Socioeconomic Disparities and Clinical Outcomes in Pediatric Acute Lymphoblastic Leukemia Across the Americas: An Integrative Review

1. Introduction

Acute lymphoblastic leukemia (ALL) is the most common malignancy in the pediatric population worldwide, characterized by uncontrolled proliferation of immature lymphoid precursors. Over the past four decades, the prognosis of this disease has undergone a radical transformation in high-income countries, where the implementation of risk-stratified protocols and universal access to supportive care has enabled five-year overall survival (OS) rates consistently exceeding 90% [1,2]. This success, however, is not uniformly distributed across the American continent. In Latin America and the Caribbean, OS rates range from 50% to 75%, revealing a systemic disparity that cannot be explained by tumor biology alone [2,3].

The survival gap reflects a deep and multifactorial problem rooted in the social determinants of health. Household income and the type of health insurance coverage are among the strongest predictors of access to timely diagnosis and innovative therapies in the region [4,5]. While health systems in North America operate under standardized guidelines developed by large cooperative groups such as the Children's Oncology Group (COG), centers in Latin America continue to face infrastructure limitations, protocol heterogeneity, and resource constraints that fragment care delivery [2,6].

One of the most critical structural barriers in the Americas is treatment abandonment, a phenomenon closely linked to economic vulnerability. Abandonment rates in developed countries remain below 1%, sustained by comprehensive patient support systems; by contrast, in rural and marginalized areas of Latin America, rates can reach 30-40%, driven by geographic distance to specialized centers, financial toxicity, and low maternal health literacy [7,8,9]. Additionally, treatment-related mortality (TRM) during induction remains alarmingly high in resource-constrained settings, attributable to opportunistic infections and nutritional deficiencies—including both undernutrition and obesity—that amplify chemotherapy toxicity [10,11].

Despite the demonstrated effectiveness of twinning programs and international collaborations in improving outcomes through resource sharing and protocol standardization, structural barriers remain insurmountable for many families, including extreme geographic distances to oncology centers and prohibitive supportive care costs [12,13]. Against this backdrop, the present integrative review was conducted to synthesize the evidence generated between 2015 and 2025 on how socioeconomic factors and access barriers shape the clinical reality of pediatric ALL across the Americas. The aim is to inform evidence-based policy and clinical interventions capable of reducing existing disparities.

2. Methods

2.1. Study Design

An integrative review of the literature was conducted. This methodological design permits the inclusion of studies employing diverse approaches—experimental, observational, and theoretical—rendering it appropriate for the examination of a multifactorial phenomenon such as socioeconomic disparities in health outcomes [14]. The review was structured according to the five stages established by Whittemore and Knafl: problem identification, literature search, data evaluation, data analysis, and results presentation.

2.2. Search Strategy

Searches were performed in PubMed/MEDLINE, Scopus, SciELO, and LILACS. A structured battery of research questions addressed four analytical dimensions: clinical efficacy, access barriers, toxicity mechanisms, and associated costs. Search strings were constructed using controlled vocabulary (MeSH and DeCS terms) combined with free-language terms and Boolean operators. A representative primary search string was: (“Precursor Cell Lymphoblastic Leukemia-Lymphoma” OR “Leukemia, Lymphoid”) AND (“Child” OR “Pediatric”) AND (“Americas” OR “Latin America” OR “North America”) AND (“Socioeconomic Factors” OR “Treatment Adherence” OR “Health Status Disparities”). The search window was restricted to studies published between January 2015 and December 2025.

2.3. Eligibility Criteria

Inclusion criteria comprised: primary studies (cohort, descriptive, and analytical designs), systematic reviews, and epidemiological reports examining pediatric ALL (ages 0-18 years) in any country of the Americas; studies reporting outcomes including OS, EFS, TRM, abandonment rates, or the impact of social determinants such as household income, maternal education, geographic distance, or nutritional status. Exclusion criteria included case reports, editorials, expert opinions without empirical basis, and studies that did not distinguish pediatric ALL outcomes from those of other pediatric cancers or adult populations.

2.4. Data Evaluation and Extraction

The evaluation stage comprised a critical appraisal of the methodological rigor of selected studies. For quantitative studies, representativeness of the sample and bias control were assessed. Given the integrative nature of the review, methodological quality was used to weight the evidence in the final synthesis rather than as an exclusion criterion. Data extraction was systematized using a standardized form capturing: author(s), year, country, disparities analyzed, key statistics (e.g., survival percentages, abandonment rates), and limitations declared by the original authors. Particular attention was paid to data on critical care utilization and induction mortality, as these represent critical indicators of regional infrastructure capacity.

2.5. Data Analysis and Synthesis

A thematic synthesis method was employed to organize the information logically and coherently. Data were coded and grouped into four analytical categories: 1) overall survival disparities between regions of the Americas; 2) impact of economic determinants and health insurance type; 3) geographic barriers and predictors of treatment abandonment; and 4) interaction between nutritional status and chemotherapy toxicity. This analysis enabled the identification of patterns, contradictions, and knowledge gaps in the contemporary literature on pediatric ALL across the continent.

3. Results

3.1. Evidence Quality and Documentary Corpus

The documentary corpus of this integrative review reflects a broad diversity of methodological designs, enabling a comprehensive understanding of the phenomenon under study. The corpus includes large-scale retrospective and prospective cohort studies, high-impact systematic reviews, population-based epidemiological analyses, and qualitative studies focused on the care experience. Research from North America, primarily associated with prestigious consortia such as the Children's Oncology Group (COG) and the Dana-Farber Cancer Institute (DFCI), demonstrated high long-term follow-up fidelity and superior technical robustness in genomic and molecular analysis [15,16]. These studies serve as the reference standard for comparing clinical outcomes against the realities of countries with variable resources elsewhere on the continent.

In Latin America and the Caribbean, a substantial increase in the quality and frequency of multicenter reports has been observed over the past decade. Noteworthy are investigations with representative samples from middle- and low-income countries examining risk factors specific to the regional population, including genetic ancestry and logistical barriers [4,17,18]. However, significant heterogeneity persists in the standardization and updating of national oncological registries in the southern region of the continent, imposing methodological challenges to the comparability of certain epidemiological subgroups [19]. This data fragmentation underscores the need to strengthen epidemiological surveillance systems to obtain a more accurate picture of the disease burden.

3.2. Continental Disparities in Overall Survival and Event-Free Survival

The five-year overall survival gap is the most critical clinical finding of this review. While in high-income countries such as the United States and Canada OS for pediatric ALL consistently exceeds 90% due to the optimization of supportive care and precise risk stratification, in Latin America and the Caribbean survival rates fall between 50% and 75% [3,15]. This disparity, reaching up to 40 percentage points, does not solely indicate greater intrinsic biological aggressiveness of the tumor. Instead, it reflects the differential capacity of regional health systems to effectively manage treatment-induced toxicity and thereby prevent premature mortality during the critical phases of therapy [6,12,20].

Longitudinal epidemiological studies confirm that the decline in mortality rates has been significantly slower and more asymmetric in the Southern Cone and Andean region compared to North America. This persistent divergence in therapeutic results demonstrates that scientific advances have not translated into equitable benefits for the entire pediatric population of the Americas [20,21]. The literature indicates that persistently elevated mortality-incidence ratios (MIR) in certain Latin American countries are an indirect indicator of systemic failures in access to salvage therapies and implementation of intensity-adapted protocols [20].

3.3. Impact of Socioeconomic Determinants and Health System Characteristics

Household income and the type of health insurance emerge as the most determinative predictors of event-free survival (EFS) in the Americas. Patients who depend exclusively on public health systems in middle-income countries exhibit significantly inferior EFS, with differences of up to 30%, compared to those with private insurance or access to high-specialty oncology centers [4,22]. This phenomenon is compounded by the so-called “biology of inequality,” whereby economic precarity and social vulnerability translate into delayed diagnoses, prolonged hospital stays, and a more aggressive clinical presentation at the time of the initial oncology consultation [1,4,5,22].

Studies conducted in Mexico, Central America, and Brazil additionally document that low maternal educational attainment and household financial insecurity act as critical mediators of therapeutic failure. These factors directly influence families' capacity to understand and adhere to treatment protocols that are inherently intensive and prolonged [3,5,18]. Food insecurity and the absence of robust social support networks correlate with a higher risk of infectious complications and lower tolerance to myeloablative chemotherapy, perpetuating a cycle of disadvantage that compromises curative potential [4,5,23].

3.4. Treatment Abandonment and Geographic Access Barriers

Treatment abandonment represents the most critical structural barrier in Latin America, constituting a systemic challenge that is virtually nonexistent at centers of excellence in North America. While abandonment rates at these centers remain below 1% due to comprehensive patient support systems, in various rural and marginalized areas of Latin America rates can reach 30-40% [7,8,24]. Evidence indicates that abandonment occurs most frequently after the induction phase, when the family's perception of immediate clinical improvement collides with the cumulative economic and logistical fatigue of long-term treatment [7,8].

Geographic distance to specialized centers constitutes an independent and fundamental risk factor in this process. Residing more than 70-150 km from the oncology hospital triples the risk of abandonment and significantly reduces the probability of successful salvage at relapse, owing to prohibitive transportation and accommodation costs [9,13,24,25]. Furthermore, low maternal health literacy correlates with poor adherence to orally self-administered chemotherapy during the maintenance phase, particularly 6-mercaptopurine, favoring the emergence of early relapses that could be prevented with adequate educational supervision [26,27,28].

Financial toxicity further compounds this vulnerability. Insurmountable out-of-pocket expenditure on transport, food, and supportive care pushes families toward protocol interruption, particularly those with low health literacy and limited maternal education [13,27,29]. The evidence is consistent in identifying lack of adherence to oral maintenance chemotherapy as a key mediator of early relapse, which could be prevented through targeted educational programs and direct supervision [3,26,28].

3.5. Treatment-Related Mortality and Critical Supportive Care

Induction mortality is substantially higher in resource-limited settings, with severe bacterial infections and neutropenic sepsis identified as the primary causes of preventable death in this review. This risk is exacerbated by the increasing prevalence of multidrug-resistant pathogens in regional hospital units and the absence of standardized protocols for the rapid management of septic shock [12,23,30,31]. TRM functions as a structural ceiling preventing many centers in the region from achieving international cure standards [17,31].

Nutritional status at diagnosis significantly modulates the therapeutic response and the incidence of serious complications. Both chronic undernutrition (growth stunting) and pediatric obesity—prevalent in urban Hispanic communities—are associated with increased grade 3-4 hematologic toxicity and greater susceptibility to lethal infections during neutropenia [10,11,23,32]. Hospital infrastructure plays a decisive role: the availability of pediatric intensive care units (PICU) and the implementation of pediatric early warning systems (PEWS) have been shown to substantially reduce mortality from acute clinical deterioration through early identification of sepsis signs [12,17,33,34].

3.6. Genomic Risk Features Linked to Ancestry

A high and clinically significant prevalence of high-risk genomic alterations has been identified in pediatric ALL patients of Hispanic and Amerindian ancestry treated across the Americas. IGH::CRLF2 rearrangements and IKZF1 deletions, which activate JAK/STAT and PI3K/AKT/mTOR signaling pathways and confer resistance to conventional chemotherapy, are significantly more frequent in Hispanic/Latino children compared to non-Hispanic White populations [35,36]. The IKZF1PLUS profile—defined by IKZF1 deletion co-occurring with CDKN2A/2B deletion, PAX5 deletion, or P2RY8::CRLF2 rearrangement in the absence of DUX4 rearrangement—has been identified as a novel high-risk feature enriched in Hispanic/Latino patients [35]. These findings suggest that pharmacogenomic profiling adapted to regional ancestral backgrounds, including NUDT15 and TPMT polymorphisms that predict thiopurine toxicity, is essential for both risk stratification and treatment individualization (Martinez-Espinosa et al., 2023; Yao et al., 2021).

3.7. Successful Interventions and Disparity Mitigation Programs

Despite the structural challenges described, several intervention models have demonstrated high efficacy in mitigating continental disparities in pediatric oncology. Patient navigation programs and Directly Observed Care (DOC) models have reduced abandonment rates from 30% to below 10% in countries such as Belize, Trinidad and Tobago, and El Salvador by providing logistical and emotional support between the hospital and the home [37,38]. These initiatives underscore the importance of addressing social determinants as an integral component of the medical protocol.

Twinning strategies between high-income institutions and regional consortia—including the Asociación de Hemato-Oncología Pediátrica de Centroamérica (AHOPCA) and programs led by St. Jude Global—have enabled the standardization of therapeutic protocols and continuous professional development. These collaborations have resulted in sustained and measurable improvements in OS across multiple nations in the region [6,13,39]. Innovative technological tools, including medication reminder text messaging and telemedicine for remote follow-up, have also emerged as viable and cost-effective strategies to improve adherence in geographically isolated populations [22,26,40].

4. Discussion

This integrative review confirms the existence of a profound and persistent survival gap in pediatric ALL across the American continent. The evidence demonstrates that socioeconomic position exerts a predictive value on outcomes at least as great as—and in many settings greater than—the tumor's intrinsic biological characteristics [2,4,5].

The finding of a survival gap of up to 40 percentage points between North America and parts of Latin America cannot be reduced to greater intrinsic biological aggressiveness in Hispanic populations. While the literature identifies a high prevalence of high-risk cytogenetic features, including IGH::CRLF2 rearrangements and JAK/STAT pathway mutations linked to Native American ancestry, these biological factors operate within a context of systemic fragility [15,35,36]. The high mortality observed in the southern region is largely a consequence of critical failures in supportive care and delayed diagnosis, rather than primary pharmacological resistance [1,18,20].

A fundamental epidemiological indicator emerging from this synthesis is the elevated mortality-incidence ratio (MIR) in Latin America. While in high-income countries the MIR has fallen sharply due to the standardization of advanced protocols under cooperative groups such as COG, in middle- and low-income nations the decline has been asymmetric and slow [20,21]. This disparity reflects the “biology of inequality,” where factors such as severe malnutrition and exposure to multidrug-resistant pathogens in hospitals with limited infrastructure act as amplifiers of pharmacological toxicity [23,30,31].

TRM constitutes an insurmountable obstacle to universal cure. This review highlights that an alarming proportion of children in the Americas do not die from refractory leukemia but from preventable infectious complications during induction, primarily neutropenic sepsis [17,31]. The lack of robust PICUs and the absence of PEWS in peripheral centers represent technical barriers that determine the clinical prognosis before the curative phases of the protocol can be completed [12,33,34].

Treatment abandonment persists as the most consequential cause of therapeutic failure in Latin America, a phenomenon virtually nonexistent in North American centers of excellence [2,7,8]. This review demonstrates that abandonment should not be interpreted as parental negligence but as a forced response to structural barriers. Geographic distance to specialized oncology centers emerges as a critical factor: residing more than 150 km from the hospital triples the risk of abandonment and correlates directly with inferior OS [9,13,24,25].

Financial toxicity intensifies this vulnerability. Unaffordable out-of-pocket expenditure on transport, food, and palliative care pushes families toward protocol interruption, particularly those with low health literacy and limited maternal education [13,27,29]. Evidence is consistent in demonstrating that poor adherence to oral maintenance chemotherapy (6-mercaptopurine) is a key mediator of early relapse that could be prevented through structured educational programs and direct supervision [3,26,28].

Patient navigation models and twinning programs have demonstrated high-impact potential. Successful models in Belize, Trinidad and Tobago, and the AHOPCA consortium in Central America have reduced abandonment from 30% to below 10% by mitigating logistical barriers and strengthening social support [6,37,38,39].

The evidence analyzed demands an urgent transition from the observation of disparities toward the implementation of biosocial solutions. A critical immediate implication is the universal adoption of PEWS and intensive nursing education in oncology, measures that have been shown to substantially reduce mortality from sepsis in variable-resource settings [17,34]. In the domain of precision medicine, it is imperative to integrate pharmacogenomic profiles adapted to the Amerindian ancestry of the region. Preventive dose adjustment based on NUDT15 and TPMT polymorphisms is essential to avoid lethal hematological toxicities in regional populations [16,41]. Equally, the strengthening of national registries and the standardization of minimal residual disease (MRD) detection by flow cytometry or next-generation sequencing are fundamental pillars for adequate risk stratification [6,18]. Future research should evaluate the role of telemedicine and mobile health in improving adherence in remote areas, reducing the economic burden of travel [22,40].

This review presents notable methodological strengths in integrating, for the first time under the Whittemore and Knafl model [14], genomic, clinical, and sociological data from across the continent. This enables a comprehensive understanding of the interaction between tumor biology and the social environment. Recognized limitations include the heterogeneity of oncological registries in Latin America and a potential publication bias toward tertiary-level centers, which may obscure more critical realities in rural or peripheral settings with reduced epidemiological reporting capacity.

In conclusion, pediatric ALL in the Americas remains a persistent reminder of health inequity. The evidence is unequivocal: a child's probability of survival should not be conditioned by household income or distance to a hospital. While science provides unprecedented curative tools, social structures continue to interpose barriers that transform treatable diseases into avoidable fatal outcomes. Closing this gap is not only a technical challenge but also an ethical and social justice imperative that demands a continental commitment to equity, ensuring that every child in the Americas, regardless of origin, is entitled to survive and thrive.