Acute lymphoblastic leukemia (ALL) is a heterogeneous neoplasm characterized by a proliferation of immature lymphoid cells. It is most common in childhood with a smaller second peak at around 50 years. The estimated overall incidence is 1.28–1.70 per 100,000 persons annually in the United States [1,2] and, although its incidence is unknown in Argentina, some studies have reported an increased frequency in South American countries [2–5].

Five-year overall survival (OS) rates consistently decrease with age. Considering chemotherapy-based treatment regimens, excluding the use of novel therapeutic agents, reported OS is approximately 93% for children, 74% for adolescents, 59% for young adults (20–39 years), 43% for middle-aged adults (40–59 years) and consistently below 30% for those older than 59 years [1]. Prognostic heterogeneity is determined by clinical characteristics, cytogenetic and molecular findings, and the response to treatment, including the measurable residual disease (MRD) status [6]. Different therapeutic protocols stratify patients into risk-adapted treatment arms of varying intensity, primarily based on the presence of high-risk features [6]. Despite advances in first-line therapies, one-third of standard-risk and up to two-thirds of high-risk patients relapse, which represents a major therapeutic challenge [6]. In general, patients classified as high-risk at diagnosis, those with positive MRD after first complete remission, and those who relapsed and achieved a second complete remission, are considered candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) [7,8].

Basic treatments appear to be generally guaranteed according to surveys among hematologists from Latin American Societies. However, considerable heterogeneity has been described regarding access to adequate diagnostic tools, high-cost therapies and allo-HSCT, mainly depending on whether patients have public or private health insurance [9].

Some reports have described particular aspects regarding clinical and prognostic characteristics, therapeutic approaches, and access or outcomes related to allo-HSCT in selected aged cohorts of ALL patients across Latin America [4,5,10–15]. Since previous studies in Argentina have focused on participants up to young adulthood [12,14], the aim of this study was to provide insights into demographic characteristics and outcomes of adolescent and adult patients with ALL in Argentina. The second purpose was to identify factors influencing the access to first-line HSCT.

Demographic and clinical characteristics as well as response rates and OS of adolescents and adults with ALL in Argentina were similar to those reported in other studies [4,5,13,16,17]. Public funding of the healthcare institution negatively influences OS with a worse outcome when patients were censored at the time of HSCT. Longer time to achieve a first-line HSCT for patients from public healthcare institutions, even when death or relapse were analyzed as competing events, may account for the worse outcome.

The observed median OS of 42 months with 54.9% at two years falls within the range reported by other Latin American groups: around 20 months for Brazilian groups [18] and 56 months for Mexico [19] with similar early death rates [5]. It was confirmed that high-risk, older age and CNS involvement were independently associated with a worse OS in accordance with reported data [16]. Moreover, public funding of the healthcare institution, as an indirect measure of the socioeconomic level, was also an adverse factor. The Argentine healthcare system is highly fragmented; individuals with higher or registered incomes have access to private insurance (either through prepaid financing systems or programs funded by labor contributions), whereas individuals with lower incomes or informal employment receive healthcare from the public sector, which is government-funded. There is vast literature around the world, including Latin America, reporting that socioeconomic level has an impact on the mortality rate [20,21].

Regarding access to appropriate risk stratification, one third of the patients lacked cytogenetic or molecular data, as previously reported in international series [22,23]. This unavailability was greater in resource-limited settings, as previously noticed for adult patients and for those with lower health security coverage [24]. On the other hand, there is broad access to MFC, which helped measure MRD status at different time points, thereby contributing to the individualization of patients with high-risk features.

BFM-like regimens were mostly adopted, and the rate of early death and complete remission (CR) were similar to those previously reported in Latin America [5]. Immunotherapies are increasingly incorporated into frontline treatment of patients with Philadelphia chromosome-positive ALL [25]. The access to Rituximab therapy was similar between public and private institutions, with no registered data on Blinatumomab or Inotuzumab. A national report, however, documented the use of these latter agents in 58 relapsed or refractory cases between 2017 and 2023, with only 3% treated in public institutions [26].

Induction regimens effectively achieve CR, but maintaining long-term remission and curing patients with ALL remains challenging. Eligible high-risk patients may proceed to first-line allo-HSCT with curative intent and to mitigate the risk of relapse. Although a second CR can be achieved in one third of patients, their prognosis is worse. In the present study, 15.1% of the overall cohort and 20.1% of patients deemed to be candidates for allo-HSCT underwent the procedure as a first-line therapy. HSCT rates vary in Latin America from 8% to 32% in different age selected cohorts [27,28]: Ferrari et al. [12] described a rate of 12% among adolescents and young adults in Argentina. Despite the fact that a survey confirms a sustained growth in transplant numbers and rates in the Latin American region between 2019 and 2022 [29], these transplant rates are lower across various diagnoses compared to Europe or the United States [30]. In particular, a Swedish study revealed a significantly higher transplantation rate of 49% among high-risk ALL patients under 60 years of age [31].

Among first-line HSCT recipients in the current cohort, the median time from ALL diagnosis to transplant was 8.4 months. Approximately 20% of the patients received the graft from an unrelated-donor, with a median time that was 10.3 months longer than the 162 days (5.4 months) for unrelated-donor HSCT reported in Canada, a high-income country [32]. This difference may reflect administrative delays and difficulty in finding suitable donors among individuals of South American descent [33]. Basquiera et al. reported a median time to transplant of 18 months for unrelated donor procedures across a cohort encompassing diverse hematological diseases, compared to eight months in the related HLA-matched group [15]. The findings of this study also indicate that being treated in a public healthcare center had a negative impact on the time to HSCT, which is consistent with previous studies from the United States and the United Kingdom [21,34]. Cumulative incidence function curves stratified by healthcare center funding source (Figure 2B) demonstrate a similar early pattern for the competing events of death and relapse, followed by a distinct later divergence in the probability of HSCT.

While the study provides valuable insights, several limitations must be acknowledged mostly in connection with its retrospective nature. Moreover, the limited number of participating centers may not fully capture the clinical landscape across Argentina. Nonetheless, these institutions, where the majority of patients were diagnosed and underwent transplantation, account for one third of all nationally accredited transplant centers.

This is the first multicenter study from Argentina to analyze demographic and clinical characteristics of adolescent and adult patients with Ph-negative ALL. Overall survival was influenced not only by classical prognostic factors but also by the treatment setting, with patients treated in public institutions having poorer outcomes. Healthcare disparities also influenced the access to first-line HSCT among high-risk patients. Expanding access to transplantation within the public healthcare system may help improve the outcomes and reduce inequities in the management of ALL in Argentina.

Conceptualization: MMC, JIR, LF, AGC, AD, NC, MMR, MM, CB. Investigation: MMC, JIR, LF, AGC, AD, NC, MMR, MM, CB. Methodology: MMC, JIR, LF, AGC, AD, NC, MMR, MM, CB. Project administration: MMC, JIR, LF, AGC, AD, NC, MMR, MM, CB. Data curation: MMC, JIR, LF, AGC, AD, LR, NC, MMR, EM, LA, CGV, JF, MEF, HDD, MMM, AN, IF, CV, MM, ALB, CB. Formal analysis: MMC, JIR, CB. Software: JIR, CGV, MMM. Resources: JIR, CGV, MMM. Funding acquisition: JIR, CGV, MMM. Writing – original draft: MMC, JIR, LF, AGC, LR, CB. Writing – review & editing: MMC, JIR, LF, AGC, AD, LR, NC, MMR, EM, LA, CGV, JF, MEF, HDD, MMM, AN, IF, CV, MM, ALB, CB. Supervision: MMC, JIR, LF, NC, CV, MM, ALB, CB. Validation: MMC, JIR, LF, NC, CV, MM, ALB, CB. Visualization: MMC, JIR, LF, NC, CV, MM, ALB, CB.

This study protocol was reviewed and approved by Comité de ética independiente del Hospital Alemán (CEIHA), Hospital Alemán, Buenos Aires, Argentina (CODE 1186, v5.0 [18-NOV-2020]). Informed consent was not obtained. Resolution 1480/2011 of the National Ministry of Health exempts retrospective cohort studies from the obligation to obtain informed consent. The confidentiality of each participant’s identity was adequately preserved according to local regulations (Administración Nacional de Medicamentos, Alimentos y Tecnología [ANMAT]).

Financial support for this study was provided by Pfizer. The funder had no role in the design, data collection, data analysis, and reporting of this study.

The data that support the findings of this study are available from the corresponding author upon reasonable request.