Effectiveness of High-Dose MTX Therapy for Adult Ph-Negative ALL By Randomized Trial: JALSG ALL202-O
Authors: Sakura Toru , Hayakawa Fumihiko , Sugiura Isamu , Imai Kiyotoshi , Usui Noriko , Fujisawa Shin , Murayama Tohru , Yujiri Toshiaki , Kiyoi Hitoshi , Ohnishi Kazunori , Miyazaki Yasushi , Ohtake Shigeki , Kobayashi Yukio , Matsuo Keitaro , Naoe Tomoki 
Published: October 2019

Abstract

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 3rd 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 5th 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.

Disclosures
Usui: Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo: Honoraria; Pfizer: Honoraria; Kyowahakko-KIrin: Research Funding; Nippon Shinyaku: Research Funding; Shionogi: Research Funding; Pfizer: Research Funding; Meiji Seika Pharma: Research Funding; Kyowahakko-KIrin: Honoraria. Kiyoi:Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Japan Blood Products Organization: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Teijin Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Eisai Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Research Funding. Kobayashi:Nippon Shinyaku: Honoraria; Pfizer: Research Funding. Naoe:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Astellas Pharma Inc.: Research Funding; Celgene K.K.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; FUJIFILM Corporation: Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding.