Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia Improved Long Term Relapse-Free Survival: 7-Year Results from a Randomized Controlled Trial, JALSG-APL204
Authors: Takeshita Akihiro , Asou Norio , Yanada Masamitsu , Sakura Toru , Ueda Yasunori , Sawa Masashi , Dobashi Nobuaki , Onizuka Makoto , Taniguchi Yasuhiro , Nakagawa Masaru , Tamaki Shigehisa , Hagihara Maki , Fujimaki Katsumichi , Furumaki Hiroaki , Fujita Hiroyuki , Usui Noriko , Kobayashi Yukio , Kiyoi Hitoshi , Ohtake Shigeki , Atsuta Yoshiko , Matsumura Itaru , Naoe Tomoki , Miyazaki Yasushi 
Published: April 2021

Abstract
Background: Tamibarotene, a new synthetic retinoid, displays (i) approximately 10-fold increased potency over ATRA at inducing in vitro differentiation of NB-4 cells (ii) enhanced chemical stability compared with ATRA (iii) low affinity for cellular RA-binding protein. The clinical efficacy of tamibarotene for the treatment of acute promyelocytic leukemia (APL) has also been reported. A prospective randomized controlled study to evaluate tamibarotene by comparison to ATRA was carried out for maintenance therapy of APL in JALSG APL204 (Shinagawa et al, 2014). The 4-year-relapse free survival (RFS) did not differ between patients treated with ATRA or tamibarotene. However, an improved efficacy of tamibarotene in high-risk patients was suggested, which warrants further investigation. Here, we evaluate the long-term outcome of the study.
Patients and Methods: Patients enrolled in this study were newly diagnosed with APL and documented cytogenetic and/or molecular evidence of t(15;17)/ PML-RARA . The age of the patients ranged between 15 and 70 years and the ECOG performance status was between 0 and 3. For remission induction therapy, ATRA was administered to all patients at a daily dose of 45 mg/m2 until complete remission (CR). The chemotherapy protocol varied depending on the initial leukocyte count and blast count in the peripheral blood. In brief, patient groups were defined as: leukocytes &lt; 3,000/µl (Group A: ATRA alone), 3,000/µl ≤ leukocytes &lt; 10,000/µl (Group B: ATRA plus IDA/Ara-C: 2+5), and leukocytes ≥ 10,000/µl (Group C: ATRA plus IDA/Ara-C: 3+5). Those patients who experienced leukocytosis received additional chemotherapy (Group D). Patients who achieved molecular remission after consolidation chemotherapy were randomly assigned to 2 groups of maintenance therapy, and administered tamibarotene at a daily dose of 6 mg/m2 divided into 2 doses for 14 days or ATRA at a daily dose of 45 mg/m2 divided into 3 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years. The primary endpoint was hematological or molecular relapse-free survival (RFS) during the maintenance and follow up period. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as C000000154.
Results: A total of 347 patients were enrolled in the study. Of the 344 eligible patients, 319 (93%) achieved CR. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment; 135 patients were assigned to ATRA, and 134 patients were assigned to tamibarotene. The mean follow-up of patients alive and relapse-free at the date of last contact was 7 years. The 7-year RFS rate was 84% for the ATRA arm and 93% for the tamibarotene arm (p=0.031) (Fig.1). When the analysis was restricted to 52 high-risk patients with an initial leukocyte count ≥ 10,000/µl, the difference was more prominent (62% vs 89%, p=0.034) (Fig.2). The 7-year RFS of induction treatment for Group A (92 cases) was 91%, Group B (38 cases) 92%, Group C (52 cases) 75% and Group D (87 cases) 91% (p=0.005). Both treatments were generally well tolerated. Secondary hematopoietic disorders were observed in 12 cases, malignancies in 9 cases, late cardiac complications (grade 3 or more) in 5 cases. However, there was no significant difference in terms of these complications between the two treatment groups.
Conclusions: Maintenance therapy with tamibarotene was effective at decreasing the relapse rate in APL patients by comparison to ATRA at the 7-year observation point. In particular, tamibarotene was significantly more effective than ATRA for high risk patients with leukocytes ≧10,000/μl. These results could lead to a new strategy for the treatment of high risk patients, which is one of the recent priority issues in the treatment of APL.

Disclosures
Takeshita: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co Ltd: Research Funding. Asou: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Ueda: KAINOS LABORATORIES INC: Membership on an entity's Board of Directors or advisory committees; Abrynx nv: Membership on an entity's Board of Directors or advisory committees; Elli LiLLY Japan KK: Other: Clinical Trial; Takeda PharmaceuticalCompany Limited: Other: Clinical TRial; Otsuka Pharmaceutical Co Ltd: Other: Clinical Trial; Celgene KK: Other: Clinical Trial; Symbio Pharmaceutical Limited: Other: Clinical Trial; AstellasPharma Inc: Other: Clinical Trial; Eisai Co. Ltd: Other: Clinical Trial. Fujita: Chugai Pharmaceutical: Honoraria. Usui: Nippon Shinyaku Pharmaceutical Co: Research Funding. Kobayashi: Pfizer, Ohtsuka, Astellas, Ariad: Research Funding. Kiyoi: Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Eisai Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; MSD K.K.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding. Atsuta: Otsuka Pharmaceutical Co., Ltd.: Honoraria. Naoe: Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Miyazaki: Nippon Shinyaku: Honoraria.