Effectiveness of High-Dose MTX Therapy for Adult Ph-Negative ALL By Randomized Trial: JALSG ALL202-O

The effectiveness of high-dose (HD) methotrexate (MTX) therapy was confirmed in pediatric acute lymphoblastic leukemia (ALL) by randomized control studies. Recently, as protocols for pediatric ALL are used for young adult ALL, HD-MTX therapy is used for adult ALL in some protocols; however, its effectiveness for adult ALL has not been confirmed in a rigorous manner. Here, Japan Adult Leukemia Study Group (JALSG) conducted a randomized phase III trial of HD-MTX therapy compared with intermediate-dose (ID) MTX therapy. Philadelphia chromosome (Ph)-negative ALL patients aged 25 to 64 were enrolled. Patients achieved complete remission (CR) and kept it at the beginning of 3^rd course of therapy were randomly assigned to the therapy containing HD-MTX (3 g/m², day1 and 15) or ID-MTX (0.5 g/m², day1 and 15). The same therapy was repeated on the 5^th course. The primary objective of this study was to assess disease-free survival (DFS) rate and the secondary aims were to assess toxicity, the complete remission (CR) rate, and overall survival (OS) rate. The protocol was approved by the Institutional Review Board of each hospital. Written informed consent was obtained from all patients. Patients of 344 were enrolled and 294 of them achieved CR. Two of them were unevaluable. CR rate was 86%. The estimated 5-year DFS rate was 42% (95% CI 34-49%, Figure 1A), and the estimated probability of the OS rate at 5 years was 52% (95% CI 46-57%). The median follow-up times were 7.8 years and 7.4 years, respectively. Patients of 126 and 123 were assigned to HD-MTX group and ID-MTX group, respectively and received those therapies. The estimated 5-year DFS of HD-MTX group was 56% and significantly better than that of ID-MTX group, 32% (p=0.0149, Figure 1B). These results established the contribution of HD-MTX therapy for better survival of adult ALL.