Integrative exercise and nutrition strategies in leukemia survivorship: implications for cognitive function and quality of life

Abstract

Leukemia survivorship presents ongoing clinical and functional challenges, including persistent fatigue, metabolic disturbances, and reduced quality of life. Integrative, non-pharmacologic strategies that combine exercise and targeted nutrition may help address these late effects. This narrative review synthesizes current evidence on the physiological, molecular, and clinical impact of exercise training and nutritional interventions among leukemia survivors. Exercise programs, ranging from aerobic and resistance training to high-intensity interval and mobile health–based formats, consistently improve cardiorespiratory fitness, muscular strength, and fatigue outcomes, while modulating inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α. Nutritional components including polyphenol-rich functional foods, omega-3 fatty acids, and microbiota-supportive diets contribute anti-inflammatory and antioxidant effects that may complement exercise in restoring immune and metabolic balance. Together, these approaches form a promising foundation for personalized supportive care in leukemia survivorship. Yet, most studies remain limited by small sample sizes, heterogeneous protocols, and short follow-ups. Future research should prioritize larger, leukemia-specific clinical trials integrating exercise and nutrition components, with standardized outcome measures to enable evidence-based recommendations for survivorship care.

Introduction

Exercise and nutrition are key modifiable lifestyle factors that influence cancer development and recovery [1]. However, despite growing awareness, global cancer-related mortality is projected to increase substantially in the coming decades [2]. Cancer patients commonly experience cancer-related fatigue, muscle wasting, diminished physical fitness, neuropathy, and reduced quality of life, particularly during intensive treatment phases [3]. While extensive research has characterized the cardiometabolic and functional benefits of exercise in cancer populations, the unique survivorship needs of individuals with hematologic malignancies remain less understood [4–8]. Leukemia survivors, in particular, often face persistent treatment-related complications, including reduced aerobic capacity, impaired muscle function, metabolic dysregulation, and immunologic vulnerability [9–12]. These issues can extend years beyond therapy completion, underscoring the need for targeted supportive care strategies that begin early in the recovery trajectory.

Integrative approaches that combine exercise and nutrition represent practical, non-pharmacologic interventions capable of enhancing physical performance, immune recovery, and psychosocial well-being in leukemia survivors. By addressing inflammation, metabolic dysfunction, and mitochondrial impairment, common sequelae of leukemia and its treatments, such strategies may meaningfully improve long-term health outcomes [13–15]. These survivorship challenges form the basis for examining mechanistic pathways, clinical evidence across leukemia subtypes, nutritional strategies, and the synergistic effects of combined exercise–nutrition interventions.

This narrative review takes a look into mechanistic and clinical evidence to explain how exercise and nutritional interventions influence inflammatory pathways, metabolic regulation, and functional capacity in leukemia survivors. It highlights opportunities for biomarker-guided personalization and identifies research gaps that currently limit translation into routine clinical practice. Unlike prior reviews that address exercise or nutrition separately, this work specifically focuses on leukemia survivorship and the intersection of molecular mechanisms with practical rehabilitation strategies.

Survivorship challenges in leukemia

As reported by GLOBOCAN, leukemia ranked as the 15th most frequently diagnosed cancer and the 11th leading cause of cancer-related deaths globally in 2018, resulting in 437,033 new cases and 309,006 fatalities. The burden of leukemia is notably more pronounced in males compared to females worldwide [16]. As research has shown chronic leukemia presents with a unimodal pattern of age distribution, with incidence rates increasing as age advances. Conversely, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), which are significant in pediatric populations, display bimodal age distributions [17].

Beyond incidence and survival trends, leukemia survivors frequently experience long-term consequences such as metabolic syndrome, chronic low-grade inflammation, and reduced physical performance. These issues underscore the importance of lifestyle-based interventions that integrate exercise and nutrition to promote healthier survivorship trajectories [18–20].

Different types of radiation exposure, including therapeutic, occupational, and wartime-related sources, chemotherapy, genetic predispositions, familial history, chemical exposure (both residential and occupational), and certain lifestyle choices, such as smoking, are among the most common risk factors for leukemia. While specific exposures have been linked to particular leukemia subtypes, several prominent risk factors affect multiple forms of the disease [21]. For instance, high doses of ionizing radiation from atomic bomb exposure in Japan have been correlated with increased mortality rates from various non-CLL leukemias, including ALL, AML, and Chronic Myeloid Leukemia (CML) [22–24]. Before 1950, exposure to ionizing radiation has been associated with heightened risk of non-CLL leukemia among nuclear industry workers and radiologists [25–27].

Search strategy

This narrative review was based on a comprehensive literature search conducted in PubMed, Scopus, and Web of Science databases for studies published between January 2000 and June 2025. Keywords included combinations of “leukemia,” “exercise,” “physical activity,” “nutrition,” “diet,” “rehabilitation,” and “survivorship.” Both interventional and observational studies were considered. Articles were included if they addressed exercise or nutritional interventions in leukemia patients or survivors. Non-English papers, conference abstracts, and studies without leukemia-specific data were excluded. Reference lists of relevant reviews were also screened to ensure completeness.

Leukemia

Leukemia encompasses a diverse group of hematological malignancies, each distinguished by unique morphological, cytogenetic, immunophenotypic, and clinical features [28]. In ALL, diagnostic approaches include microscopic examination of cell morphology, immunophenotyping for lineage identification and classification, and detecting minimal residual disease. Chromosomal abnormalities are assessed using fluorescence in-situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or advanced methods like next-generation sequencing (NGS), which enable comprehensive genomic analysis [29]. AML diagnosis is established by identifying ≥ 20% myeloid blasts through peripheral blood or bone marrow morphological evaluation. Flow cytometry immunophenotyping confirms the myeloid origin and determines AML subtypes, while cytogenetic studies and mutation screening identify prevalent rearrangements and abnormalities of genes [30]. CLL is characterized by monoclonal B lymphocytosis exceeding 5 × 10⁹/L in the peripheral blood, verified via flow cytometry. Morphologically, CLL cells exhibit a small size, mature appearance, condensed chromatin, and minimal cytoplasm [31]. CML diagnosis involves detecting agranulocytosis and a unique blood count profile. The presence of the Philadelphia chromosome (22q-) or BCR-ABL1 transcripts in blood or bone marrow confirms CML [32] (Table 1).

Table 1.

Major four types of leukemia and their diagnosis

Leukemia subtype	Key diagnostic criteria	Common molecular/cytogenetic markers	Reference
Acute lymphoblastic leukemia (ALL)	≥ 20% lymphoblasts in blood or bone marrow; immunophenotyping confirms B- or T-cell lineage; flow cytometry to detect minimal residual disease	t(12;21) ETV6-RUNX1, t(9;22) BCR-ABL1, hyperdiploidy	[29]
Acute myeloid leukemia (AML)	≥ 20% myeloid blasts in blood or marrow; flow cytometry for myeloid markers (CD13, CD33); morphology and cytogenetics classify subtypes	t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MYH11, NPM1, FLT3 mutations	[30]
Chronic lymphocytic leukemia (CLL)	≥ 5 × 10⁹/L monoclonal B cells in peripheral blood persisting ≥ 3 months; confirmed by flow cytometry	del(13q), del(11q), trisomy 12, TP53 mutation	[31]
Chronic myeloid leukemia (CML)	Leukocytosis with left shift; basophilia; splenomegaly; confirmed by detection of Philadelphia chromosome or BCR-ABL1 fusion transcript	t(9;22) BCR-ABL1 fusion	[97]

Abbreviations: MRD = minimal residual disease; FISH = fluorescence in situ hybridization; RT-PCR = reverse transcription polymerase chain reaction

Mechanistic pathways of exercise and nutrition

Leukemia survivors experience substantial physiological disruption due to disease- and treatment-related inflammation, immune dysregulation, mitochondrial impairment, metabolic disturbances, and declines in cardiorespiratory capacity. Exercise has emerged as a promising nonpharmacological strategy to counteract these effects. Although studies remain heterogeneous in design, leukemia subtype, and timing along the treatment continuum, a consistent pattern is evident: exercise induces measurable biological changes that correspond with improvements in strength, endurance, mobility, fatigue, and overall physical functioning. In this merged section, we integrate mechanistic pathways, biomarker responses, and functional outcomes to present a cohesive narrative of how exercise influences leukemia survivors across age groups and clinical settings.

Molecular and cellular mechanisms of exercise in leukemia

Several molecular pathways influenced by exercise are relevant to leukemia and its treatments. Chronic inflammation and immune activation are common in this population, and many mechanistic findings, though often drawn from broader oncology or chronic-disease cohorts, help explain the physiological improvements observed in leukemia trials. Repeated aerobic and resistance training has been associated with reductions in lipopolysaccharide (LPS)-stimulated cytokine secretion and downregulation of toll-like receptor 4 (TLR4) and CD14 expression on monocytes [33–35]. These adaptations are clinically meaningful, as lower TLR4 expression and reduced inflammatory monocyte activation directly reflect a blunted innate immune response to LPS exposure [36]. Consistent with these observations, physically active individuals tend to exhibit lower circulating CRP, fewer CD14⁺CD16⁺ inflammatory monocytes, and lower spontaneous TNF-α production compared with inactive individuals [37].

Exercise-induced mitochondrial and metabolic changes further support improved physiological resilience. Activation of the AMPK–PGC-1α axis during training promotes mitochondrial biogenesis, enhances oxidative metabolism, and improves redox balance [38]. These adaptations may counter chemotherapy-related mitochondrial dysfunction, a contributor to fatigue, muscle weakness, impaired aerobic capacity, and reduced physical endurance frequently observed in leukemia patients. Together, immune-modulatory and mitochondrial responses provide a biological foundation for the functional gains documented in exercise trials (Figs. 1 and 2).

Fig. 1.

Schematic presentation of molecular targets of exercise in leukemia

Fig. 2.

Pathways by which exercise affects patients with leukemia, including reducing cancer-related fatigue and improving physical performance

Biomarker responses: inflammation, immune function, and metabolic health

To evaluate how exercise influences physiology, several biomarkers have been repeatedly investigated in leukemia cohorts. Clinically accessible inflammatory markers, such as CRP, IL-6, and TNF-α, are commonly measured and provide insight into systemic inflammation [14, 39, 40]. Newer inflammatory signatures such as GlycA offer additional sensitivity. GlycA, derived from NMR spectroscopy, captures composite glycoprotein acetylation and correlates strongly with chronic inflammatory burden [41–43]. In chronic lymphocytic leukemia (CLL), cardiorespiratory fitness (VO₂peak) has been inversely associated with GlycA and neutrophil-to-lymphocyte ratios, suggesting that fitness is meaningfully linked to systemic inflammatory regulation [44].

Exercise also influences cytokine and epigenetic profiles in leukemia. In older adults with myeloid malignancies, a mobile-health walking intervention resulted in CpG-specific increases in TNF-α promoter methylation, with step counts and resistance-training volume correlating with methylation levels, even though circulating TNF-α concentrations remained unchanged [45]. These findings suggest that exercise may influence inflammatory gene regulation prior to detectable shifts in plasma cytokines.

Pediatric ALL studies further demonstrate the sensitivity of immune biomarkers to exercise. During maintenance therapy, an acute treadmill-based protocol produced increases in absolute neutrophil count and improved oxidative capacity, indicating preserved innate immune responsiveness despite ongoing treatment [46]. In long-term childhood ALL survivors, a 16-week home-based program reduced eleven inflammatory plasma proteins related to insulin resistance and vascular inflammation, markers such as CXCL6, CCL4, MCP-1, and TSLP, indicating an exercise-induced shift toward a less inflammatory proteomic profile [47]. Taken together, these biomarker findings illustrate that exercise exerts regulatory effects at multiple biological levels, from inflammatory protein expression to immune-cell behavior and epigenetic modification. These changes align with the functional outcomes consistently reported across leukemia exercise trials.

Mechanistic effects of nutritional bioactives

Beyond macronutrient balance, specific functional food components may influence molecular pathways relevant to inflammation, mitochondrial health, and immune restoration in leukemia survivorship (Table 2). Among these, polyphenols, omega-3 fatty acids, and microbiota-targeted interventions have attracted increasing attention for their complementary roles alongside exercise training. Polyphenols such as curcumin, resveratrol, and epigallocatechin gallate (EGCG) act through overlapping anti-inflammatory and antioxidant mechanisms. They inhibit the NF-κB signaling cascade, thereby reducing the transcription of pro-inflammatory cytokines including TNF-α and IL-6, while simultaneously activating the Nrf2 pathway to enhance expression of antioxidant enzymes such as HO-1, SOD, and NQO1. These changes support mitochondrial biogenesis and redox stability, counteracting oxidative stress commonly induced by chemotherapy. Experimental models indicate that curcumin and resveratrol improve mitochondrial membrane potential, reduce ROS accumulation, and modulate apoptotic balance toward cell survival in non-malignant tissues. Such molecular effects parallel the AMPK–PGC-1α axis activated by endurance and resistance exercise, suggesting that dietary polyphenols could amplify exercise-induced adaptations in leukemic patients during recovery [48, 49].

Table 2.

Summary of studies examining combined nutrition and exercise interventions in leukemia, including study design, intervention type, and key outcomes

Design & sample size	Population	Intervention / Comparator	Main outcomes	Key limitations	Ref
Pilot (n = 10)	Adults with acute leukemia during chemotherapy	3 × weekly combined aerobic + resistance training vs. usual care	↑ Cardiorespiratory endurance; ↓ fatigue & depression; no change in QoL	Very small sample; short duration; heterogeneity of disease stage	[98]
Single-arm mHealth pilot (n = older adults with myeloid malignancies)	Myeloid malignancy survivors	Remote exercise via mobile health app	Modest ↑ TNF-α promoter methylation; no change in serum cytokines	No control group; exploratory biomarkers	[89]
Pre–post (n = 21)	Young adult ALL survivors	16-week home-based exercise	↓ 11 inflammatory proteins (CXCL6, CCL4 etc.)	Small sample; no long-term follow-up	[90]
Non-randomized pilot (n = 18)	Treatment-naïve CLL	12-week HIIT + resistance training vs. control	↑ Leg strength (g = 2.52), ↑ NK cell activity; good adherence	Pilot nature; no survival data	[91]
RCT (n = 40)	Pediatric ALL	Modified strength training vs. aerobic training	↑ Muscle strength; no difference in QoL	Short term; small sample	[58]
RCT (n = 60)	Adults with AML on chemotherapy	12-min daily walking × 3 weeks vs. control	↓ Fatigue, anxiety, depression; ↑ walking distance	Limited duration; hospital setting	[92]
RCT (n = 40)	Acute leukemia/lymphoma inpatients	Exercise + nutritional supplement vs. exercise alone	↑ Muscle strength (handgrip, knee extension)	No change in mass or QoL; short follow-up	[93]
Crossover (n = 22)	Pediatric ALL in remission	8 wk strength training + 8 wk probiotic phase	↑ Microbiota diversity; ↑ BMI z-score	Small sample; no functional gain	[82]

Omega-3 fatty acids (EPA and DHA) contribute to the resolution rather than mere suppression of inflammation. Through their metabolites, resolvins, protectins, and maresins, they downregulate NF-κB and STAT3 signaling, promote macrophage polarization toward an anti-inflammatory phenotype, and support hematopoietic regeneration. Clinical and preclinical studies indicate that omega-3 supplementation can reduce circulating IL-6 and CRP levels, improve muscle protein synthesis, and preserve lean body mass in patients undergoing chemotherapy [50]. These effects complement the immune-modulating and anti-cachectic benefits of regular physical activity, reinforcing the rationale for integrative dietary-exercise interventions.

Clinical evidence organized by leukemia subtype

Acute Myeloid Leukemia (AML)

AML survivors demonstrate wide variability in baseline functional capacity, and lower pre-treatment physical function has been associated with poorer survival outcomes [51]. Exercise interventions during induction or consolidation have produced improvements in mobility, VO₂peak-related parameters, and strength despite treatment-related challenges [52, 53]. Though sample sizes remain small, available findings suggest that structured exercise can attenuate the steep functional decline characteristic of AML treatment and may support better recovery during remission Fig. 1.

Acute Lymphoblastic Leukemia (ALL)

Patients with acute leukemia face profound physical decline during induction chemotherapy, driven by prolonged hospitalization, severe cytopenias, catabolism, and high symptom burden. Observational studies have reported progressive deterioration in functional status and quality of life (QoL) over the course of induction [54, 55]. Despite this, multiple clinical trials demonstrate that supervised, individualized exercise programs are feasible and beneficial in this setting. Short inpatient programs combining aerobic and resistance training have shown gains in 6-min walk distance (6MWT), lower-limb strength, and measures of cardiorespiratory capacity, even though QoL improvements are often modest during periods of highest treatment burden [14, 56]. A simple structured walking protocol, consisting of 12 min of daily walking, was associated with reduced fatigue and improved walking capacity during AML induction [57]. Another inpatient walking-based program resulted in significant improvements in mobility (Timed Up and Go test) and meaningful reductions in fatigue compared with controls [58]. These findings collectively indicate that even low-to-moderate intensity exercise can counteract functional decline during intensive treatment.

Chronic Lymphocytic Leukemia (CLL)

Evidence in CLL, particularly treatment-naïve patients, highlights robust adaptability when exercise intensity is appropriately prescribed. A 12-week program combining high-intensity interval training (HIIT) with resistance exercise produced large improvements in leg strength (g = 2.52), increases in NK-cell cytotoxicity, and moderate increases in VO₂peak [59]. These findings are notable because they demonstrate that higher-intensity training can not only be tolerated but also produce meaningful immunological and functional benefits in older adults with untreated CLL.

Pediatric leukemia survivors

Children undergoing treatment or in survivorship often exhibit deficits in aerobic capacity, muscle strength, coordination, and mobility. Several trials have shown that exercise interventions, whether supervised in hospital settings or delivered via home-based programs, produce marked improvements. Intrahospital resistance plus aerobic training increased VO₂peak, ventilatory threshold, trunk strength, and lower-body strength, with some gains (particularly strength) persisting after detraining, whereas aerobic variables sometimes declined without continued training [60, 61]. Randomized trials comparing strength-focused vs. aerobic-focused training in pediatric ALL have reported greater strength improvements in targeted muscle groups in resistance-based protocols, although QoL differences were not always significant [62]. Exergaming interventions have also demonstrated benefits, including reductions in cancer-related fatigue and improved walking performance, offering a child-friendly modality that can enhance adherence [63]. Across pediatric cohorts, functional tests such as the 6MWT and TUG show consistent improvement, though many children continue to fall below age-matched normative values, particularly those with higher BMI or more intensive treatment histories [64, 65].

Cancer-Related Fatigue (CRF)

Importantly, exercise interventions differ between inpatient induction settings (e.g., AML during chemotherapy) and outpatient or long-term survivorship contexts (e.g., pediatric ALL), where goals and measurement tools such as PROMIS-Fatigue, PedsQL Fatigue, 6MWT, and TUG vary accordingly.

The National Comprehensive Cancer Network (NCCN) provides a widely accepted and thorough definition of Cancer-Related Fatigue (CRF), characterizing it as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion associated with cancer or its treatment that is not commensurate with recent activity and disrupts daily functioning” [66]. This definition emphasizes the multifaceted nature of CRF, highlighting that, in contrast to the fatigue experienced by healthy individuals, CRF is often unrelieved by rest. There exists a discussion regarding whether CRF represents varying dimensions of a single symptom or if it consists of distinct symptoms that are collectively referred to as fatigue [67]. The complex interplay between mental and physical fatigue supports the notion that these symptoms may be independent occurrences, thereby reinforcing that CRF is a concept with multiple symptoms [68, 69].

The incidence of CRF fluctuates based on whether it is evaluated during active treatment or post-treatment. Most cancer survivors, defined by the US National Coalition for Cancer Survivorship as individuals with a cancer history from diagnosis through their lifetime, should have to deal with CRF during active treatment [66]. It is indicated that their fatigue levels typically peak toward the end of this phase and subsequently decrease [70–74]. Importantly, a considerable number of disease-free survivors continue to experience fatigue for years following the conclusion of their active treatment [75, 76]. CRF management has been explored in numerous studies, employing a wide array of interventions that can be classified into pharmacological and non-pharmacological categories. Over 450 studies have been published that analyze the relationship between CRF and various populations affected by different types and stages of cancer, employing a range of interventions [77]. Nonetheless, no definitive standard for the management or treatment of CRF has been established. This absence of a gold standard may be attributed to the condition’s multifactorial etiology and the complex mechanisms underlying fatigue in cancer patients [78]. Some studies have reported that different types of exercise training can reduce CRF in patients with leukemia which will be discussed further in this section. To investigate the impact of a home-based aerobic exercise program aimed at alleviating fatigue in children diagnosed with ALL, a six-week exercise intervention was conducted. This outpatient survivorship study used the PedsQL Multidimensional Fatigue Scale. Although general fatigue improved at one-month follow-up, changes did not exceed clinically relevant thresholds across the three fatigue subscales [38].

An investigation employed a pre- and post-test framework involving a total of 50 patients diagnosed with acute myeloid leukemia (AML) who were receiving chemotherapy and were engaged in 30 min of walking each day for a duration of ten days. Results indicated statistically significant reductions in CRF on both the fifth and tenth days of the intervention. Therefore, it is concluded that the structured walking intervention presents a simple and cost-effective strategy for alleviating CRF among patients with leukemia [79]. Another study has been conducted on the outcomes of a four-week exercise regimen performed four times a week, twice daily on fatigue levels in adults diagnosed with acute leukemia who are undergoing induction chemotherapy. The study which involved adult participants aged 28 to 69 years, who were newly diagnosed with acute leukemia indicated a median reduction in fatigue of -5.95 for the intervention group, which reflects a clinically significant improvement according to the Patient-Reported Outcomes Measurement Information System (PROMIS). While the intervention group demonstrated a decrease in TUG performance by 1.73 s, the control group-maintained stability. Thus, this investigation elucidates the beneficial effects of exercise on fatigue as well as psychosocial parameters in patients with acute leukemia [58]. Fatigue was measured using PROMIS-Fatigue, where a median reduction of − 5.95 points met the minimal clinically important difference (MCID) for AML inpatients. Functional mobility improvements were confirmed via TUG (− 1.7 s), indicating enhanced physical capacity despite chemotherapy burden [58].

Chang and colleagues have studied the impacts of a daily 12-min walking exercise program (WEP) (five days per week over three consecutive weeks) among patients with AML undergoing chemotherapy. Fatigue was assessed using a visual analog scale, and reductions exceeded MCID benchmarks for symptom improvement during active inpatient chemotherapy. They reported that patients suffering from AML in the week three of WEP experienced a significantly greater improvement in their 12-min walking distance compared to those in the control group. Furthermore, patients in the WEP exhibited reduced levels of fatigue intensity as well as symptom distress, anxiety, and depressive symptoms relative to the control group. Thus, it is implied that a structured walking exercise regimen over three weeks can be in alleviating fatigue-related experiences for AML patients receiving chemotherapy [57]. Another clinical trial involving 45 children aged between 6 and 14 years employed a moderate-intensity exergaming program lasting 60 min, twice weekly, over a three-week period. Another group of participants engaged in an educational session outlining the benefits of physical activity (PA) alongside recommendations to engage in PA for 60 min, also twice per week. Functional changes were captured using 6MWT and pediatric symptom scales, reflecting relevance to post-treatment survivorship limitations. Findings revealed that the exergaming group exhibited a significant decrease in cancer-related fatigue, along with notable improvements in functional capacity and endurance compared to controls throughout the five-week study duration. However, the intervention was short-term and involved a relatively small sample size, limiting the ability to assess long-term sustainability of these effects. Additional research with extended follow-up and larger cohorts is warranted to determine whether the observed fatigue reduction persists over time. Therefore, it is concluded that the exergaming protocol appears effective in reducing short-term CRF while improving functional capacity and physical activity among children diagnosed with ALL undergoing chemotherapy [63].

Nutrition interventions in leukemia survivorship

Having reviewed exercise- and nutrition-specific findings separately, this section focuses on studies that integrate both approaches, emphasizing feasibility and combined benefits.

The integration of nutritional interventions with physical exercise has demonstrated significant advantages for individuals diagnosed with leukemia, as well as for those who have survived the disease, by effectively addressing both metabolic dysfunctions and physical limitations that arise as a consequence of the illness and its associated treatments. Dietary approaches that emphasize the consumption of anti-inflammatory foods, sufficient protein levels, and micronutrient supplementation have the potential to bolster immune responses and mitigate the adverse effects related to treatment. When these nutritional strategies are combined with customized exercise regimens, encompassing both aerobic and resistance training, such interventions work in a complementary fashion to enhance muscular strength, cardiovascular endurance, and overall physical performance. This comprehensive methodology not only facilitates recovery and enhances functional capacity but also plays a crucial role in achieving improved clinical outcomes and elevating the QoL for patients. Recent studies underscore the significance of individualized, biomarker-informed strategies to optimize the therapeutic efficacy of the integrated application of nutrition and exercise in the management of leukemia (Table 3).

Table 3.

Biomarkers and functional correlates relevant to exercise–nutrition interventions in leukemia

Category	Example markers	Clinical relevance / threshold	Feasibility	Current evidence status
Inflammatory	hs-CRP, IL-6, TNF-α, GlycA	Elevated levels reflect systemic inflammation; GlycA correlates with VO₂ fitness	Routine clinical assays (except GlycA = NMR only)	Validated in general oncology; limited leukemia-specific data
Functional (“physiologic biomarkers”)	VO₂ peak, 6-min walk test (6MWT), grip strength, SPPB	6MWT MCID ≈ 25–50 m; grip strength cut-offs per EWGSOP2 criteria	High, feasible in most rehabilitation settings	Strong predictors of QoL and mortality in cancer survivors
Metabolic	Fasting glucose, insulin, HOMA-IR	Indicate insulin resistance; affected by diet and exercise	Routine laboratory tests	Supported by observational data; needs RCTs
Microbiome	Diversity indices (Simpson/Shannon), butyrate-producing taxa	Reflect gut health and immune recovery	Research only; 16S/shotgun sequencing required	Exploratory; promising for future stratification

Gut microbiota modulation represents another emerging nutritional target in leukemia survivorship. Chemotherapy, antibiotics, and hospitalization often disrupt microbial diversity, increasing intestinal permeability and systemic inflammation. Probiotic supplementation, particularly with Lactobacillus casei and Bifidobacterium longum, and prebiotic fibers such as inulin have shown potential to restore short-chain fatty acid–producing bacteria, improve barrier integrity, and reduce mucosal inflammation [80, 81]. Exercise training itself can enhance microbial diversity and metabolic function, suggesting synergistic potential when combined with microbiota-supportive nutrition. Although evidence in leukemia populations remains preliminary, these findings highlight promising avenues for restoring immune and metabolic homeostasis after therapy.

Another investigation explored the implications of physical exercise and probiotic supplementation on gut microbiota composition, physical fitness levels, and overall health outcomes in pediatric patients diagnosed with ALL who are currently in remission. In a crossover design involving 22 children, participants engaged in an 8-week regimen of strength training, subsequently followed by an 8-week period of daily probiotic administration, specifically incorporating Lactobacillus casei. The administration of probiotics resulted in a significant enhancement of gut microbiota diversity and an increase in beneficial microbial populations, including butyrate-producing bacteria. Although exercise exhibited a relatively modest effect on the gut microbiome, it demonstrated a marked improvement in weight and body mass index (BMI) percentiles. No appreciable alterations were recorded in physical strength or jump performance metrics. These findings indicate that probiotics contribute to the restoration of gut health, whereas exercise facilitates physical recuperation among pediatric survivors of ALL [82].

Nutritional composition and timing

Reported nutrition components across trials generally included balanced macronutrient approaches emphasizing lean protein (1.0–1.5 g/kg/day), complex carbohydrates, and unsaturated fats, often coupled with micronutrients such as vitamin D or omega-3 fatty acids. Most interventions encouraged peri-exercise protein or amino acid supplementation within 60 min post-training to optimize muscle recovery, although regimens varied substantially in dosage and compliance [83–85].

Mediterranean dietary pattern

Observational studies have associated adherence to a Mediterranean-style diet which is rich in fruits, vegetables, whole grains, olive oil, and fish, with improved metabolic health and reduced inflammation in cancer survivors. However, these associations are largely observational and may be confounded by lifestyle and treatment factors; thus, causality cannot be inferred. Prospective, leukemia-specific dietary trials are still needed to establish optimal composition and timing for synergy with exercise [86–88].

Integrated exercise–nutrition approaches

The investigation assessed the efficacy of integrated exercise and nutritional interventions on physical capabilities and overall QoL in individuals diagnosed with acute leukemia or malignant lymphoma undergoing inpatient chemotherapy. In a randomized controlled trial, both the intervention and control cohorts engaged in resistance and aerobic exercise; however, only the intervention group received nutritional supplements on a bi-daily basis. The findings indicated that the intervention cohort exhibited significantly enhanced muscle strength (as measured by handgrip and knee extension) in comparison to the control group, whereas no substantial differences were detected in walking tests, muscle mass, QoL, nutritional status, or fatigue levels. These findings suggest that integrating nutritional support with exercise may augment muscle strength during chemotherapy [80]. Another investigation explored the effects and viability of a 12-month home-based nutritional and physical exercise regimen on cardiovascular fitness, muscular strength, and flexibility in pediatric subjects aged 4 to 10 years diagnosed with standard-risk ALL undergoing maintenance therapy. Participants were randomly assigned to either the intervention group or the control group. While both cohorts exhibited comparable age, body dimensions, and dietary intake, those allocated to the intervention group demonstrated more significant enhancements in physical activity levels and cardiovascular fitness between the 6-month and 12-month intervals. The results indicated that engaging in home-based physical exercise during maintenance therapy can substantially improve physical activity and cardiovascular health among children with ALL, thus necessitating further investigation involving larger sample sizes [89].

A comprehensive investigation involving 117 adult survivors of childhood ALL scrutinized the association between dietary habits, levels of physical activity, and metabolic health outcomes. Through the implementation of dietary assessments and monitoring of physical activity, the researchers established that a higher adherence to a Mediterranean dietary pattern was correlated with reduced visceral and subcutaneous adipose tissue, diminished waist circumference, and a lower body mass index (BMI). Specifically, each incremental increase in the Mediterranean Diet Score was found to decrease the likelihood of developing metabolic syndrome by 31%. Notably, elevated dairy consumption was found to be associated with heightened insulin resistance, whereas other dietary components did not demonstrate statistically significant effects. The energy expenditure associated with physical activity did not exhibit an independent association with metabolic outcomes, but it was found to correlate with a lower BMI. In summary, adherence to a Mediterranean diet was related to enhanced metabolic health and body composition indices among survivors of ALL [90]. The investigation encompassed a cohort of 337 pediatric leukemia patients in Saudi Arabia, aimed at evaluating their levels of physical activity and nutritional status across various demographics, including gender, age, types of leukemia, and stages of treatment. The findings revealed that 60% of the pediatric subjects failed to achieve the recommended levels of physical activity. Male participants exhibited significantly superior nutrient-dense dietary patterns in comparison to their female counterparts. Children in remission demonstrated the lowest levels of physical activity, whereas those in the maintenance phase exhibited the highest levels of energy expenditure. The motivation to participate in physical activities was most pronounced among children aged 8 to 9 years. These findings underscore the necessity for tailored nutrition and exercise interventions that address the unique characteristics of individual patients, with the aim of enhancing health outcomes and overall QoL during the course of leukemia treatment [91]. Another investigation assessed the impact of a 4-week supervised mixed-modality exercise regimen on fatigue and associated symptoms in adults diagnosed with acute leukemia who were undergoing induction chemotherapy. Seventeen patients with recent diagnoses were categorized into an intervention cohort and a control cohort. Findings indicated that the exercise cohort experienced a statistically significant reduction in fatigue and enhancements in physical performance (as evidenced by a quicker Timed Up and Go test), whereas cognitive function deteriorated in both cohorts throughout the hospitalization period. Compliance with the exercise regimen was notably high, with participants attending an average of six sessions per week. The investigation underscores the advantages of exercise in alleviating fatigue and enhancing physical functionality in patients with acute leukemia during their treatment phase [58]. The research delineates the methodology for a six-month intervention focused on technology-driven exercise and nutritional practices (TLC4ALLKids) designed to enhance physical activity and nutritional habits among pediatric survivors of ALL aged between four and twelve years. A total of twenty-four participants will be allocated randomly to either the TLC4ALLKids initiative, which encompasses weekly virtual coaching and physical activity sessions conducted through video conferencing, complemented by tracking tools, or standard enhanced care. Both cohorts will be provided with Fitbit devices to facilitate the monitoring of physical activity levels. The investigation will evaluate feasibility through metrics such as recruitment rates, attendance, and adherence, while also examining outcomes including anthropometric measurements, levels of physical activity, dietary intake, sleep patterns, and overall QoL at baseline, three months, and six months’ intervals. Semi-structured interviews will be conducted to identify potential enhancements to the program. Should this remote intervention prove effective, it could represent a practical approach to fostering healthier lifestyle choices among ALL survivors [92].

A clinical case report delineates an octogenarian patient diagnosed with chronic lymphocytic leukemia (CLL) characterized by the presence of del(11q), a chromosomal aberration indicative of a poor prognostic outcome, who exhibited a substantial abdominal mass and significant cachexia (BMI 16.4 kg/m²). The therapeutic regimen for the patient encompassed the administration of ibrutinib, adequate nutritional intervention, and a systematically designed physical activity protocol incorporating both aerobic and resistance training exercises on five separate days each week. Over a duration of several months, the patient exhibited marked clinical amelioration, evidenced by a reduction in lymphadenopathy and the complete resolution of the del(11q) chromosomal anomaly. The synergistic effect of targeted pharmacotherapy, nutritional enhancement, and muscular rehabilitation contributed to the restoration of his autonomy and overall physical health, thereby underscoring the critical significance of a multidisciplinary approach in the management of elderly patients suffering from cachectic CLL [93]. Noteworthy, exercise and nutritional interventions in leukemia survivors are generally safe when appropriately supervised and individualized. Most inpatient and outpatient trials reported no adverse events related to exercise participation. Exercise sessions were typically postponed during episodes of neutropenia, fever, or severe cytopenia, and resumed upon hematologic recovery. Use of central venous catheters required avoidance of upper-body strain or contact risk, and intensity was adjusted for fatigue and steroid-induced myopathy. Nutritional interventions, mainly involving dietary counseling, protein supplementation, or functional foods, were well tolerated, with adherence rates exceeding 80% in most studies. Collectively, these findings suggest that tailored, supervised exercise and nutrition strategies are feasible and safe for leukemia survivors during and after therapy [14, 94–96].

Research conducted to this point consistently indicates that integrative nutritional and physical exercise interventions among patients with leukemia and those in remission yield substantial enhancements in physical capabilities, immune functionality, and overall life quality. Empirical evidence implies that these comprehensive strategies can mitigate treatment-induced adverse effects, improve metabolic health, and facilitate prolonged survivorship. Nevertheless, although the findings are encouraging, numerous studies underscore the necessity for more extensive, rigorously controlled trials to validate effectiveness, refine intervention methodologies, and establish standardized protocols for clinical application.

Limitations

Despite the encouraging evidence that underpins integrative nutrition and exercise interventions within the context of leukemia survivorship, several limitations warrant careful consideration. Firstly, a substantial portion of the extant research originates from studies characterized by small sample sizes or observational methodologies, thereby constraining the capacity to establish causal relationships and generalize findings across a heterogeneous array of patient populations. The diversity inherent in leukemia subtypes, therapeutic regimens, and survivor attributes further exacerbates the challenges associated with the formulation of standardized intervention protocols. Secondly, there exists a notable deficiency of validated and widely endorsed biomarkers specifically designed to inform nutrition and exercise interventions in leukemia, which significantly impedes the accuracy and customization of these approaches. Moreover, inconsistencies in study designs, durations of interventions, and measures of outcomes present formidable challenges for the comparative analysis and synthesis of results across different studies. Third, numerous interventions have predominantly concentrated on short-term outcomes, with a paucity of data regarding the long-term effects, adherence rates, and the sustainability of lifestyle modifications. Psychosocial factors, socioeconomic impediments, and patient motivation, elements that critically impact the success of interventions, are frequently inadequately examined in the extant literature. Lastly, challenges pertaining to implementation, including the integration into clinical workflows, access to interdisciplinary care teams, and the availability of resources, may constrain the applicability of these interventions in real-world settings. To address these constraints, it will be imperative to conduct more rigorous and expansive studies along with comprehensive frameworks to facilitate the effective translation of research findings into clinical practice. Additional limitations include considerable heterogeneity across leukemia subtypes, treatment phases (induction, maintenance, or post-therapy), and variations in exercise and nutrition protocols. Furthermore, few studies have evaluated cost-effectiveness, feasibility in routine clinical practice, or long-term implementation outcomes. These gaps highlight the need for standardized, scalable, and economically viable interventions to ensure broader applicability of supportive care strategies. Most available studies also feature small sample sizes and short intervention periods, which limit generalizability. Moreover, the lack of standardized biomarker assessments, particularly for inflammatory markers such as interleukin-6 (IL-6) and glycoprotein acetylation (GlycA), hampers comparison across trials and the development of unified recommendations.

Conclusions and future directions

Integrative approaches that combine exercise and targeted nutrition represent promising non-pharmacologic strategies to enhance recovery and long-term quality of life in leukemia survivors. Evidence to date indicates beneficial effects on cardiorespiratory fitness, muscle strength, fatigue reduction, and inflammatory modulation. These interventions may also improve immune regulation and metabolic balance, complementing conventional treatments during and after therapy. Despite encouraging results, existing studies are limited by small sample sizes, heterogeneous methodologies, and variable adherence to exercise and dietary protocols. Additional factors, such as differences among leukemia subtypes, treatment phases, and patient-specific comorbidities, further complicate interpretation. Moreover, few studies have examined long-term cost-effectiveness, feasibility, or implementation outcomes in real-world settings. Future research should prioritize well-designed, adequately powered clinical trials that integrate exercise and nutritional interventions across different stages of leukemia treatment and survivorship. Incorporating biomarker-based monitoring and individualized prescription models may help optimize efficacy while ensuring safety and sustainability. Interdisciplinary collaboration among oncologists, physiologists, dietitians, and rehabilitation specialists will be essential to develop scalable, evidence-based programs that can be implemented in both inpatient and outpatient care. By bridging molecular mechanisms with practical applications, integrative lifestyle interventions have the potential to transform survivorship care in leukemia, promoting physical and psychosocial resilience while reducing treatment-related burden and enhancing long-term outcomes.

Author contributions

SY, QY, RQ, SR helped in the writing, investigation, editing, design, drafting, and conception of the paper. All authors confirmed to the final version.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent for publication

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.