Can Caloric Restriction Improve Chemotherapy Response in Overweight Patients With ALL?

Previous reports have found that patients who are overweight or obese during B-cell acute lymphocytic leukemia (B-ALL) induction therapy are at a higher risk of chemoresistance. Results from a new study published in Blood Advances suggest caloric restriction may improve disease response to chemotherapy and reduce insulin and fat gain in these patients.

The IDEAL trial, led by Etan Orgel, MD, of Children’s Hospital Los Angeles, enrolled 40 patients between ages 10 and 21 with newly diagnosed high-risk B-ALL (HR-ALL) who were just beginning treatment with a Children’s Oncology Group (COG)-style four-drug induction regimen.

Patients underwent caloric and nutrition restriction interventions designed to achieve a caloric deficit of 20% or greater through a combination of reduced caloric intake and increased energy expenditure. Interventions were performed during the four-week induction period, beginning as early as was feasible after chemotherapy initiation and prior to day four of induction.

Each intervention was personalized to the patient’s preferences and diet and exercise choices. Family was included in nutrition education, and the investigators implemented weekly reinforcement with motivational interviewing techniques.

The primary endpoint of the study was percentage change in fat mass during the induction phase. Secondary endpoints included measurable residual disease (MRD) at end of induction (EOI) and feasibility of and adherence to the caloric-restriction intervention. Patients were considered adherent to the program if they completed 75% or more of the prescribed intervention and self-reported physical exercise. Feasibility of the intervention was defined as completion of 80% or more of the weekly study visits.

A total of 36 patients were evaluable by dual-energy X-ray absorptiometry (DXA) for the primary endpoint, 38 were evaluable for MRD, and 39 were evaluable for adherence and feasibility of the caloric-restriction intervention. As a comparison arm, a historical control group including 80 consecutively treated patients (age = 14.7±2.5 years) were also evaluated. Thirty-six of the historical control patients were also enrolled in a body composition study with paired DXA results both before and after induction.

“As exercise is challenging for patients, [these findings] may support potential benefit from dietary caloric restriction alone.”

—Etan Orgel, MD

In both the IDEAL trial and the historical control cohort, a relatively high proportion of patients were of Hispanic ethnicity (65% and 83%, respectively). Half of the IDEAL trial participants were obese, while one-third of patients in the control group were obese and 11% were overweight.

Overall, researchers found no significant difference in the change from baseline in median fat mass between those who received the caloric and nutrition restriction regimen versus the historical DXA control (5.1% vs. 10.7%; p=0.13). Patients who were considered adherent to the intervention gained the least fat mass over the study, with a median change of 2.4%.

An exploratory subgroup analysis found that overweight and obese patients on the intervention gained significantly less fat mass than controls who were also overweight and obese (1.5% vs. 9.7%; p=0.02). Based on these findings, the investigators suggest a possibility that adipocytesrespond differently to caloric restriction in patients who are overweight or obese versus those who are lean.

According to a multivariable analysis, the caloric- and nutrient-restrictive IDEAL intervention significantly correlated with a reduced risk of EOI MRD positivity (odds ratio [OR] = 0.30; 95% CI 0.09-0.92; p=0.02). In addition, those who underwent the intervention had significant reductions in detectable MRD compared with the historical control group (OR=0.16; 95% CI 0.04-0.52; p=0.002).

The average adherence rate among the 39 patients with follow-up assessments was 82.1%. Most patients (92%) had a negative calorie balance during induction. Adherence to exercise was 31.2%, with Fitbit data showing 59% compliance with activity monitoring for half or more of the induction period. The authors noted that “poor adherence to the exercise component was prevalent, and was further compounded by physical inactivity. As exercise is challenging for patients, this may support potential benefit from dietary caloric restriction alone.”

Limitations of this proof-of-principle trial were its nonrandomized, single-arm design. Additionally, obesity rates, Hispanic patients, and only COG-style HR-ALL therapy were highly prevalent within the overall cohort, which may reduce the generalizability of the findings.

The authors report no relevant conflicts of interest.

Reference

Orgel E, Framson C, Buxton R, et al. Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: The IDEAL trial. Blood Adv. 2021;5:1853-1861.