Long-Term Outcomes of Children with Acute Lymphoblastic Leukemia Treated under the TR-ALL-2000 Protocol: A 15-Year Single-Center Experience

Background: Before minimal residual disease (MRD) monitoring became standard practice, risk stratification in pediatric acute lymphoblastic leukemia (ALL) relied mainly on clinical and morphological features. Evaluating outcomes from this pre-MRD era is important for interpreting current risk-adapted therapies. This study examined long-term outcomes of children treated with the TR-ALL-2000 protocol, a large pre-MRD pediatric ALL cohort from Turkey. Methods: This single-center retrospective cohort included 296 patients aged 1–18 years diagnosed with ALL and treated uniformly with the TR-ALL-2000 protocol (2000–2014). Clinical characteristics, early response, toxicities, relapse patterns, and survival outcomes were obtained from institutional records. Early response was assessed morphologically on days 8, 15, and 33. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan–Meier analysis; prognostic factors were evaluated using univariable tests. Results: The mean age at diagnosis was 6.4 ± 4.1 years; 86.5% had B-cell ALL. Early response was favorable, with M1 marrow in 90.2% on day 15 and 96.9% on day 33. Eight-year EFS was 84.9% in standard-risk, 78.3% in intermediate-risk, and 50.0% in high-risk patients. Relapse occurred in 11.5% and was associated with splenomegaly (p = 0.03). Overall mortality was 22.6%, nearly half infection-related. High leukocyte count, elevated uric acid, day-15 M2/M3 marrow, and failure to achieve remission by day 33 predicted mortality. Conclusion: The TR-ALL-2000 protocol yielded good long-term outcomes in standard- and intermediate-risk pediatric ALL but inferior survival in high-risk patients. Relapse patterns, toxicity-related interruptions, and infection-related mortality highlight the need for MRD-based monitoring, molecular risk stratification, and stronger supportive care. Title: Long-Term Outcomes of Children with Acute Lymphoblastic Leukemia Treated under the TR-ALL-2000 Protocol: A 15-Year Single-Center Experience Authors and Affiliations 1. Kenan Degirmenci, MD Department of Pediatrics Sanliurfa Education and Research Hospital Sanliurfa, Turkey Email: [email protected] ORCID: 0009-0000-3847-8139 2. Fatih Isleyen, MD (Corresponding Author) Department of Neonatology Sanliurfa Education and Research Hospital Sanliurfa, Turkey Email: [email protected] ORCID: 0000-0002-5015-621X 3. Turkan Patiroglu, MD, Professor Division of Pediatric Hematology (Retired) Erciyes University Faculty of Medicine Kayseri, Turkey Email: [email protected] ORCID: 0000-0003-2471-764X Corresponding Author Fatih Isleyen, MD Department of Neonatology Sanliurfa Education and Research Hospital 63250 Sanliurfa, Turkey Email: [email protected] ORCID: 0000-0002-5015-621X Word Count Abstract: 248 words Main Text: 2,466 words Tables, Figures, and Supporting Information Tables: 5 Figures: 2 Supporting Information Files: 0 Running Title Long-Term Outcomes in TR-ALL-2000

acute lymphoblastic leukemia; TR-ALL-2000 protocol; long-term outcomes; event-free survival; relapse

Background: Before minimal residual disease (MRD) monitoring became standard practice, risk stratification in pediatric acute lymphoblastic leukemia (ALL) relied mainly on clinical and morphological features. Evaluating outcomes from this pre-MRD era is important for interpreting current risk-adapted therapies. This study examined long-term outcomes of children treated with the TR-ALL-2000 protocol, a large pre-MRD pediatric ALL cohort from Turkey.

This single-center retrospective cohort included 296 patients aged 1–18 years diagnosed with ALL and treated uniformly with the TR-ALL-2000 protocol (2000–2014). Clinical characteristics, early response, toxicities, relapse patterns, and survival outcomes were obtained from institutional records. Early response was assessed morphologically on days 8, 15, and 33. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan–Meier analysis; prognostic factors were evaluated using univariable tests.

The mean age at diagnosis was 6.4 ± 4.1 years; 86.5% had B-cell ALL. Early response was favorable, with M1 marrow in 90.2% on day 15 and 96.9% on day 33. Eight-year EFS was 84.9% in standard-risk, 78.3% in intermediate-risk, and 50.0% in high-risk patients. Relapse occurred in 11.5% and was associated with splenomegaly (p = 0.03). Overall mortality was 22.6%, nearly half infection-related. High leukocyte count, elevated uric acid, day-15 M2/M3 marrow, and failure to achieve remission by day 33 predicted mortality.

The TR-ALL-2000 protocol yielded good long-term outcomes in standard- and intermediate-risk pediatric ALL but inferior survival in high-risk patients. Relapse patterns, toxicity-related interruptions, and infection-related mortality highlight the need for MRD-based monitoring, molecular risk stratification, and stronger supportive care.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and with the implementation of modern risk-adapted treatment strategies, five-year survival rates now approach 85–90% [1,2]. This substantial improvement reflects the combined impact of integrating minimal residual disease (MRD) monitoring into therapeutic decision-making, employing highly sensitive methods to assess early treatment response, and advances in supportive care [3–6]. The establishment of MRD as a robust prognostic determinant has ushered in a therapeutic paradigm that extends well beyond classical morphology-based risk stratification, enabling treatment intensity to be more precisely tailored to underlying biological risk. The Berlin–Frankfurt–Münster (BFM) study group protocols—central to this transformation—have become the international standard in pediatric ALL therapy through their comprehensive risk-classification framework incorporating age, initial leukocyte count, immunophenotype, and dynamic measures of early response [3,4]. However, before MRD monitoring became routine clinical practice, reliance on morphology-based remission assessment limited the accuracy of relapse prediction and constrained efforts to optimize the balance between treatment efficacy and toxicity [5,6]. Consequently, the analysis of large, well-defined clinical cohorts from the pre-MRD era remains essential for contextualizing the historical performance of contemporary MRD-driven and molecularly risk-adapted protocols. In Turkey, pediatric ALL treatment became markedly standardized in the early 2000s with the nationwide adoption of the TR-ALL-2000 regimen, a modified version of the ALL-BFM-95 protocol. This regimen incorporates several distinctive elements—including high-dose methotrexate during consolidation, a unique risk-definition algorithm, and dose-adjusted intrathecal therapy. National reports from the same period demonstrated five-year event-free survival (EFS) rates typically ranging from 70% to 80%, while early mortality and treatment failure were predominantly driven by infections and therapy-related toxicities [7–10]. These findings align with international literature underscoring the decisive influence of supportive care capacity on outcomes in low- and middle-income settings [11,12]. Despite the protocol’s widespread use, comprehensive single-center analyses detailing long-term survival outcomes, treatment-related toxicities, and prognostic determinants for patients treated with the TR-ALL-2000 regimen remain limited. The insufficient characterization of real-world outcomes from the pre-MRD era complicates efforts to determine the incremental survival benefit conferred by modern MRD-guided strategies. Moreover, detailed examination of this historical period offers important opportunities to more accurately identify high-risk subgroups, clarify key areas for reducing infection- and toxicity-related mortality, and refine current risk-adapted treatment approaches. Accordingly, the objective of this study was to comprehensively evaluate the clinical characteristics, treatment response, toxicity profile, long-term survival outcomes, and prognostic factors associated with relapse and mortality in a large pediatric ALL cohort treated with the TR-ALL-2000 protocol. Our aim was to provide the most extensive dataset to date describing treatment performance in Turkey during the pre-MRD era, thereby addressing a major gap in the national literature and strengthening the historical framework upon which modern risk-adapted treatment strategies are built.

Study Design and Ethical Approval This study was designed as a retrospective, single-center historical cohort analysis of pediatric acute lymphoblastic leukemia (ALL) cases treated with the TR-ALL-2000 protocol between 1 January 2000 and 31 December 2014. Data were retrieved from the archival records of the Department of Pediatric Hematology–Oncology at Erciyes University Faculty of Medicine, and all patient identifiers were anonymized prior to analysis. The study was approved by the Ethics Committee of Erciyes University Faculty of Medicine (decision no: 2014/428) and conducted in accordance with the ethical principles of the Declaration of Helsinki. Patient Selection A total of 296 patients aged 1–18 years at diagnosis who completed all phases of the TR-ALL-2000 protocol were included. Exclusion criteria comprised ALL diagnoses not confirmed by bone marrow aspiration or biopsy, patients who died before the initiation of treatment, those with secondary malignancies, and individuals who received therapies that deviated from the TR-ALL-2000 protocol. Clinical and Laboratory Evaluation Clinical findings at diagnosis—including hepatosplenomegaly, lymphadenopathy, mediastinal mass, and central nervous system (CNS) involvement—were documented using standardized forms. Hematologic and biochemical parameters (hemoglobin concentration, leukocyte and platelet counts; LDH and uric acid levels; and liver and renal function tests) were also recorded. The diagnosis of ALL was established based on morphological, cytochemical, immunophenotypic, and, when available, cytogenetic assessments. Because MRD monitoring was not routinely implemented during the study period, early treatment response was evaluated exclusively according to morphological criteria. Risk Stratification and Early Treatment Response Risk stratification was performed in accordance with the TR-ALL-2000 protocol, incorporating age at diagnosis, initial leukocyte count, immunophenotype, CNS involvement, and early response indicators. Peripheral blast count on day 8 and bone marrow evaluations on days 15 and 33 were used to determine early treatment response. Treatment Protocol The TR-ALL-2000 protocol is a modified version of the ALL-BFM-95 regimen. All patients received the following treatment phases: Induction: vincristine, prednisolone, daunorubicin, and L-asparaginase. Consolidation: high-dose methotrexate administered as a 36-hour infusion at a dose of 1 g/m². Reinduction: a standardized regimen based on the BFM approach. Maintenance: daily oral 6-mercaptopurine and weekly methotrexate. All patients received intrathecal CNS prophylaxis. Cranial radiotherapy was reserved for high-risk patients and for those with CNS involvement at diagnosis or during treatment. Toxicity and Infection Assessment Febrile neutropenia, culture-proven bacterial or fungal infections, hepatotoxicity, nephrotoxicity, and hematologic toxicities leading to treatment delays were systematically extracted from patient records. Although toxicity grading could not fully adhere to the Common Terminology Criteria for Adverse Events (CTCAE) due to limitations inherent to the study period, classifications were based on the standardized documentation available in clinical charts. Definitions of Relapse and Mortality Relapse was classified according to ALL-BFM criteria. Relapses occurring within the first 36 months after diagnosis were defined as early relapse, whereas those occurring beyond 36 months were considered late relapse. The site of relapse was categorized as bone marrow, CNS, testicular, or combined. Causes of mortality were categorized as infection, treatment-related toxicity, or disease progression. Follow-up Duration All patients were followed for a minimum of 24 months from the date of diagnosis, with a mean follow-up duration of 78 months (range: 6–192 months). Patients who were lost to follow-up were censored at the date of last contact in survival analyses. Statistical Analysis Statistical analyses were performed using IBM SPSS Statistics version 26.0. The distribution of continuous variables was assessed using the Shapiro–Wilk test. Normally distributed variables were summarized as mean ± standard deviation, whereas non-normally distributed variables were presented as median (interquartile range). Between-group comparisons were conducted using Student’s t-test or the Mann–Whitney U test for continuous variables, and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Owing to the high rate of missing data inherent to the extended study period, multivariable analyses could not be performed; results were therefore based on univariable analyses. A p-value < 0.05 was considered statistically significant.

Patient Characteristics A total of 296 pediatric patients with ALL treated according to the TR-ALL-2000 protocol were included. Overall, 57.8% were male (male-to-female ratio, 1.36), and the mean age at diagnosis was 6.4 years (SD, 4.1); 70.9% were 1–9 years of age. The most frequent physical findings at presentation were hepatomegaly (62.0%), splenomegaly (50.2%), and lymphadenopathy (21.6%). A mediastinal mass was present in 3.7% of patients, and central nervous system (CNS) involvement was documented in 17 patients (5.7%). Tumor lysis syndrome was observed in 5.6% of cases (Table 1). Diagnostic Laboratory Parameters At diagnosis, anemia was present in 91.9% of patients, thrombocytopenia in 67.9%, and leukocytosis in 42.2%. Elevated LDH (66.9%) and uric acid (28.4%) levels were consistent with a high proliferative disease burden. Elevated liver enzymes were noted in 23.0% of patients for AST and 13.9% for ALT (Table 2). Morphology, Immunophenotype, and Early Treatment Response According to FAB morphology, 71.6% of cases were classified as L1, 26.3% as L2, and 2.1% as L3. Immunophenotyping showed a predominance of B-cell ALL (86.5%), whereas T-cell ALL accounted for 13.5% of cases. Early treatment response rates were high: eighth-day steroid response was 90.6%, day-15 M1 marrow status 90.2%, and day-33 M1 status 96.9%. Risk stratification according to the TR-ALL-2000 algorithm categorized 29.1% of patients as standard risk, 60.8% as intermediate risk, and 10.1% as high risk (Table 3). Treatment-Related Toxic Effects During induction, febrile neutropenia occurred in 13.3% of patients, transient hepatotoxicity in 39.8%, and tumor lysis syndrome in 4.0%; treatment interruption for any cause was documented in 10.1%. During consolidation, febrile neutropenia, hepatotoxicity, and documented bacterial infection were observed in 24.6%, 20.3%, and 16.9% of patients, respectively, and treatment delay occurred in 67.5%. In the maintenance phase, treatment interruption increased to 56.3%. Relapse occurred in 4.7% of patients during maintenance, with an additional 4.3% relapsing after completion of therapy (Table 4). Relapse Overall, 34 patients (11.5%) experienced relapse. Among these, 20.6% occurred during consolidation, 41.2% during maintenance therapy, and 38.2% after the end of treatment. The presence of splenomegaly at diagnosis was significantly associated with relapse (p = 0.03). In contrast, baseline leukocyte count, FAB subtype, hemoglobin level, and platelet count were not significantly associated with relapse (Table 5). Mortality The overall mortality rate was 22.6%. In univariable analyses, higher baseline leukocyte count (p = 0.001), elevated uric acid level (p = 0.02), M2/M3 marrow status on day 15 (p = 0.003), failure to achieve remission by day 33 (p < 0.001), and the occurrence of relapse (p = 0.001) were each significantly associated with mortality. These findings indicate that early morphologic response remained a key prognostic marker in this pre-MRD, TR-ALL-2000–based treatment setting. Survival Eight-year event-free survival (EFS) rates in the standard-, intermediate-, and high-risk groups were 84.9%, 78.3%, and 50.0%, respectively (Figure 1). Eight-year overall survival (OS) according to baseline leukocyte count was 84.1% for 100 × 10⁹/L (log-rank p = 0.001) (Figure 2). Survival was markedly lower in the high-risk group and among patients presenting with elevated leukocyte counts.

This study reports long-term outcomes for 296 pediatric ALL patients treated with the TR-ALL-2000 protocol between 2000 and 2014, representing one of the largest retrospective cohorts from Turkey’s pre-MRD era. The use of a uniform treatment protocol combined with extended follow-up provides a unique framework for contextualizing the historical performance of contemporary MRD-driven therapeutic strategies. The eight-year EFS rates of 84.9% in the standard-risk group and 78.3% in the intermediate-risk group align with previously published outcomes from Turkey using ALL-BFM–based protocols [7]. In the period before routine MRD monitoring, morphologic remission served as one of the most powerful prognostic markers, and our findings reaffirm this classical observation. In high-income settings, five-year EFS rates of 85–90% have been attributed to intensified chemotherapeutic strategies, refined risk stratification, and advanced supportive care [1,2,4]. Despite the absence of MRD-guided adaptation in our cohort, survival in standard- and intermediate-risk patients approached these benchmarks, suggesting that the TR-ALL-2000 regimen was effective for these subgroups. In contrast, the substantially lower eight-year EFS of 50% among high-risk patients mirrors outcomes reported from low- and middle-income countries, where challenges in supportive care and constraints on treatment intensity disproportionately affect high-risk ALL [11]. The relapse rate of 11.5% falls at the lower boundary of the 10–20% range described in the literature [13]. The distribution of relapse across consolidation, maintenance, and post-treatment phases resembles the long-term patterns reported by the ALL-BFM study group [4]. The significant association observed between splenomegaly and relapse may reflect increased disease burden or the presence of extramedullary reservoirs. Conversely, the lack of association between baseline leukocyte count and relapse suggests that, in the absence of MRD assessment, early morphologic response may have overshadowed conventional presenting features as the primary prognostic indicator. Consistent with findings from the ALL-REZ BFM 2002 study, frequent treatment interruptions in our cohort—particularly due to hepatotoxicity and febrile neutropenia—may have contributed to inferior outcomes in high-risk patients. The therapeutic landscape of pediatric ALL is increasingly shaped by MRD kinetics and molecularly defined risk groups. Aricò and Conter describe this shift as a transition from traditional chemotherapy toward more precise and targeted approaches [14]. Real-world evidence from Radu et al. further demonstrates the expanding incorporation of biologically informed risk adaptation into routine practice [15]. Collectively, our findings highlight the enduring prognostic value of early treatment response in the pre-MRD era and provide a critical historical baseline against which the incremental benefit of modern MRD-guided and genomically informed therapies can be assessed. The overall mortality rate in our cohort was 22.6%, with approximately half of the deaths attributed to infection. This finding reflects one of the most critical limitations in ALL management within low- and middle-income countries—insufficient supportive care capacity [10]. In high-income settings, early treatment-related mortality has declined to 2–4%, largely due to advances in infection prophylaxis, intensive care support, nutritional optimization, and toxicity management [1,4]. Reports from Turkey have consistently demonstrated higher mortality rates, which is in line with our findings [7]. The significantly lower OS among patients with elevated baseline leukocyte counts is consistent with the poor prognosis associated with biologically aggressive subtypes; in a global analysis, Ding et al. reported that aggressive variants disproportionately increase mortality, particularly among younger children [16]. Large-scale modern genomic studies have shown that the biological heterogeneity of pediatric ALL strongly influences treatment response and relapse risk [17]. The inability to perform genomic risk classification during the TR-ALL-2000 era limits detailed assessment of the biological risk distribution in our cohort. The impact of bacterial and fungal complications on survival during intensive chemotherapy has been clearly demonstrated by Yigit et al. in a pediatric ALL population [18]. Additionally, long-term physical and psychosocial consequences among ALL survivors—affecting children, siblings, and caregivers alike—have been well documented by Kızmazoğlu et al. and Faust et al. [19,20]. Considering the toxicity burden observed during the TR-ALL-2000 treatment era, these psychosocial effects are likely even more pronounced. Strengths of this study include its large sample size, extended follow-up duration, use of a uniform treatment protocol, and comprehensive evaluation of clinical determinants associated with relapse and mortality. Key limitations include the absence of MRD data, restricted availability of molecular and genetic markers, and the inherent constraints of a retrospective study design. Large-scale analyses from low- and middle-income countries have consistently highlighted that disparities in infrastructure and supportive care are major contributors to survival inequalities in childhood cancer; our findings align with this overarching conclusion. In summary, while the TR-ALL-2000 protocol yielded acceptable long-term survival outcomes for standard- and intermediate-risk pediatric ALL patients, high-risk patients exhibited a substantial survival disadvantage compared with outcomes reported for modern MRD-guided protocols. Patterns of relapse, treatment interruptions due to toxicity, and infection-related mortality collectively underscore the urgent clinical need for implementing MRD-based monitoring, molecular risk stratification, and personalized treatment strategies in Turkey. This study provides an important historical reference for understanding treatment outcomes in the pre-MRD era and offers a foundation for meaningful comparison with contemporary treatment approaches. Conflict of Interest Statement The authors declare no conflicts of interest. Funding The authors received no specific funding for this work. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Data are not publicly available due to institutional restrictions and patient confidentiality. Supplementary Material File (tables all.docx) - Download - 31.46 KB

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Authors Metrics & Citations Metrics Article Usage 261views 131downloads Citations Download citation Kenan Degirmenci, Turkan Patıroglu. Long-Term Outcomes of Children with Acute Lymphoblastic Leukemia Treated under the TR-ALL-2000 Protocol: A 15-Year Single-Center Experience. Authorea. 24 November 2025. DOI: https://doi.org/10.22541/au.176400735.50545973/v1 DOI: https://doi.org/10.22541/au.176400735.50545973/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.