Objective To evaluate the impact of high-dose methotrexate (HD-MTX) consolidation on survival outcomes and relapse risk in patients with B-cell acute lymphoblastic leukemia (B-ALL) undergoing autologous hematopoietic stem cell transplantation (auto-HSCT).

Methods This single-center retrospective study included 165 consecutive B-ALL patients in first complete remission (CR1) who underwent auto-HSCT between May 2012 and May 2024. Consolidation regimens were determined based on physician discretion: 64.2% of patients received HD-MTX intravenously (median dose: 2 g/m²; range: 1.5–4 g/m²), while the remainder received alternative non-MTX regimens. Clinical and survival data were obtained from institutional medical records and telephone follow-up, with outcomes censored as of December 2024.

Results Of the 165 patients analyzed, a majority were treated with HD-MTX consolidation. Notably, 83.1% of patients in the non-MTX group were treated after 2019, reflecting evolving clinical practice trends. Patients in the HD-MTX group presented with significantly lower baseline white blood cell counts (9.4 vs. 20.82 ×10⁹/L; p=0.045) and were more frequently conditioned with total body irradiation (TBI)-based regimens (75.5% vs. 45.8%; p<0.001). No significant differences were observed in pre-transplant disease risk stratification (p=0.117) or minimal residual disease (MRD) status after three chemotherapy cycles (p=0.142).

After a median follow-up of 4.37 years (range: 0.01–12.83), HD-MTX consolidation showed no survival advantage. Five-year overall survival (OS) was 65.6% (95% CI: 56.2–76.5) in the HD-MTX group versus 84.3% (95% CI: 73.6–96.6) in the non-MTX group (p=0.110). Five-year leukemia-free survival (LFS) rates were 61.3% (95% CI: 52.1–72.0) and 67.8% (95% CI: 54.6–84.3), respectively (p=0.441). The cumulative incidence of relapse (CIR) was also comparable between groups (34.7% vs. 27.4%; p=0.402). Subgroup analyses further confirmed the absence of survival benefit attributable to HD-MTX.

Multivariate analyses identified persistent MRD positivity following three cycles of chemotherapy as the strongest independent predictor of adverse outcomes, significantly increasing the risk of mortality (OS: HR=2.37, 95% CI: 1.19–4.74; p=0.015), treatment failure (LFS: HR=2.87, 95% CI: 1.57–5.26; p<0.001), and relapse (HR=4.08, 95% CI: 2.18–7.65; p<0.001). Philadelphia chromosome positivity (Ph+) was associated with a trend toward elevated relapse risk (HR=1.86, 95% CI: 1.00–3.48; p=0.051).

Five patients experienced isolated central nervous system (CNS) relapse post-transplant. Neither HD-MTX administration, the number of pre-HSCT lumbar punctures, nor the use of TBI-based conditioning was significantly associated with CNS relapse risk (p=0.763, p=0.465, and p=0.223, respectively). However, HD-MTX was associated with considerable non-hematologic toxicity, observed in 39.6% of recipients. The most frequent adverse events were renal impairment (16.0%), oral mucositis (13.2%), and hepatotoxicity (7.5%).

Conclusion HD-MTX consolidation prior to auto-HSCT in B-ALL does not improve survival or reduce relapse yet contributes significantly to treatment-related toxicity. Persistent MRD positivity remains the most robust predictor of poor outcomes, underscoring the need for MRD-guided post-remission strategies rather than uniform intensification with HD-MTX.

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2025
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