer risk, and point to the need for more research to determine the relationship between obesity and other pediatric malignancies, the investigators said.

“ALL is a rare outcome and our data require further validation, but I think [high-risk B-ALL risk] can be added to the long list of reasons obesity can be detrimental to children’s health,” Turcotte noted. “It really is a public health and public policy issue.”

“We should continue to advocate for public health initiatives that bridge the gap between dietary guidelines and affordability, availability, and accessibility of healthy foods to children in all environments,” agreed Neha Manjari Akella, PhD, a postdoctoral fellow at University of British Columbia.

Meanwhile, the prospective, randomized Improving Diet and Exercise in ALL (IDEAL) trial shows that nutrition and exercise interventions can work. In 40 overweight/obese pediatric patients between the ages of 2 and 30 with newly diagnosed B-ALL, the IDEAL plan reduced calories by 20% or more prior to day 4 of induction.

When compared with 80 historical controls treated with the same COG-style induction regimen but not the IDEAL intervention, the strategy significantly reduced MRD risk in all patients, regardless of initial BMI (OR 0.30, 95% CI 0.09-0.92, P=0.02). The IDEAL plan also increased circulating adiponectin and reduced insulin resistance, identifying both as potential biomarkers of B-ALL chemosensitivity, the researchers reported.

“This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response,” wrote Etan Orgel, MD, director of the Medical Supportive Care Service at the Cancer and Blood Disease Institute of Children’s Hospital Los Angeles, and colleagues in Blood Advances.

An NCI-funded consortium trial will validate the findings, beginning this summer, Orgel told MedPage Today. “We are excited by the success of the intervention.”

Patients and their families “enthusiastically embraced” the intervention early in therapy, Orgel added. “We found that our patients were happy to be actively involved in their leukemia therapy, beyond simply taking the pills and medicines prescribed. The high levels of adherence in the trial open a new door for timing of these types of interventions with the possibility of making positive changes from day 1 of therapy.”

The strategy, which includes an at-home exercise program, can be implemented wherever patients are being treated: in hospital or at home, and in larger centers or smaller clinics, Orgel pointed out. “If the IDEAL intervention is successful in this broader setting, it could easily be incorporated into routine practice for all patients with B-ALL.”

The next study will explore whether adiponectin acts directly on ALL cells or is an indirect marker of something else, co-author Steven Mittelman, MD, PhD, chief of pediatric endocrinology at UCLA Mattel Children’s Hospital, told MedPage Today. “Understanding the multiple different ways that obesity, diet, and exercise interact to affect leukemia cell chemoresistance will hopefully allow us to better hone our interventions to make them even more effective.”

Although more than 75% of patients stuck to the IDEAL diet, most did not adhere to the strategy’s home-based exercise regimen, Orgel noted. In the successor trial, weekly visits with a physiotherapist have been added to encourage patients, with step goals and movement reminders aimed at increasing general activity each day.

“Together, we believe these will help improve the intervention response, and particularly, help reduce the loss of muscle in the first month of therapy,” he said.

“I am hopeful that non-pharmacologic strategies like this could improve outcomes in B-ALL,” Turcotte said of the IDEAL intervention. “As a pediatric oncologist, I can envision the challenges of carrying out an intervention like this during induction, but if we have data to support its efficacy, we may have greater success at getting patient and family buy-in. We are often asked by families if there are things they could or should be doing to optimize treatment and this seems promising.”