Trial in Progress: Update on the TACL T2020-003 Randomized Phase 2 Trial to Improve Diet and Exercise in Acute Lymphoblastic Leukemia (IDEAL-2)

Background and Significance: Overweight and obesity (OW/OB) are well-characterized risk factors for relapse in children, adolescents, and adults with high-risk acute lymphoblastic leukemia (HR-ALL). Children presenting with OW/OB at ALL diagnosis have a 30-50% higher risk for relapse, a finding replicated in adults with ALL treated on the inter-consortia CALGB 10403 trial (Stock Blood 2019). The mechanisms by which OW/OB induce chemoresistance are emerging and include systemic effects on ALL cells from insulin resistance, and local interactions with marrow adipocytes.

Past clinical data and mouse models of dietary modification in ALL show that the adverse impact of OW/OB on relapse is modifiable, with the initial Induction chemotherapy phase of particular importance. Risk for minimal residual disease (MRD) positivity (≥0.01% by flow cytometry) at end of induction was >2-fold higher in patients beginning ALL chemotherapy with OW/OB. Following these translational observations, we conducted the Improving Diet and Exercise in ALL [IDEAL-1] trial in 40 pediatric patients investigating whether caloric restriction could reduce risk for MRD positivity (Orgel Blood Adv 2021). The IDEAL-1 intervention consisted of a 10% caloric dietary deficit via a low carbohydrate, low glycemic load, low-fat, and high protein dietary plan accompanied by a guided home exercise program. Despite intensive chemotherapy and steroid-induced hyperphagia, >90% adherence to caloric restriction was achieved. However, poor adherence to home exercise (<50% of daily goals) and sedentary behavior (SB, <2,000 steps/day) were common. As compared to historical controls, the IDEAL-1 intervention successfully reduced fat gain in those with OW/OB. Importantly, the IDEAL-1 trial also found that caloric restriction reduced odds for MRD positivity by ~70% (p=0.02).

Trial Design & Update: Following proof-of-principle from IDEAL-1, we designed the successor IDEAL-2 randomized Phase 2 trial. IDEAL-2 is actively accruing within the Therapeutic Advances in Childhood Leukemia/Lymphoma consortium with a target enrollment goal of 220 evaluable pediatric HR-ALL patients (T2020-003, NCT05082519). Subjects receive health promotion education and are then randomized within strata (±OW/OB, ±presenting WBC≥50K/uL) 1:1 to institutional routine care versus the IDEAL-2 intervention. Chemotherapy is not prescribed by the trial; patients may receive any eligible four-drug Induction regimen. IDEAL-2 incorporated lessons from the prior trial. Based on excellent dietary adherence in IDEAL-1, IDEAL-2 targets an augmented 15% caloric deficit, with the same macronutrient goals. Conversely, limited home exercise and SB in IDEAL-1 prompted integration of supervised exercise >1x/week and a new SB intervention consisting of step goals and movement reminders via a wearable fitness tracker device. Correlative biology uses metabolomics, cytometry, and RNA sequencing to investigate the impact in ALL cells of OW/OB and the IDEAL-2 intervention on insulin signaling, AKT, and chemoresistance.

During the trial, we identified the logistical challenges of national variability in the availability of dietitians and physical therapists at sites to implement the intervention and travel barriers to study visits. As such, the trial is being amended to reduce these barriers through use of telehealth and incorporation of supervised exercise trainers. In acknowledging the resource-intensive nature of diet and exercise interventions on families, the trial will add an integrated assessment of household material hardship. Disparities in ALL outcomes remain a critical challenge across populations. These design changes will reduce real-life obstacles to support widespread clinical implementation of a diet and exercise intervention.