Diagnosis and treatment of acute lymphoblastic leukemia in Latin America

ABSTRACT Objective to discuss the status and challenges associated with the management of acute lymphoblastic leukemia (ALL) in Latin America. Methods This review summarizes various insights gained from information regarding diagnostic approaches and treatment strategies in adult patients with ALL in Latin American Countries. Results Information regarding ALL in Latin America is scarce; however, many efforts have been made to overcomes these barriers. Nevertheless, major obstacles to successful treatment in Latin America and LMIC remain poor adherence, abandonment of treatment, and lack of supportive therapy and new therapeutic agents. Conclusion Further improvements in survival should be pursued by developing more Latin American registries, forming cooperative groups, developing educational models to facilitate earlier diagnosis and prevention of complications, better support therapy and management of infections, and adapting treatment strategies.


Introduction
Crucial technological advances and increasing knowledge of the diagnosis and management of acute lymphoblastic leukemia (ALL) have emerged in the last decades. The development of new therapeutic agents has increased the access to cellular therapies, and the implementation of high-precision tests to identify diagnostic and prognostic markers has contributed to improving the survival rate of this disease with a cure rate approaching 90% in children living in developed countries [1]. Unfortunately, this is not the reality for Latin America and other low-middle income countries (LMIC) where outcomes for both pediatrics and adults are drastically worse than those considered by international standards [2,3].
In Latin America, Chile and Argentina have demonstrated significant advances in pediatric ALL care by achieving a percentage survival of more than 70%. In comparison, an estimated survival rate of about 50% has been achieved in Mexico [4].
Differences in epidemiology and biological characteristics have been reported in our region, with a higher incidence of ALL in the Latino population and even Hispanic patients receiving care in high-income countries (HIC) have lower survival rates, suggesting that genetics is a contributing factor [5][6][7]. The Hispanic population has a higher prevalence of the B-ALL phenotype than Caucasians, and a significant number of Hispanic patients meet traditional highrisk criteria [8]. Additionally, the highest incidence of ALL, with >35 cases per million in the Hispanic population has been documented [9]. In contrast, 44.9 and 52.2 of pediatric cases per million have been reported in Mexico City and Costa Rica, respectively [10,11].
Pollyea et al. [5] conducted a study in California where many Hispanic and non-Hispanic white patients were treated, and reported that cytogenetic alterations associated with a good prognosis, such as hypodiploidy (50 versus 30%) and t(12:21) (13 versus 24%) were significantly less common in Hispanic patients. Worse outcomes in ALL have been reported in children and adults living in Latin American countries compared with international standards [2,3]. However, underlying cause of these observations remains unknown. However, several hypotheses have been postulated, including disparities in socioeconomic status, delayed diagnosis, environmental risks, differences in population biology, inherited genetic background, abandonment of therapy, higher toxic death rates, and lower access to quality supportive care [7]. Information regarding novel diagnostic approaches is limited in Latin America, but despite some disadvantages, economic, creative approaches and treatment modifications have been introduced in Latin American countries to improve the quality of life and survival rates of ALL patients [12]. This review is aimed to discuss the status and challenges associated with ALL management in Latin America.

Challenges in diagnosis
The diagnostic capabilities available in Latin American countries are diverse, and more sophisticated tests based on cytogenetics or molecular biology vary considerably and depend on the economic resources. Many patients in Latin America and other LMIC do not have healthcare insurance, and in many instances, diagnostic procedures and treatments may require out-of-pocket expenditure. For instance, the tools available in Brazil for diagnosing acute leukemia include cytological examination of the bone marrow (BM), peripheral blood (PB), and immunophenotyping [13]. Currently, measuring residual disease (MRD) is the most important independent prognostic factor in patients with ALL and allows us to adapt the intensity of chemotherapy or adjust the consolidation strategies. Standardized methods for studying MRD require specialized equipment and personnel that are not always accessible in Latin American centers [14]. Assays based on polymerase chain reaction (PCR), or flow cytometry can detect one ALL cell among 10,000-100,000 normal cells in clinical samples. Determining clinically relevant residual disease through flow cytometry is more accessible and affordable than PCR in Latin American centers. Despite all the evidence supporting the usefulness of this technique in the treatment of patients with leukemia, these tools are not available, are not standardized, or are not performed optimally in many Latin American centers. Therefore, the assays do not reach the expected sensitivity and can lose their value. Many centers must outsource the MRD detection to outside laboratories, leading to a delay in its clinical application.
Risk stratification through cytogenetics and response to therapy are the major determinants of prognosis. Thus, appropriate risk stratification is a mainstay of ALL treatment and allows the optimal intensity for each patient while minimizing side effects and risks [15]. Risk classification makes it possible to achieve the best DFS rates by decreasing the intensity in low-risk patients, allowing the use of less toxic regimens, and the increasing intensity in highrisk patients. In the ideal setting, conventional cytogenetics with high-resolution G-banding is the gold standard, and molecular genetics (qPCR or FISH) is used to investigate prognostically important fusion genes (ETV6-RUNX1, TCF3-PBX1, BCR-ABL1) [13]. In contrast, Philadelphia-like ALL (Ph-like), intra-chromosomal amplification of chromosome 21 (iAMP21), and IKAROS deletions are not routinely performed in an increasing number of adult centers. It has been noted that the prevalence of Ph-like ALL in the Latin American population is higher than in others [16]. A 53% prevalence of Ph-like ALL has been reported in children in Mexico City [10], in contrast to Colombia, which has a prevalence of 12.4% [17,18]. However, in many Latin American centers, it is not possible to routinely search for Ph-like ALL rearrangements; and the detection of CRLF3 protein overexpression by flow cytometry is an affordable strategy that can be implemented routinely as it can detect approximately 50% of cases [19]. Undoubtedly, cytogenetic and molecular assessments can improve treatment decisions. However, when patients pay for out-of-pocket treatment the cost of performing genetic assays is prohibitive; therefore, access to chemotherapy should be prioritized. In addition, although genetic abnormalities are independent predictors of survival, a considerable proportion of patients with high-risk features and negative MRD can achieve good OS and DFS regardless of their high-risk features [20]. Therefore, affordable and adaptable genetic risk assessment methods are required.

Treatment of ALL in Latin America
Most treatment protocols for ALL have been developed in Europe and the United States and vary across regions. Similarly, in Latin America, a broad diversity of protocols is employed across regions, making it difficult to obtain comparative data [21,22]. The delivery of therapy in LMIC can be challenged by several barriers, including a lack of diagnostic testing capacity, reduced chemotherapy and immunotherapy access, hospital bed availability, quality of supportive care, education, treatment abandonment, and financial toxicity. Additionally, some Latin American countries have described the lack of availability of pediatric hematologists/oncologists with a lower number of multidisciplinary teams and high-volume reference centers in contrast to HIC [23].
In a different arena, the optimal ALL chemotherapy used for HIC is not necessarily the best in Latin America. In 2017 Howard et al. [24] discussed the need to adapt treatment protocols because there is a lack of optimal support therapy in most Latin American countries. This study describes the real-world application results of the Total XI in in Latin American countries, which achieved a 72% EFS in the United States, 32% in Recife, Brazil, and 10% in El Salvador. In addition, they found that the main obstacles in to the adaptation of protocols were the lack of registration and patient follow-up, casework overload of the treating physicians, and lack of education and interest in research [24]. Similarly, Silva et al. [16] studied an adapted GMALL protocol (07/2003) in a public hospital in Brazil. Unfortunately, despite a good complete remission rate (76%), most patients eventually die of sepsis, particularly during induction and salvage procedures.
Methotrexate (MTX) is one of the most important drugs used for ALL management. However, in LMIC, it is difficult to safely administer high-dose methotrexate (HD MTX) because of the required use of intravenous hydration, urine alkalinization, and folinic acid typically performed in an in-patient setting, with close MTX level monitoring that is generally not available, and it has not been implemented in most LMIC settings [25]. Outpatient infusions of MTX have been successfully established in Brazil and Argentina for other indications and can be implemented [26].
In Latin America, there are many limitations to providing adequate supportive care for highly myelosuppressive regimens such as hyper-CVAD. Pediatricinspired regimens seem to be alternatives with more manageable complications in the context of limited resources and can be administered in an outpatient setting. In this regard, Almanza-Huante et al. [12] recently compared two pediatric-inspired regimens to Hyper-CVAD in Hispanic adolescents and young adults with ALL in Mexico City and found higher complete response rates, lower relapse rates, and OS with pediatric-inspired regimens than with hyper-CVAD. In addition, higher induction-related mortality occurred in the hyper-CVAD group, probably due to higher hematologic toxicity resulting in infectious complications. In Brazil, the hyper-CVAD regimen in adult patients showed a CR >90%, 5-year OS curves of 35%, and Mexico reported CR rates between 60% and 80%. However, it seems that hyper-CVAD is not the best option in low-income countries, and as mentioned above, its hematological toxicity in patients with a lack of supporting settings has a higher risk of complications such as infections, thus increasing their mortality. Owing to the lack of necessary treatments, delay in the administration of drugs, and abandonment of treatment, among other factors [12].
Jaime-Perez et al. [27] demonstrated a CR of 71.3% and a 5-year OS of 31.1% with the BFM regimen compared to 90% in developed countries in China or the United States [28].

Relapsed/refractory ALL
Refractory/relapsed (R/R) ALL represents a challenge for low and middle-income countries (LMICs) where access to new drugs is limited. Effective novel therapies considered standard in RR ALL such as the bispecific anti-CD19 antibody blinatumomab or anti-CD22 antibody inotuzumab are inaccessible to most of our population [29,30]. Therapies using chimeric antigenic receptor T-cells (CAR-T) have shown excellent results in patients with refractory/relapsed ALL [31]. Despite the wide use of this cell therapy in the United States, Europe, and China, its development is limited to developing countries in Southeast Asia, Africa, and Latin America [31,32]. In addition, the current cost of these therapies with CAR-T makes it unaffordable for most of the people living in LMIC; strategies such as point of care automated manufacturing and independent development of vectors, socalled 'academic' CAR-T may be the alternative that makes this therapy accessible to Latin America [31]. Direct comparison of protocols in Latin America is difficult because of differences in resources, risk stratification criteria, availability of treatments, and competing causes of treatment failure [33].

Challenges in the management of resource constraints setting
In high-income countries, the leading cause of failure to treat ALL is relapse, whereas for LMIC, treatment toxicity is the key reason for poor survival [25]. Compared with treatment results in HIC, Latin American countries have higher early mortality and lower overall survival rates. Some of the causes include structural limitations of public services (use of shared rooms in hospitals and lack of high-efficiency filters), poor nutritional status, low socioeconomic status, and high treatment abandonment rates [22,24,[34][35][36] as reported in Latin American countries and other LMIC.
Poor nutritional status has been associated with 3.5 times more likely of death during maintenance chemotherapy in Latin American centers [37]. In addition, undernutrition patients are predisposed to relapse compared to well-nourished patients [38].
Mortality associated with infectious complications during the treatment of ALL is a major problem in Latin America and LMIC, which remain the leading cause of death in ALL patients with acute lymphoblastic leukemia and neutropenia. Torres et al. [39] reported a 27% treatment-related mortality rate due to infectious complications at the National Cancer Institute in Mexico, whereas Silva et al. [16] reported an early mortality rate of 17% in Brazil.
Historically, a group of pediatric patients have been cured with very simple chemotherapy regimens [30][31][32][33][34][35]. Currently, one of the strategies that we must use in Latin America is adaptation to international protocols according to the available support therapy and the appropriate risk classification that allows for reducing the intensity of chemotherapy in a group of patients. In a study by Pedrosa et al. [33], 101 patients with B-ALL selected by a combination of presenting features and degree of early response were successfully treated with a mild myelosuppressive chemotherapy regimen with 5-year EFS and OS rates of 92% and 96%, respectively. This suggests that in limitedresource countries, attempts to increase the treatment intensity for children with ALL have not translated into improved outcomes. This is a good example to reproduce in other centers in Latin America [40].

Overcoming the barriers
Treatment toxicity exponentially increases treatment costs [41,42]. To overcome this problem, outpatient regimens have been introduced in many LA centers [43,44]. The outpatient approach is advantageous when there is a lack of beds and allows a reduction in exposure to drug-resistant microbes, can avoid the use of central venous catheters and associated complications, and reduces time toxicity and costs, which are especially important when patients pay out-of-pocket therapy [43][44][45][46].
Various strategies have been implemented to reduce this abandonment. For instance, Antillon et al. [47] reduced abandonment from 23.4% to 2.7% through strong intervention by psychosocial services, they were able to classify the living conditions of patients at the time of diagnosis and provide support, including a family food basket, money for travel, housing for parents, a program for parents' education to improve their understanding of the disease, special care needs, and the administration of oral chemotherapy in Guatemala.
Another strategy is to establish programs in which patients travel outside the country to receive chemotherapy. Belize, in collaboration with the ÓHorán General Hospital in Mérida, México, improved the 5year survival rate from 38 to 77% after the implementation of this twinning program [23].
There is global concern regarding the gap between ALL survival in children from Latin America and developed countries. Therefore, collaborative efforts have been made to establish early diagnoses, timely treatments, reduce treatment abandonment, and optimal management of complications to reduce mortality associated with toxicity, which will help to improve the survival and quality of life of children and adolescents with cancer in Latin America [48]. Successful examples of regional and transnational Latino initiatives are Asociación de HematoOncología Pediátrica de Centro América (AHOPCA) which includes Nicaragua, El Salvador, Guatemala, Honduras, Costa Rica, Panama, Dominican Republic, and Haiti and have proven to be a model of sustainable development to improve the survival of children with cancer in Central America through the implementation of common treatment guidelines for different cancers; the Consorcio Latinoamericano de Enfermedades Hemato-oncológicas Pediátricas (CLEHOP), which currently comprises 12 of the largest pediatric oncology centers in six countries (Argentina, Brazil, Ecuador, Guatemala, Mexico, and Peru) is a network of pediatric oncology centers in Latin America. In addition, the Pan-American Health Organization (PAHO) has developed collaborative strategies and highlights support from high-income countries such as St Jude Children's Research Hospital with training opportunities, projects for the timely application of antibiotic therapy, and support with cytogenetic and molecular analyses [49].

Conclusions
Information regarding ALL in Latin America is scarce; however, many efforts have been made to overcome these barriers. Nevertheless, major obstacles to successful treatment in Latin America and LMIC remain poor adherence, abandonment of treatment, lack of supportive therapy, and new therapeutic agents [2,[25][26][27][28]35].
Further improvements in survival should be pursued by developing more Latin American registries, forming cooperative groups, developing educational models to facilitate earlier diagnosis and prevention of complications, better support for therapy and management of infections, and adapting treatment strategies.

Geolocation information section
Latin America.

Disclosure statement
No potential conflict of interest was reported by the author (s).