Not All Populations of Hispanic Children Have an Increased Frequency of Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) represents the most common neoplasm in children (1). It has been informed that children from a Black ethnicity displays a decreased incidence of childhood ALL compared with other ethnic groups (2). Conversely, the highest incidence rates have been reported for Hispanics living in the American Continent (2). In the study by Montes-Rodríguez and colleagues recently published in this journal, the authors communicate that the Puerto Rican Hispanic (PRH) children had higher incidence rates of ALL than non-Hispanic Blacks, similar rates than the non-Hispanic Whites (NHW) but lower rates than the U.S. Hispanic (USH) population. Nonetheless, a significant increasing trend in the incidence of ALL was observed in the PRH group (5%) while only 0.9% among USH children (3).

Although PRH children differ from the USH population in the incidence of ALL, they are not different in relation to the survival rates which are lower than the reported for the NHW patients (3). The differences in survival were noted since the first year of treatment and more evident at the 3 and 5 years after diagnosis. In this regard, Gupta and colleagues have reported a dismal prognosis in children from a Hispanic origin in comparison with NHW children regardless of the use of the same chemotherapy protocol, improvement of the facilities and resources for attending ALL children (1). Therefore, in future reports, it would be interesting to gather information about the number and type of hospitals attending children with ALL in Puerto Rico, the treatment regimens as well as the prognostic stratification scheme used to identify the predictors of the low survival rates observed. It is well known that treatment stratification based on the detection of minimal residual disease and molecular characterization of patients with ALL is associated with better outcomes. Particularly in the United States, when these differences can be controlled, the survival of children may be similar to the NHW independently of the ancestry composition of the population (1). Moreover, in the study by Montes-Rodriguez and colleagues, the highest frequency of mortality occurred in the group of infants and adolescents, for whom it has been described that the MLL gene rearrangements and the Ph-like phenotype are highly prevalent and associated with the incidence of ALL in these age groups (3, 4). Hence, it would also be interesting to know the frequencies of these molecular subtypes in the PRH population (3). On the other hand, it is of great interest the finding of Montes-Rodriguez and colleagues about lower survival rates in girls than boys. In the study by Moore and colleagues, it was communicated that Hispanic girls with ALL had lower survival rates than boys (5). Then, the influence of the ancestry and child's sex in the drug metabolism and its impact on the survival in Hispanic children with ALL is relevant to be studied further (5, 6). In Mexico, a study is being conducted to identify how the population ancestry in different regions of Mexico, which has about 68 different ancestral groups, may be related to drug metabolism and how this is associated with chemotherapy toxicity-related deaths in children with ALL. On this subject, Rivera-Luna and colleagues summarized in a hypothesis called “The triple-hit” the possible explanation for the worse prognosis of pediatric ALL among Hispanic children. The “first hit” is related to the socioeconomic and demographic conditions of the population affected; the “second hit” refers to biological features and the aggressiveness of the disease; and the “third hit” which considers an inadequate treatment and support measures (7). Regarding this last point is also important to consider the Hispanics less accessibility to participate in clinical trials where better therapeutic options are tested in comparison with other ethnic groups as Gupta and colleagues had reported previously (1).

A recent publication presented the differences in the incidence of childhood ALL worldwide and not all populations of Hispanic children have an increased frequency of ALL (Supplementary Table S1 in ref. 2). For example, there are Hispanic populations such as those living in the State of Nuevo Leon, a Mexican state bordering the United States where the incidence of ALL is similar to the general U.S. population (8), and Nuevo Leon has not reported changes in the incidence of the disease. However, we do not know what course the incidence of childhood ALL in the Hispanic population of Puerto Rico will follow, taking into account the 5% annual increase reported by Montes-Rodriguez and colleagues, which, if it continues in this way, could soon reach similar incidence rates for childhood ALL as the great majority of Hispanic populations with a greater predominance of Amerindian ancestry (2). Something that may be relevant to comment is the example of what happened in Mexico City during the 1980s (9). During those years, the frequency of ALL was lower than that reported in the United States. The frequency was at 22.19 cases per 1 million children under 15 years of age while the overall incidence in the United States was around 27 per million (10). From that moment on, it could be noticed that there was an increasing trend in the incidence of ALL in Mexico City and although it was not properly calculated, it showed a very accelerated trend almost reaching the 1990s (9). Afterward, at the beginning of the present century, using a better method of evaluating the incidence of ALL in Mexico City, it was observed that it had already surpassed the frequency of childhood ALL in the United States and was very similar to that of Hispanics living in the United States (11, 12). Recently, it has been observed that this incidence continues to increase, becoming Mexico City one of the regions of the world with the highest incidence rates for ALL during childhood (2, 12, 13). During those years, no epidemiologic studies were done to identify which risk factors had been changing that could be associated with the marked increase of ALL in Mexico City. This makes the study by Montes-Rodriguez and colleagues very interesting because on the one hand, the phenomenon of the increasing incidence trends they are observing could be marking a moment of alert because the Hispanic population of Puerto Rico in the coming years could reach the incidence of ALL observed in the Hispanic population of the United States (3) but on the other hand, Puerto Rico should be the focus of attention at this time for conducting population-level epidemiologic studies to identify the environmental factors associated with an increased risk of ALL. If there is a factor or several factors that are being able to cause a 5% annual increase in the incidence of ALL in Puerto Rico, now could be an appropriate region of the world to identify the environmental factors associated with the development of childhood ALL. This might be a unique opportunity in the world to identify the risk factors that have led to the marked increase in the incidence of ALL among Hispanics and to possibly identify more accurately the environmental factors that contribute to this disease.

Recently, Wiemels and Gallant (14) mentioned that the sum of factors rather than a single factor could be contributing to the development of ALL, encouraging studies where not only one risk factor for ALL is sought, but the sum of several of them to determine the causality of childhood ALL quickly and accurately (14, 15). It is indisputable that the Hispanic population has a genetic background that predisposes to a greater susceptibility to the disease (6), but fortunately not all children with this susceptibility develop the disease, so the participation of environmental factors is certainly required. In addition, the exposure to an environmental risk factor that is likely to cause the development of ALL will show its greatest effect as the susceptibility to develop the disease also increases (16). Taking this into consideration, the more susceptible subjects there are in a population, the more cases the environmental factor will be able to cause (Fig. 1).

In the example of the Fig. 1, although we do not know how many individuals will develop ALL, we could assume that even if the frequency of the risk factor was similar among the three populations because there is a greater susceptibility to the disease in one of them, a greater number of cases of the disease would be expected there. This is the same that happens in the case of vaccine-preventable infectious diseases, where there is more vaccination coverage, a lower number of cases of the disease is expected, and vice versa, the lower the vaccination coverage in a population, the higher the number of cases of the disease would be expected for the same exposure. In the article by Montes-Rodriguez and colleagues, the authors focused the discussion of the incidence results in the context of the ancestry composition of the population summarizing the findings of Quiroz and colleagues who informed that where there is a greater predominance of Amerindian ancestry there is a higher frequency of ALL, while, where there is a greater predominance of an African American ancestry there is a lower frequency of ALL in the American continent (17).

Following the hypothesis represented in the Fig. 1, if we consider the populations with greater African American ancestry, those with greater European ancestry and those with greater Amerindian ancestry, and the exposure to an environmental factor capable of causing ALL, we expect more cases of ALL in the population with Amerindian ancestry, fewer in the population with European ancestry and even fewer cases in the population with African ancestry. Thus, in populations with a greater susceptibility to the disease, given that there would also be a greater number of cases associated with the risk factor, it would be more likely to identify that factor as associated with the disease.

Down syndrome children are a population with a high susceptibility to develop acute leukemia (18). Several environmental factors such as smoking, exposures to chemicals in the home (19), exposure to extremely low-frequency magnetic fields (20, 21), early infections (22, 23), or the use of vitamins (24) have been associated with the risk of developing ALL. The risks for these factors have been reported to be higher than those found in non-Down syndrome populations (20–22). Taking into consideration the rarity of the association (childhood ALL and Down syndrome), it is very difficult to evaluate the effect of the environmental factors on the incidence of the disease. Then, it is so important to investigate for environmental factors related to the etiology of ALL in Hispanic populations because this is a group with a high susceptibility to develop ALL and a very large population group.

The most important aspect of this is that if the risk factor or factors that are causing the increase in the trend of the incidence of ALL in children from Puerto Rico could be identified and are susceptible to being modified, it will not only allow the reduction of ALL in populations with a high susceptibility, but in all populations because in all populations this risk factor or risk factors may cause ALL.

Finally, we must take advantage of the information provided by the study of Montes-Rodriguez and colleagues who studied the Hispanic population of children from Puerto Rico and, as they mention in their article, their information can be a guide for future research in these minority populations because the risk factors that are causing this large increase in the incidence of ALL may be in front of us, but also the possibility of modifying them and thus may reducing the incidence of ALL in the world (3).

No disclosures were reported.

This work is funded by CONACYT (CF-2023-G-1399, J.M. Mejia-Arangure).