Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer affecting the pediatric population, with a higher incidence between 0 and 4 years of age (1). In the United States, about 3,000 patients aged 1–19 years are diagnosed with this pathology yearly (2). First-line treatment for ALL consists of a combination regimen of chemotherapeutic agents, which usually includes the phases of remission induction, consolidation, intensification, and maintenance. Allogeneic hematopoietic stem cell transplantation is restricted to patients at very high risk of relapse, those with persistent minimal residual disease (MRD) throughout treatment, and cases of relapse (3).

In recent decades, amendments in chemotherapy treatment protocols and improved supportive care have made it possible to increase survival in children and adolescents with ALL. Progress in the etiopathological understanding of the disease has also been aiding in the progression of outcomes, as it enables better risk stratification and the development of targeted therapies (3–5). Survival rates for children aged 0–14 years before 1990 were around 73%, and after 2010, there was a substantial increase reaching up to 93% (6). However, these outcome improvements occur primarily in developed countries (7). In developing countries, survival rates are usually lower, even though chemotherapy treatment protocols are similar (8). It is plausible that this inferiority in outcomes results from the shortage of high-cost diagnostic and prognostic tests, with the consequent difficulty of proper and individualized diagnosis and correct risk stratification (9). It is also likely that inadequate hospital support infrastructure and demanding access to specialized treatment centers may contribute to unfavorable outcomes (8). Many clinical characteristics may modulate the outcome of patients with ALL. Based on the immunophenotype, patients with T-cell ALL have worse outcomes than patients with B-cell ALL. T-cell ALL is also more frequent among male patients; some genetic markers are related, although the precise mechanism is not fully understood. In addition, adolescents (10–19 years old) present more treatment-related morbidities (10).

Cancer epidemiology and survival rates data are poorly reported in developing countries (11). According to data from the Instituto Nacional de Câncer (INCA), the estimated risk of childhood cancer (aged 0–19 years) for 2023–2025 in Brazil is 135 per million. Regarding the distribution by sex, the risk is estimated at 140 per million for males and 129 per million for females. A similar value is estimated for the world population (155.8 per million) (12). The incidence, prevalence, mortality, and survival rates are essential health system quality indicators and are able to elucidate possible barriers related to unfavorable outcomes, as well as potential solutions for improving healthcare (13).

Considering the lack of data in the literature regarding pediatric ALL in Brazil, its low survival rates compared to developed countries, and its clinical relevance, it is necessary to investigate the pediatric population affected by ALL and identify the factors associated with unfavorable outcomes. Thus, the objective of this study was to analyze the treatment outcomes of ALL in children and adolescents as well as the clinical-epidemiological profile in an onco-hematology treatment center.

The therapeutic protocols for ALL have evolved over the last years with diagnostic techniques in molecular biology and cytogenetics, which allowed better risk stratification and, consequently, a substantial increase in the OS and EFS of patients. In Brazil, few single-center, retrospective cohort-type studies present literature data about pediatric ALL survival (11, 15–21). The OS rates obtained by such studies vary from 29 to 76.5%, consistently lower than those observed in developed countries, as previously shown in studies developed in the Netherlands with OS of 91% (22), in the United Kingdom with OS of 89% (23), and in the United States with OS of 94% (24). The survival results obtained in our study, which pioneered the analysis of pediatric patients with ALL in southern Bahia, Brazil, are in agreement with those obtained in previous national studies, as well as with results from other developing countries (25–29). The global disparity regarding survival in pediatric ALL is evident, even though chemotherapy regimens are very similar (8, 9) between developed and emerging countries.

Proper identification of LR patients may improve OS during pediatric ALL treatment in developing countries, which typically account for more than 50% of cases. These patients may receive lower-intensity chemotherapy treatment, increase the odds of cure, and would be less exposed to treatment-related adverse effects (9). Among the Brazilian studies, the exception is the Rella05 study protocol, conducted in Recife, Brazil, which proposed systematically performing the MRD research by flow cytometry at the end of remission induction. With this prognostic tool, it was possible to properly allocate many patients to the LR group when the MRD research was negative. Thus, these patients received less intense chemotherapy treatment, reducing adverse effects and treatment-related fatal complications. Therefore, an OS of 96% was achieved in this group (30), matching the results expected for developed countries.

Relapse is thought to be related to decreased survival. Thus, many patients who relapsed end up dying due to the toxicity of the restart of chemotherapy as well as the toxicities related to Allogeneic Hematopoietic Stem Cell Transplantation (31). The findings of our study support these data since 24 deaths occurred among the 30 relapses. Therefore, when there is not enough clinical-laboratory evidence for patient allocation to HR or LR group, allocation as HR is often used to reduce the chance of relapse upon receiving more intense treatment (9). However, the higher intensity of chemotherapy treatment can, in turn, add more severe adverse effects, which can be fatal, especially in developing countries that generally have inadequate hospital infrastructure to address such events (30).

This study allocated 66 (60.5%) patients to the HR group. Of these, 40 did not have access to cytogenetic and molecular studies at diagnosis and the possibility of evaluating MRD at the end of induction to determine rapid response to treatment, characterizing insufficient data for proper risk stratification. Six patients were allocated to the HR group due to the use of corticoids prior to diagnosis before entering the treatment center. The use of corticosteroids before treatment can cause rapid destruction of lymphoblasts (32) and, consequently, a decrease in leukocyte counts, thus interfering with the prognostic value of the latter at diagnosis.

Our study evidenced a predominance of males in the HR group with statistical relevance, in contrast to two recent national studies (18, 30). However, no statistically significant difference between OS and EFS between the sexes was evidenced in this study. In our cohort, diagnosis >30 days was associated with risk stratification. The same period was observed in a different study, which reported 30 days from the onset of the symptoms to the first hospital visit (33). In terms of the frequency of the deaths, no statistically significant association was found. Nevertheless, a recent study suggests that patients whose treatment begins within 30 days had a statistically improved survival rate (33).

Furthermore, among the 34 patients with unfavorable outcomes (relapse and/or death), 32 did not have MRD testing at the end of remission induction, and 25 did not have any chromosomal alteration testing (G-banding karyotype, FISH, or molecular biology methods). These tests are not available at the study treatment center and require costly and complex logistics of air shipment of biological material for analysis at the specialized laboratory of the Instituto Nacional de Câncer, in Rio de Janeiro state, Brazil. This center is a contracted center for GBTLI diagnostics. In Brazil, few centers perform these exams, so the material aspirated from the BM at diagnosis must be sent for analysis (34). Moreover, even in these reference laboratories, sometimes there is a lack of materials to perform these exams (35, 36).

The unavailability of prognostic tests mentioned above, as is the case of research on MRD, cytogenetics, and molecular analysis, hindered the proper risk stratification, which may have led more patients to the allocation to the HR group, with the consequent toxicities associated with higher intensity of treatment. The unavailability of these tests may also have been a critical factor for the possible inadequate allocation of patients in the LR group, since a high relapse rate was verified in this group, and, therefore, no statistical difference in OS and EFS was seen between the HR and LR groups.

Elevated leukocyte counts are a well-established negative prognostic factor (3). In this study, leukocyte counts greater than 50,000/mm³ (but less than 100,000/mm³) were not associated with worse outcomes. On the other hand, leukocyte counts equal to or higher than 100,000/mm³ were associated with worse overall survival (p = 0.03), as observed in another national study (18).

In this study, the logistic regression model suggests that clinical characteristics (leukocyte counts, gender, risk stratification, immunophenotyping, and minimal residual disease) are dependently associated with the clinical outcome of patients (alive or dead), and leukocyte counts were independently associated with the outcome, corroborating data in the literature (37–39).

Another factor to be considered is the need for better support in treatment backup hospitals. Chemotherapy's complications and adverse effects can lead to fatal outcomes when not adequately addressed. In developing countries, due to financial shortages, some of the support hospitals do not have the adequate infrastructure (40). In specialized centers, oncological and supportive diagnosis and treatment can increase survival chances (41).

Febrile neutropenia, found with great frequency in this study, also requires treatment by trained personnel in the backup hospital. This event is an emergency that can lead to death when not treated with intravenous broad-spectrum antibiotics. Like other types of infection, febrile neutropenia occurs more frequently in the HR patients group (as we found herein), due to the greater intensity of chemotherapy treatment with consequent bone marrow toxicity (42, 43). Infections were also the most significant cause of death (46.4%) in this study, corroborating findings from previous studies (31, 43).

In places with few onco-hematology treatment centers, such as developing countries, the distance between the patient's home and the treatment center may hinder treatment success. Some studies suggest that excessive distance can lead to reduced attendance at consultations, the difficulty of access in the face of intercurrence related to the disease or treatment, and even the abandonment of treatment by the difficulty of locomotion (44, 45). The treatment center of our study is a reference for pediatric onco-hematology treatment in the region and has pacts with several surrounding municipalities. For those living farther away, a vacancy is available at the support house belonging to the center, maintained by the philanthropic institution Grupo de Apoio à Criança com Câncer (GACC). This availability has made it possible for many to continue the treatment in the early stages of the protocol when visits to the treatment center are more frequent. Thus, it was possible to reduce patients' lack of adherence and therapy abandonment from distant cities.

Prospective studies, combined with data already obtained in national studies, may elucidate the reality of pediatric ALL in Brazil, enabling public policies directed towards more promising results. In this sense, a study with the new GBTLI protocol (GBTLI-21) proposed by the Sociedade Brasileira de Oncologia Pediátrica (SOBOPE) is underway. With financial support from the Confederação Nacional de Instituições de Suporte e Assistência às Crainças e Adolescentes com Câncer (Coniac) and with an international partnership with St Jude Children's Research Hospital and the Keira Grace Foundation, there will be prospective data collection from pediatric ALL patients who join this protocol. This prospective research has the perspective of tracing a more reliable profile of children and adolescents with ALL in Brazil and may point to directions for results more comparable to those of developed countries (46).

Our single-center experience found that 5-year OS was 71.5%, and the estimated EFS was 65%. Statistical analysis revealed no significant difference in OS or EFS between the HR and LR groups; infectious conditions were the primary cause of death. In our cohort, the rates of OS and EFS are comparable to those reported in a few prior similar studies in Brazil though lower than those conducted in developed countries. The absence of prognostic tests may have interfered with risk stratification, which may have impacted the seen outcomes.