Two decades of risk directed therapy for childhood acute lymphoblastic leukemia in a resource limited setting: Lessons from a modified st. jude total XV protocol Free

Survival for pediatric acute lymphoblastic leukemia (ALL) now exceeds 80% in high-income countries (HICs) with risk-adapted therapy. However, outcomes in low- and middle-income countries (LMICs) remain suboptimal. In 2005, our center adopted a modified St. Jude Total Therapy XV regimen to address this disparity. We report the 20-year outcomes of this approach in an LMIC setting.

Methods Between June 2005 and November 2024, 993 children (aged 1–18 years) with newly diagnosed ALL were treated using a modified Total Therapy XV protocol. After 2014, therapy was de-escalated for low-risk patients and intensified for those with high-risk features—older age, adverse cytogenetics, or persistent minimal residual disease (MRD). Cranial irradiation was reserved for patients at highest risk of CNS relapse. Risk stratification incorporated St. Jude/NCI criteria, cytogenetics, and MRD assessments on day 15 and at end-of-induction. Among the cohort, 940 patients received chemotherapy alone, while 53 underwent allogeneic hematopoietic cell transplantation (HCT) in first remission. Subgroup analyses included infants (<1 year), ETV6/RUNX1-positive B-ALL, T-cell ALL, induction failure (defined as MRD ≥1% or persistent disease after 4–6 weeks), asparaginase discontinuation, and treatment-related mortality (TRM). Outcomes were analyzed using Kaplan–Meier methods and compared across risk groups, immunophenotypes, and MRD response.

Results The median age was 5.4 years. B-ALL accounted for 82% of cases, T-ALL for 18%. ETV6-RUNX1 was the most common cytogenetic subtype (14%). MRD-negative remission at end-of-induction was achieved in 95% of patients. Five-year event-free survival (EFS) and overall survival (OS) were 76% and 84%, respectively. Outcomes varied significantly by risk: low-risk patients had EFS 87% and OS 94%, compared to EFS 62% and OS 72% in high-risk patients (p<0.001); standard-risk patients (EFS 75%, OS 81%). ETV6/RUNX1-positive patients showed excellent outcomes (EFS 90%, OS 99%). EFS was slightly higher in B-ALL vs. T-ALL (76.5% vs. 72.5%, p=0.50). Infants had the poorest outcomes (5-year EFS 56%, OS 62%), followed by patients with induction failure (EFS 32%, OS 38%). Patients undergoing HCT (n=53) had lower 5-year EFS (68% vs. 76%, p=0.19) and OS (72% vs. 84%, p=0.054) than those receiving chemotherapy alone. Early asparaginase discontinuation significantly reduced EFS (67% vs. 77%, p=0.009) and OS (76% vs. 85%, p=0.001) in standard/high-risk groups. TRM declined from 3.2% before 2014 to 2.3% after protocol modifications.

Univariate analysis showed better EFS and OS among patients aged 1–9 years, with WBC <50×10⁹/L, female sex, low-risk disease, favorable cytogenetics, and MRD negativity at day 15 and end-of-induction (all p<0.05). Inferior survival was associated with CNS status 2, traumatic lumbar puncture with blasts, and post-2014 treatment (all p<0.05).

In multivariate analysis, EFS was independently worse with traumatic LP with blasts (HR 2.66; 95% CI: 1.66–4.25; p<0.001), unfavorable cytogenetics (HR 2.87; 95% CI: 1.40–5.89; p=0.004), and MRD ≥1% at end-of-induction (HR 3.65; 95% CI: 2.22–5.99; p<0.001). OS was adversely affected by traumatic LP with blasts (HR 1.89; 95% CI: 1.06–3.39; p=0.032), unfavorable cytogenetics (HR 6.23; 95% CI: 1.73–22.46; p=0.005), MRD ≥1% (HR 5.01; 95% CI: 2.85–8.79; p<0.001), and age <1 or ≥10 years (HR 0.39; 95% CI: 0.17–0.88; p=0.023).

Conclusion Implementing a modified Total XV protocol in a resource-limited setting yielded survival rates approaching those in HICs. MRD-guided stratification allowed for safe de-escalation in low-risk responders and appropriate intensification for high-risk cases. Strengthened supportive care reduced TRM. However, outcomes remain suboptimal in infants, patients with induction failure, and those discontinuing asparaginase. Further improvements require enhanced access to alternative asparaginase formulations, integration of novel immunotherapies, and prevention of infection-related mortality to continue closing the global survival gap.