Keywords

Introduction

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed during childhood [1]. Once considered a terminal diagnosis, pediatric ALL is now curable in approximately 90% of cases with contemporary therapy [2]. Despite significant improvements in the treatment of pediatric ALL, racial and ethnic disparities still persist. In particular, compared to non-Latino White populations, Latinos have both a higher incidence of pediatric ALL and less favorable outcomes [3]. Disparities in pediatric ALL outcomes are likely due to a number of factors, including ethnic variability in somatic molecular profiles, comorbidities, treatment adherence, and response to chemotherapy. Notably, exposure to central nervous system (CNS)-directed chemotherapy during ALL treatment is associated with a risk of acute and long-term neurotoxicity [4, 5]. Emerging research from our group and others suggests Latino patients with ALL may be particularly vulnerable to the adverse neurologic side effects of CNS-directed therapy [6,7,8]. Therefore, we provide an overview of ethnic disparities in treatment-related neurotoxicity and recommendations for future research directions.

Acute Neurotoxicity During ALL Therapy

The antifolate agent methotrexate is an important component of contemporary curative pediatric ALL protocols. Current ALL chemotherapy regimens typically include intravenous (IV), intrathecal (IT), and oral methotrexate. The antineoplastic effects of methotrexate are attributed to the competitive inhibition of the dihydrofolate reductase (DHFR) enzyme involved in tetrahydrofolate synthesis. The resulting tetrahydrofolate deficiency disrupts DNA and RNA synthesis, leading to cell cycle arrest. Methotrexate preferentially inhibits rapidly dividing cells, such as leukemic cells. However, because methotrexate is a folic acid analogue, prolonged use or exposure to high doses of methotrexate may deplete folate stores and result in adverse side effects. Specifically, approximately 10% of pediatric patients with ALL experience acute or subacute neurotoxicity, typically occurring within 14 days of receiving CNS-directed high-dose IV or IT methotrexate [4, 5]. Acute and subacute methotrexate-related neurotoxicity often manifests clinically as a combination of seizure, aphasia, altered mental status, stroke-like symptoms, and encephalopathy [6,7,8]. Although these symptoms are typically transient [9], the clinical management of methotrexate-related neurotoxicity often leads to delays or modification of cancer therapy, potentially limiting treatment efficacy. In fact, recent evidence from our group suggests that patients with suspected neurotoxic events during ALL therapy receive an average of two fewer doses of IT methotrexate [8]. Although follow-up was limited in this cohort, we also observed a statistically significant (p < 0.05) trend toward an increased risk of relapse in patients with a history of methotrexate-related neurotoxicity.

Despite neurotoxicity being a serious complication of methotrexate chemotherapy, information on the factors which modify the risk of methotrexate-related neurotoxicity is limited. Several independent studies have reported associations between older age at diagnosis and treatment intensity and the incidence of acute and subacute neurotoxicity [4, 5, 8, 10]. Recent case series further suggest that susceptibility to methotrexate-related neurotoxicity may vary across racial and ethnic groups. Giordano et al. [7] presented information on five ALL patients with acute or subacute neurotoxicity, all of whom were Latino, while Afshar et al. [6] described the presentation of clinical neurotoxicity in 18 pediatric oncology patients, including 12 Latino cases. Most recently, we conducted one of the largest evaluations of acute and subacute methotrexate-related neurotoxicity in a multisite study of patients treated on recent pediatric ALL protocols [8] and found significant differences in the incidence of neurotoxicity by ethnic group (Fig. 4.1). This analysis of 280 newly diagnosed (between 2012 and 2017) patients found that neurotoxicity occurred in 21.8% of Latino compared to 6.8% of non-Latino patients, corresponding to a nearly 2.5-fold increased risk of neurotoxicity after accounting for other clinical and demographic factors.

Fig. 4.1
A line graph on Days from end of induction versus cumulative hazard on Latino, and non-Latino white. Latino is on a high trend from (0,0.00) to (450,0.32), whereas non-Latino from (0.0) to (400,0.08). Values are estimated.

Cumulative hazard of acute and subacute methotrexate-related neurotoxicity between Latino and non-Latino White patients with pediatric ALL

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Growing evidence supports an association between genome-wide genetic ancestry and racial/ethnic disparities in pediatric ALL outcomes, including relapse [11], suggesting that genetic variants, which impact antileukemia therapy pharmacodynamics and pharmacokinetics, may co-segregate with areas of the genome associated with differing ancestral populations [12]. Because Latino ethnicity encompasses a genetically diverse population with various degrees of European, African, and Native American genetic admixture, we sought to evaluate the association between genetic ancestry and methotrexate-related neurotoxicity in a prospective cohort of pediatric patients with ALL. We estimated the proportions of European, African, East Asian, and Native American genetic ancestry using genome-wide genotype data available on 190 pediatric patients with ALL, including 35 individuals with a history of acute and subacute methotrexate-associated neurotoxicity, and publicly available reference populations [13, 14]. The proportion of genetic variation that co-segregates with Native American ancestry was overrepresented in individuals with methotrexate-related neurotoxicity (mean = 34.9%; Fig. 4.2) compared to individuals without a history of neurotoxicity (mean = 23.2%, p = 0.025). In multivariable proportional hazards regression models accounting for sex, age at diagnosis, and treatment risk group, every 10% increase in the proportion of Native American genetic ancestry was associated with a 16% increase in neurotoxicity incidence (HR = 1.16; 95% CI: 1.02–1.32). These findings highlight that ethnic-specific differences in inherited genetic variation likely contribute to disparities in the incidence of treatment-related toxicity.

Fig. 4.2
Two triangle-shaped graphs depict the genetic variation among Africans, Native Americans, and Europeans. In a non-Hispanic white, Hispanic, Non-Hispanic black, and Other are plotted. In b No neurotoxicity and neurotoxicity are plotted.

Observed variability in the proportions of African, European, and Native American genetic ancestry among pediatric cases of acute lymphoblastic leukemia by self-reported race/ethnicity (a) and the incidence of methotrexate-related neurotoxicity (b)

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Neurocognitive Late Effects of ALL Therapy

Contemporary treatment protocols for childhood ALL have largely eliminated the use of prophylactic cranial radiation in favor of CNS-directed chemotherapy [4, 15, 16]. Efforts to reduce exposure to cranial radiation have also reduced many adverse effects of ALL therapy, including neurocognitive deficits. Although cognitive functioning in survivors treated with contemporary chemotherapy is better preserved than in those treated with cranial radiation, survivors treated with chemotherapy alone continue to demonstrate deficits relative to their unaffected peers [17,18,19,20,21]. In fact, neurocognitive difficulties are estimated to be one of the most prevalent late effects of childhood ALL chemotherapy, affecting nearly 50% of survivors [22]. Neurocognitive difficulties are commonly detected in the domains of attention, executive functioning, working memory, and processing speed among long-term survivors of childhood ALL [17, 23, 24]. Neurocognitive changes in this population appear to be related to the effects of methotrexate, which have been associated with demyelinating white matter injury and vascular damage in the developing brain. Specifically, survivors treated with chemotherapy only have been found to have total white matter volume loss [25], notably in the frontal [26] and subcortical regions [27], and abnormal or reduced white matter connectivity [27,28,29], with children diagnosed at younger ages being particularly vulnerable to these adverse effects of treatment [27]. Children and adolescents experiencing clinical findings of acute or subacute methotrexate neurotoxicity during treatment may be at particularly increased risk for long-term neurocognitive deficits [30]. For example, children who experienced seizures during treatment for ALL demonstrated reduced attention, working memory, and processing speed relative to children who did not develop seizures and had normative scores at the end of treatment; additionally, these difficulties persisted over a two-year follow-up period [30]. However, other therapeutic exposures, including anesthesia, have been associated with persistent neurocognitive issues among survivor [31]. These cognitive deficits not only impede learning and academic achievement but also have long-term educational and economic consequences [32,33,34].

Despite increased incidence of ALL and neurotoxic events during therapy among Latino patients coupled with increased neurocognitive risk among Latinos more broadly, there is an extreme lack of population diversity in neurocognitive outcomes research for pediatric ALL to date. According to recent meta-analyses summarizing sociodemographic factors and neurocognitive outcomes in ALL, only one-third of studies reported the ethnic/racial composition of their sample, and when race/ethnicity was reported, the overwhelming majority (almost 80%) self-identified as White or Caucasian [21, 35]. Two studies have been conducted among Latino cohorts, and they indicate that survivors are at risk for neurocognitive late effects and school-based learning difficulties [36, 37]. Specifically, Latino survivors of pediatric ALL demonstrated reduced performance relative to the normative mean in neurocognitive domains typically affected in non-Latino patients including working memory, processing speed, visual reasoning, executive functioning, and visual learning [37]. In addition, Latino survivors demonstrated reduced verbal reasoning and reading comprehension skills, which are not typically implicated in late effects research of predominantly non-Latino populations. Despite a focus on Latino survivors, models did not account for socioeconomic status (SES), though proxies for the general socioeconomic standing of the sample were described.

Emerging Research Needs

Most models of neurotoxicity in pediatric patients with ALL have focused on clinical predictors, often excluding sociodemographic and molecular factors known to influence neurologic development and outcomes in unaffected populations. For example, neurocognitive abilities of children in the general population are adversely impacted by many factors, including SES and native language [38, 39], which disproportionately affect racial and ethnic minorities. Despite the fact that ethnic disparities in ALL outcomes and toxicity are well documented [3, 11, 40,41,42,43], few studies have evaluated neurotoxicity in multiethnic populations, much less evaluated the role of SES and acculturation [24, 36, 37, 44]. Moreover, the considerable inter-patient variability in susceptibility to neurotoxicity might be partly explained by underlying molecular variation. However, the role of these factors in treatment-related neurotoxicity has received limited attention. Additional research on the roles of socioeconomic, cultural, and biologic factors in ethnically diverse populations is needed to advance our understanding of neurological outcomes in vulnerable populations.

Incorporating Information on SES and Acculturation

Survivors of childhood ALL who are from racial/ethnic minority groups and lower SES are at increased risk for cognitive deficits. SES refers to a combination of income, education, and occupation [45]. Therefore, generally speaking, the relationship between ethnicity and neurocognitive outcome is complex, given that ethnicity and SES can be highly related, particularly among Latino families [46]. In particular, Latinos who immigrate to the United States have, on average, a lower SES [47], though there is considerable variability depending on country of origin. For example, Cuban-Americans graduate from college at three times the rate of Mexican-Americans [48]. Among healthy children, associations are documented between SES and cognitive abilities. The domains most affected by SES disparities include language abilities, executive functioning, attention, and memory [38, 39]. Overall, few studies have considered SES in relation to neurocognitive outcome among survivors of childhood leukemia; however, when these factors are considered the observed associations are typically consistent with individuals of lower SES having an increased risk of impairment [49].

Among Latino families, acculturation may simultaneously impact cognitive and academic skill development along with socioeconomic factors, though acculturation is not necessarily related to such factors. Language is an important aspect of determining an individual’s level of acculturation. Parent language acculturation in Latino families, namely English proficiency and primary language in the home, is important for children’s academic readiness and academic success in higher grades [50, 51]. Furthermore, Latino children whose native language is Spanish perform significantly worse than non-Latino children on the Wechsler Intelligence Scales, the most commonly used measure of intelligence in childhood, with specific adverse effects exhibited on verbal subtests [52]. While there are a number of proxies for acculturation, such as generational status and number of years of US residency, none of them are adequate for providing insight into the influence on the acculturative experience on neurocognitive development and performance.

Molecular Predictors of Neurotoxicity

In addition to variability in patient characteristics and therapeutic exposures, a number of factors likely contribute to disparities in pediatric ALL toxicity and outcomes, including underlying genetic variation. To date, few studies have evaluated inherited single nucleotide variants; however, associations have been reported between clinical neurotoxicity and candidate variants in SHMT1, MTHFR, and GSTP1 [53, 54]. In particular, the missense C677T polymorphism in MTHFR (rs1801133) has been associated with adverse responses to methotrexate therapy in pediatric and adult patients treated for rheumatoid arthritis and various malignancies [55,56,57]. Several publications have speculated that inherited variation in MTHFR may also contribute to the risk of methotrexate-related neurotoxicity in children with ALL [54, 58], but direct evidence that MTHFR genetic variation affects neurotoxicity susceptibility is limited. Compared to individuals who are homozygous for the reference allele (CC), carriers of the alternate allele (CT/TT) exhibit decreased MTHFR enzymatic activity and increased plasma homocysteine levels [59]. Homocysteine concentrations are transiently elevated following methotrexate therapy, and cerebrospinal fluid levels of homocysteine have been linked to neurotoxicity in children undergoing treatment of ALL [60, 61]. Notably, the frequency of the C677T missense variant appears to vary across ancestral populations. Based on the 1000 Genomes data [62], the C677T alternate allele frequency is approximately 9.0% in individuals of African ancestry, 36.5% in individuals of European ancestry, and 47.0% in admixed American populations comprised individuals of Latino ethnicity. Additional research is needed to better characterize the genetic contribution to methotrexate-related neurotoxicity and disparities in susceptibility. However, genome-wide association studies have not yet successfully identified and replicated susceptibility loci due to challenges in assembling large cohorts to sufficiently power these studies [4]. Alternative approaches that examine the association between local Native American genetic ancestry and neurotoxicity risk using methods such as admixture mapping may prove more powerful at identifying novel susceptibility loci responsible for the ethnic disparities observed in neurotoxicity risk.

Conclusion

Current treatment strategies for pediatric ALL are associated with acute and long-term neurotoxicity. The incidence of acute and subacute neurotoxicity during pediatric ALL therapy potentially jeopardizes treatment efficacy, while long-term neurocognitive impairment profoundly affects quality of life in survivors of ALL. Emerging evidence indicates that Latino patients may be particularly susceptible to these adverse side effects of therapy. In fact, we recently reported that Latino patients with ALL experience acute and subacute neurotoxic events at a rate far exceeding their non-Latino counterparts [8]. Some evidence suggests that acute toxicity predisposes affected individuals to long-term neurocognitive and behavior complications as survivors [30]; therefore, Latino survivors may be particularly vulnerable. Unfortunately, studies of neurotoxicity during pediatric ALL therapy have largely neglected Latino populations. Future well-designed studies are needed to characterize neurotoxicity outcomes in Latino patients, while considering factors associated with disparities in cognitive performance in the general population, including SES and acculturation. Ultimately, a better understanding of the various factors likely responsible for disparities in neurotoxicity, including inherited genetic variation, clinical characteristics, and sociocultural differences, is needed to improve outcomes for Latino populations.