Improved survival with intermediate-intensity pediatric-inspired regimen and allo-HSCT in adults with ALL in a resource-limited setting

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is associated with inferior overall survival (OS) and progression-free survival (PFS) in adults due to biological factors and lower tolerance to chemotherapy. Many pediatric-inspired protocols have been used worldwide; however, there is no standard of care. Therefore, protocol selection is often based on physician and center experience. In resource-limited countries, healthcare disparities and limited access to new therapies and diagnostics may impair the performance of internationally reported protocols, ultimately leading to inferior outcomes and higher mortality. Moreover, patients in these settings might face diagnostic delays and higher rates of severe infections with high-intensity protocols. To address this issue, our study aimed to compare the outcomes of two historical cohorts of adult ALL patients grouped according to time period and protocol intensity, with or without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Material and Methods: A retrospective Brazilian single-center study reviewed medical records and the institutional database (UNIFESP) of all adult patients diagnosed with ALL between 2013 and 2025. The following variables were recorded: time from symptom onset to diagnosis, age, WBC/CBC, cytogenetic/molecular classification, uric acid, fibrinogen, MRD, treatment protocol, allo-HSCT, relapse, death and follow-up time. Patients were grouped according to treatment intensity: high intensity (HI), including GRAALL and HyperCVAD versus intermediate intensity (II), adapted St. Jude TOTAL XVI and COG-ALL0434, standardized in our center since 2021. The statistical survival analysis was performed using Cox proportional hazards model, Kaplan-Meier survival curves and log-rank test. Associations between investigational categorical variables were explored through chi-squared or Fisher's exact test (univariate) and multivariate logistic regression. For numerical variables, Wilcoxon rank-sum test and Student's t-test were used, according to the distribution of each variable. Results: A total of 71 patients were included; 47.9% were male, and the mean age at diagnosis was 42.9 years (range 18-75) with 78.0% (56) B-ALL (including 18 Ph+ cases); 13.7% (9) T-ALL and 8.3% (6) biphenotypic leukemia. Median WBC was 22.5x109/L (range 0.7-478.6); 22.5% presented central nervous system involvement and 17.0% had abnormal cytogenetics. Regarding treatment, 34 patients received HI protocols and 37 II protocols. Regarding the response, 84.8% vs 84.3% (HI vs II) achieved complete remission (CR). MRD-negative status after consolidation was achieved in 76.9% vs 68.8% (HI vs II p=0.697); 4-month mortality rate was lower in II group than HI: 21.1% vs 30.3% (p=0.421); 45.5% and 50.0% underwent allo-HSCT in first CR in HI and II groups, respectively. After a median follow-up of 3.5 years, the 3-year estimated PFS was superior in II group 54.1% (95%CI 34.1-70.4%) vs HI group 33.3% (95%CI 18.2-49.2%), log-rank test, p=0.005. Treatment-related mortality and relapse mortality were: 28.9% and 17.0% in the II group versus 39.4% and 27.3% in the HI group. Overall, univariate analysis revealed several risk factors associated with worse PFS compared to those who remained alive and progression-free: age (47.7 vs 36.7 years, p=0.005), Comorbidity Index (median CCI 3 vs 2, p=0.01), fibrinogen (292 vs 429 mg/dL, p=0.018), and a trend toward higher uric acid (6.4 vs 5.3 mg/dL, p=0.083). Median time from symptom onset to diagnosis was 40 days (interquartile range 25th-75th: 25-71 days), this interval was not associated with PFS. However, a longer time was observed in Ph+ patients (63 vs 39 days p=0.069) and complex karyotype (84 vs 30 days p=0.035). In multivariate analysis, intermediate intensity treatment (OR 0.22, 95%CI 0.06-0.82, p=0.025) and allo-HSCT (OR 0.60, 95%CI 0.10-1.10, p=0.020) were associated with superior PFS. Conclusion: This single-center study demonstrates positive experience by incorporating intermediate intensity pediatric-inspired protocols, adapted St. Jude Total XVI and COG-ALL0434, in B-ALL and T-cell ALL, respectively, followed by allo-HSCT in most patients. This approach relies on lower cumulative doses of anthracyclines and cytarabine during induction and early consolidation, which could be more feasible in resource-limited settings. In this context, wider access to blinatumomab in consolidation may improve outcomes.