The described findings define pediatric acute lymphoblastic leukemia (ped-ALL) as a public health matter in Mexico.

Recent studies suggest that, despite the country of residency or immigration status, children residing in Hispanic enclaves in HIC experience poorer overall survival, finding that society and culture represented by living in areas with high concentrations of Hispanic immigrants, ethnic-specific businesses, and language isolation (that often implies a socioeconomic deprivation) are determinants of a lower overall survival (13).

Hispanic children in the USA have a higher incidence of ALL than Caucasian and Black children. Census data show that legal Mexican first-generation and the Mexican American population account for 62 million people in the USA (14). Therefore, according to the census of Mexican Americans and the recent legal and illegal immigrants, approximately 74 million Hispanics live in the USA, which makes up 22% of the total population (4, 6). There are 20 million Hispanic children of Mexican descent, according to Pew Research Center findings in 2019. The research results from this center outlined that 27% of this Hispanic Mexican population are under the limits of poverty, and 34% are without any type of Health Insurance (12). Additionally, low income favors a poor prognosis in US children regardless of race (15).

Initial theories attributing this burden exclusively to socioeconomic factors have been broadly studied, resulting in clinical model proposals implemented in LMIC (16, 17). However, Hispanic children are between 1.2 and 1.75 times more likely to develop ALL and have a 40% higher death rate than their counterparts even after correcting for socioeconomic factors (17–20). Since the outcome for Hispanics with Ped-ALL is worst despite the country of treatment or socioeconomic condition, interest in a biological explanation has arisen over the past ten years (21). Important differences in the genetic background of Hispanic patients have been revealed (22, 23).

When analyzing leukemia in Hispanics, some genetic results are conditioned by the ethnic composition of the study population (24). For example, a California study found that acute promyelocytic leukemia (APL) is more commonly diagnosed in Hispanic adults, and non-APL acute myeloid leukemia (AML) appears less common in Hispanics (25). In contrast, a study made in Florida showed that AML was more common in Hispanics, regardless of subtype (24). This discrepancy may be associated with ethnic background; in California, 84% of the Hispanic population is from Mexican origin; in Florida, this is only 23.6%, demonstrating the heterogeneity among the Hispanic population (24). These observations revealed that the genetic background of Mexicans is involved in the biology and presentation of leukemia.

Since T cell ALL is less common among Hispanic patients, differences are mainly attributed to B cell precursors (pre-B) ALL, which is highly incident and presents individual differences in genetic characteristics (24). Genetics studies of patients diagnosed at our Institution in Mexico City revealed discrepancies in the frequencies of the classical abnormalities in this subtype. Table 1 demonstrates the incidence of recurrent translocations, ploidy levels, and frequent abnormalities observed in patients with pre-B ALL without recurrent translocations (B-other) in Mexican, Hispanic, and non-Hispanic patients from Los Angeles, California. The most relevant differences in Mexican patients are: the lower incidence of t (12, 21)(ETV6::RUNX1), similar to Hispanics (22, 26). The t (1, 19)(TCF3::PBX1) is slightly more frequent in Mexicans than in Hispanics and non-Hispanics (22, 27); abnormalities in CRLF2 are particularly frequent in Mexicans, with a similar incidence of IGH::CRLF2 compared to Hispanics, and P2RY8::CRLF2 is present with a higher frequency, all patients with these rearrangements presented CRLF2 overexpression (28–30); the iAMP21 is also frequent (10.1% in B-Others) (26, 29). This means that in Mexicans, ETV6-RUNX1, associated with standard prognosis, is reduced, and rearrangements of CRLF2 and iAMP21, which confer high risk, are widely represented among Mexican patients. Most of these findings have been replicated and confirmed by other groups in Mexico ( Table 1 ) (31, 32), although they must be compared to data from other regions in our country.

Likewise, specific polymorphisms associated with the risk of developing pre-B ped-ALL and lower survival rates have been detected more frequently in Hispanic patients (23). In a cohort of Mexican patients with ped-ALL, we analyzed seven polymorphisms in the transcription factor ARID5B gene, including rs10821936. We found that the frequency of all risk alleles was higher in our patients than in Hispanics with ped-ALL residing in the USA (23, 33).

The polymorphisms of genes involved in the metabolism of chemotherapeutic agents are another crucial biologic characteristic that affects the prognosis of ALL and differs among populations. Thiopurine S-methyltransferase (TPMT) participates in the toxicity and therapeutic efficiency of thiopurine drugs such as mercaptopurine, thioguanine, and azathioprine. Patients with low or undetectable levels of TPMT activity have better outcomes. However, such patients may be at higher risk of developing therapy-related toxicities such as myelosuppression and infection (34). In comparison, patients with high TPMT activity present a reduced clinical response to these agents and are prone to relapse (35–37). Based on this, it is possible to adjust the dose of purine analogs according to TPMT activity (34). The frequency of 12 TPMT polymorphisms was analyzed in 1270 Mestizos and 20 Mexican Natives and compared to Mexicans of Los Angeles, California (MXLA). Significant differences in allele frequency were detected; the key variant for thiopurine dosing TPMT*3B rs1800460 was two-fold more frequent in Mestizos compared to Natives and 10% higher than in MXLA (38). The same study also analyzed the polymorphism NUD2T15*3 rs116855232. It has clinical usage since reduces or abolishes the enzyme activity, diminishing tolerance to thiopurines. The NUDT15 polymorphism was observed with two-fold and 1.3-fold higher allele frequency in Natives and Mestizos compared to Caucasians, respectively. Considering these results, polymorphism analysis of TPMT and NUDT15 must be performed in Mexican children with ALL to prescribe thiopurines (38).

Ped-ALL in Hispanics, particularly Mexicans, differs from other populations towards higher risk. As described ( Table 1 ), well-known genetic risk abnormalities are frequently augmented, and good prognosis biomarkers are diminished. Added to the molecular/pharmacogenetic and social factors described the response to treatment contributes to the outcome gap for these patients.

Collaborative work has been crucial for the progress of oncology; cooperative efforts have allowed previously incurable diseases to now have cure rates that exceed 90% in some diseases, breaking a paradigm that associates cancer with a death sentence. These collaborations are based on a structured model of clinical care, which, through the standardization of criteria, structured registries, and clinical care protocols, allows for the continuous evaluation of results and favors the proposal of modifications that translate into less morbidity and more survival for patients optimizing the use of resources (39).

The need to replicate these collaborative models in the regions that serve the Hispanic population (Latin America) is evident; however, despite the linguistic similarity, the social, cultural, and geographical disparity, and the limited resources make this challenge a titanic mission. Global medicine efforts have failed to match the cancer treatment outcomes between LMIC and HIC. Particularly for the Hispanic LMIC, this failure may find an explanation in the ped-ALL biology, which is an adverse factor to the already serious social, economic, and health access issues of this mainly Hispanic population countries (40).

The patients in Mexico face an important challenge, i.e., increased rates of relapse, treatment-related toxicity, and treatment abandonment. Around 7–15% of patients die during the induction phase of the treatment, over 25% of patients with ped-ALL die from treatment toxicity, mainly due to infections, around 25–35% of patients relapse, and the abandonment rate may reach up to 50% in some areas of the country (6, 19, 41).

Limited access to adequate pediatric intensive care, geographical and social barriers for well-timed detection and attention of complications for patients in treatment favor the risk of death during treatment for patients, not only in LMIC like Mexico but also for patients in HIC living in Hispanic enclaves (13, 42, 43).

Recent efforts by both local actors in LMICs and global health initiatives led by HIC institutions are aimed at lowering the survival gap by improving supporting care and applying intensified risk-based treatment protocols with appropriate patient education and treatment response assessment on follow-up, considering a comprehensive approach to society, leukemia biology, and treatment based of risk biologic factors (43, 44).