Obesity Linked to Worst Outcomes in Children With ALL

Alexander M. Castellino, PhD

October 27, 2014

Obese children with B-cell acute lymphocytic leukemia (ALL) have significantly worse outcomes following induction chemotherapy compared with their lean counterparts, researchers report.

Previous studies have shown that obese children with ALL have a 50% increased risk for disease relapse following induction therapy.

Now, obesity at diagnosis is linked to a 2.5-fold higher likelihood of minimal residual disease (MRD) following induction chemotherapy, researchers report from a study published October 27 in Blood.

The study, from the Children's Hospital Los Angeles, is based on a retrospective analysis of 198 predominantly Hispanic patients with B-cell ALL, the most common of all childhood leukemias.

Co–senior author Steven D. Mittelman, MD, PhD, director of the Diabetes and Obesity Program at the Children's Hospital Los Angeles, told Medscape Medical News: "This is the first study to show that the effect of obesity is seen as early as the end of induction chemotherapy."

"Induction chemotherapy provides a patient's best chance for remission or a cure. Our findings indicate that a patient's obesity negatively impacts the ability of chemotherapy to kill leukemia cells, reducing the odds of survival," Dr Mittelman commented in a statement.

This is a provocative study, according to Kevin Oeffinger, MD, director of the Cancer Survivorship Center at Memorial Sloan Kettering Cancer Center, New York City. MRD is a good indicator for early event-free survival (EFS) and relapse, he added.

Dr Oeffinger also provided insights into obesity and cancer trends.

There is a growing interest in obesity at diagnosis in the pediatric and adult cancer world alike. In the current obesity epidemic, many cancer centers are seeing more obese cancer patients at diagnosis, he told Medscape Medical News.

Indeed, the link between obesity and cancer has been noted in other malignancies, and the American Society of Clinical Oncology has issued a position statement on the topic, as reported by Medscape Medical News.

The Children's Hospital Los Angeles Study

The study at the Children’s Hospital Los Angeles was initiated to understand why obesity was associated with a greater likelihood of relapse. "We wanted to see where the effect of obesity first occurred — at the initial stage of therapy, or whether it was cumulative," Dr Mittelman told Medscape Medical News.

Researchers analyzed data from patients aged 1 to 21 years who had been diagnosed with ALL between 2008 and 2013.

Height and weight at diagnosis and at the end of induction therapy were used to calculate body mass index (BMI); the BMI was converted to a percentile on the basis of Centers for Disease Control and Prevention thresholds: 95% and higher was considered obese; between 85% and 94% was considered overweight.

Overall, 79% of patients were Hispanic; 127 patients (64%) were classified as lean, 30 (15%) as overweight, and 41 (21%) as obese.

Induction therapy was administered for a month, either as a four-drug regimen or a three-drug regimen, depending on whether patients showed high-risk disease or not.

MRD was determined from bone marrow specimens at the end of induction therapy; presence of leukemia cells was evaluated from flow cytometry.

MRD and EFS Is a Function of Weight Category

After induction therapy, MRD (defined as ≥0.01% leukemia cells) was reported in 23% of the lean patients, 27% of the overweight patients, and 44% of the obese patients.

In a multivariate analysis that took into account several factors, including age, sex, ethnicity, white blood cell count, cytogenetics, and BMI, three variables were found to influence worst outcomes after induction therapy.

Not surprisingly, initial WBC count and cytogenetics are associated with MRD following induction. But obese and overweight children were at a 2.5 to 2.75 higher risk for MRD compared with the lean cohort. This was the provocative observation, according to Dr Oeffinger.

After up to 5 years of follow-up, EFS was significantly longer for children who were lean at diagnosis. Children who were lean and free of MRD after induction had the best EFS.

Obese and overweight children were at a greater risk for an event within 5 years. In addition, children who had MRD after induction had an approximately 3.5 greater risk for an event (hazard ratio for EFS: 3.48; 95% confidence interval: 1.00 - 12.12; P = .045).

Another important observation of the study related to children who were lean at diagnosis but who gained weight during the 1 month of induction therapy; these children did not have a higher risk for MRD compared with the lean cohort. This is important, inasmuch as weight gain during the month of induction is not uncommon, owing to the fact that steroids are used as part of induction chemotherapy.

However, Dr Oeffinger indicated that this is a short-term observation. "We have no idea how weight gain in the short term will affect long-term EFS," he said. He was concerned that weight gain would increase the likelihood of developing metabolic syndrome, possibly leading to late recurrences, in addition to other comorbidities.

"We need to do a better job with nutrition education in these children," Dr Oeffinger commented.

Principal author Etan Orgel, MD, attending physician, Leukemia, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, agrees.

"The results of our study have raised the urgency to begin intervening for obese children with ALL. After seeing the potential impact obesity has on MRD and survival, my team and I have begun to incorporate diet and activity guidance into our initial talks with families right alongside the education for their leukemia and chemotherapy," Dr Orgel told Medscape Medical News.

By actively working with families to target obesity from the day they walk in the door, they're hoping to give each child the best chance of obtaining a deep remission and long-term survival, he added.

What Does This All Mean?

Dr Mittelman indicated that children in the study are representative of the local Los Angeles community. Obesity disproportionately affects minorities, and there is evidence that Hispanics are at an increased risk for leukemia, he added.

Given the predominantly Hispanic population, Dr Mittelman conceded that the link between obesity and MRD at the end of induction requires confirmation in a heterogeneous population and across other ethnicities.

"Obesity affects clinical outcomes in ways that we have not teased apart," Dr Oeffinger said. Disruption of the normal endocrine function of fat cells will, in the long term, affect response and possibly recurrence, he said.

Currently, there are no mechanistic explanations as to why obesity affects induction outcomes. There is speculation that fat cells in the adipose tissue "protect" leukemia cells from chemotherapy. Dr Mittelman’s laboratory is trying to find out how.

According to the researchers, fat cells represent a major component of the bone marrow microenvironment and are more prominent following induction chemotherapy. Adipocyte-leukemia interactions represent a largely unexplored microenvironment that may mediate the adverse impact of obesity noted in pediatric ALL, they write.

But for now, how do we go forward in treating children with B-cell ALL who are obese at diagnosis? The researchers of the study state: "Approximately one in five children with SR-ALL remain MRD positive following induction therapy and are routinely 'escalated' to receive augmented and toxic intensive chemotherapy to reduce risk of relapse."

Fat changes the burden of the body to responses from an immune and metabolic standpoint, Dr Oeffinger told Medscape Medical News. He indicated that a documentation of glucose tolerance and insulin sensitivity may also add information on how response is affected. However, this was not available in the current study.

Dr Oeffinger commented: "In general, several questions are raised when it comes to treating obese patients. When radiation is used, a radiologist has to determine the appropriate radiation field. With chemotherapy, it becomes important to know if patients are receiving an adequate dose of chemotherapy."

The study was funded by a Translational Research program grant from the Leukemia and Lymphoma Society. The authors have disclosed no relevant financial relationships.

Blood. Published online October 27, 2014. Abstract

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