Robust assessment of early MRD levels could further improve treatment outcomes in low-risk patients of pediatric acute lymphoblastic leukemia: The Report of Taiwan Pediatric Oncology Group (TPOG)-ALL Study

Abstract Treatment modification, including but not limited to deintensifcation, for pediatric acute lymphoblastic leukemia (ALL) without compromising treatment outcomes remains a major issue for low-risk patients. Taiwan Pediatric Oncology Group (TPOG)-ALL-2002 study demonstrated that two courses of reinduction therapy provided no additional benefit compared to one course for standard-risk (SR) patients, whose criteria were similar to the low-risk groups defined in other cooperative studies. Based on these findings, the concept of reinduction deintensification in SR patients was subsequently incorporated into later TPOG-ALL protocols. The implementation of measurable residual disease (MRD) enables a precision medicine approach to further address the challenge of therapy modification. TPOG-ALL-2013 (TPOG-2013), the first nationwide MRD-directed protocol in Taiwan, enrolled 899 newly diagnosed ALL patients between January 2013 and December 2020. Final risk groups were determined based on MRD levels on day 15 of induction (MRD1) and at the end of induction (MRD2). In TPOG-2013, 662 (73.6%) patients with exact adherence (EA) to both MRD time points were assigned to the MRD EA group. Among them, 321 patients (48.5%) were classified as the SR group after induction therapy, including the genetic subtype of patients with hyperdiploidy (HD, >51 chromosomes)(29%), ETV6::RUNX1 (33%), or NCI-SR without HDand ETV6::RUNX1 (NCI-SR, 35%). As of August 2022, the median follow-up time for the 316 surviving patients was 7.1 years (IQR, 3.3-7.3 years). The 5-year event-free survival (EFS) and overall survival (OS) were 94.9+1.4% and 98.2+0.8%, respectively. In subgroup analysis, only patients with MRD1 levels of 0.1-1% had significantly inferior EFS (P =0.03) and OS (P =0.049) compared to those with MRD1 <0.1%. EFS and OS were not significantly affected by age at diagnosis, initial WBC counts, NCI risk group, genetic subtype, or MRD1 negativity. Further analysis by genetic subgroup showed that the significantly inferior EFS (P = 0.008) and OS (P = 0.009) associated with MRD1 of 0.1–1% were observed only in the ETV6::RUNX1 group, but not in HD or NCI-SR groups. No other factors significantly impacted EFS or OS within any genetic subgroup. Accordingly, in the newly launched TPOG-ALL-2021 (TPOG-2021) protocol, SR patients with MRD1 of 0.1–1% received an additional course of early intensification with cyclophosphamide and cytarabine after achieving remission with negative MRD2, which was not administered to patients with MRD1 <0.1%. During consolidation, they were given four courses of methotrexate at a dose of 5 g/m², instead of 2.5 g/m² for those with MRD1 <0.1%. Subsequent treatments were identical for both groups. Between January 2021 and August 2024, 166 patients had been enrolled and classified as final SR group in TPOG-2021, comprising HD (33.1%), ETV6::RUNX1 (39.2%) and NCI-SR (25.3%). As of April 2025, the 3-year EFS and OS were projected to be 97.8+1.6% and 100%, respectively. The median follow-up time was 2.4 years (IQR, 1.5-3.4 years). No statistically significant differences in EFS or OS were observed between patients with MRD1 <0.1% and 0.1–1%, either in the overall group or within any genetic subgroup. Similarly, EFS and OS were not significantly influenced by age, WBC count, NCI risk group, genetic subtype, or MRD1 negativity within the TPOG-2021 SR cohort. While longer follow-up is ongoing, robust assessment of MRD1 levels—conducted two weeks after induction—has demonstrated strong potential to guide treatment modification in the TPOG-ALL-2021 protocol and improve outcomes for low-risk pediatric ALL patients in Taiwan.