Nutritional intervention as adjuvant therapy for T-cell acute lymphoblastic leukemia

TO THE EDITOR:

A recent study by Simony et al,¹ published in Blood Advances, highlights the negative effects of obesity on toxicity and survival in adolescents and young adults with acute lymphoblastic leukemia (ALL). An elevated body mass index was associated with an increase in hepatotoxicity, hyperglycemia, and worse nonrelapse-related mortality, event-free survival, and overall survival. Research involving nutrition and exercise may lead to improving the biology associated with the deleterious effects of elevated body mass index.^2-4 

One example of a nutritional intervention aimed at impacting the effect of obesity on ALL is the IDEAL (Improving Diet and Exercise in ALL) trial. In a study by Orgel et al, the IDEAL trial investigated the effects of caloric and nutrient restriction through diet and exercise on fat mass gain and minimal residual disease in patients with B-cell ALL (B-ALL).⁵ Although the intervention did not significantly reduce fat mass gain overall, it showed benefits in overweight/obese individuals through a feasible intervention with significant patient adherence without any toxicities. Importantly, the intervention significantly reduced the risk of minimal residual disease after considering the prognostic factors. Integrated biology analysis revealed positive changes in biomarkers related to overweight/obesity physiology as well. These results suggest that caloric restriction via diet and exercise, while not changing obesity or decreasing fat mass gain, could still enhance chemotherapy efficacy and improve disease response in patients with B-ALL, highlighting the need for further clinical trials to not only validate these findings but also uncover the mechanism.

With support for improvement in disease response related to caloric restriction,⁵ the next step in diet intervention in ALL should optimize meeting patient metabolic demands while exploiting specific cancer biology. One potential mechanism for the effects of caloric restriction may be due to changes in amino acid intake, particularly a decrease in dietary intake of the essential amino acid valine. A valine-reduced diet has been shown to increase hepatic insulin sensitivity and ketogenesis, thus increasing energy or caloric expenditure.⁶ Accordingly, reducing dietary branched-chain amino acids, including valine, has the potential to prevent obesity and insulin resistance in mouse models, adults, and children.^7,8 Elevated levels of branched-chain amino acids have also been reported to be an early event in tumor development in some cancers.⁹ As such, the dietary manipulation of amino acids for cancer therapy has shown promise, specifically in mouse models of breast cancer and blood malignancies.^10,11 

Moreover, preclinical studies have found that T-cell ALL (T-ALL) has a strong dependency on the amino acid valine.¹² Recently published in Nature, it was reported that NOTCH1, which is mutated in most T-ALL, regulates valine transfer RNA biogenesis, and dietary limitation of valine increased apoptosis in leukemic blasts.¹² When the impact on leukemic burden was compared between the dietary absence of valine, lysine, or asparagine, it was most pronounced with valine deprivation. Mechanistically, valine availability was also identified to be essential for increased energy production in T-ALL blasts by affecting the translation of electron transport chain messenger RNAs, which is critical for their survival. Reducing valine intake in human xenograft models of T-ALL significantly delayed tumor progression and increased overall survival as monotherapy in tumor-bearing mice.¹² 

Acute total deprivation of valine depletes hematopoietic stem cells and is associated with systemic toxicity and even early death in preclinical models.^13,14 Valine, an essential amino acid requiring dietary intake, necessitates precise control of its availability in the body to achieve a therapeutic index without adverse toxicity of valine imbalance. Supporting this, decreasing valine intake without complete depletion significantly decreased T-ALL progression and improved survival in preclinical animal models with no loss in hematopoietic stem cells, body weight, or other observable toxicities.¹² A titrated partial reduction of valine intake also previously showed a response in animal models of adenocarcinoma without any associated weight loss.^15,16 These findings offer the potential for a dietary adjuvant strategy in the frontline and relapse settings of T-ALL. Investigating the safety, feasibility, and sex-specific differences in such trials will be of utmost importance to ensure that modification of the diet content of an essential amino acid will not increase the toxicity profile associated with standard-of-care therapy or produce adverse effects associated with valine depletion. To achieve clinical outcomes, only a minimal or intermittent decrease in valine may be required, as mouse models demonstrated efficacy with only partial restriction.¹² If this can be demonstrated to be safe and feasible in patients receiving chemotherapy, the dosing levels of valine restriction should be explored.

Amino acid deprivation therapy has been a promising strategy using L-asparaginase, which depletes the amino acid L-asparagine, playing a critical role in the treatment of T-ALL. Notably, the current standard-of-care courses may include 7 to 9 doses of L-asparaginase.^17,18 Valine restriction may enhance L-asparaginase efficacy, which could translate into a greater likelihood of attaining and sustaining remission. Although this would be valuable in both B- and T-ALL therapies as L-asparaginase is incorporated in both, currently there are fewer promising options for the treatment of T-ALL, and a diet intervention would be far more cost-effective and more readily available than the development of a new drug trial. Nonetheless, a mechanistic study of a valine-restricted diet could provide a foundation for future targeted therapies.

Additional studies are needed in patients with T-ALL, in which outcomes lag behind B-ALL; however, whether valine restriction is effective in other subtypes of ALL remains to be examined. It would be interesting to investigate whether caloric restriction in B-ALL, as reported Orgel et al,⁵ is associated with a reduction in amino acid levels, particularly valine. There may be potential for coupling caloric restriction with valine restriction when studying their potential interrelationship. The authors look forward to further supporting the advancement of metabolic nutritional interventions for the treatment of leukemia.

Contribution: M.B.G. and P.T. conceptualized, wrote, reviewed, edited, and approved the submitted version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Miriam B. Garcia, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1487, Houston, TX 77030; email: mbgarcia@mdanderson.org.