-Author name in bold denotes the presenting author
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Clinically Relevant Abstract denotes an abstract that is clinically relevant.

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Ticketed Session denotes that this is a ticketed session.

1477 Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, Clinical Research, Diseases, Myeloid Malignancies, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Chikashi Yoshida, MD, PhD1, Hiroki Yamaguchi, MD, PhD2*, Noriko Doki3*, Kazunori Murai, MD, PhD4, Masaki Iino, MD, PhD5*, Yoshihiro Hatta, MD, PhD6, Makoto Onizuka, MD, PhD7, Norio Yokose, MD, PhD8*, Katsumichi Fujimaki, MD, PhD9*, Masao Hagihara, MD10*, Gaku Oshikawa, MD, PhD11*, Kayoko Murayama, MD, PhD12*, Takashi Kumagai, MD, PhD13, Shinya Kimura, MD, PhD14*, Hideharu Muto, MD, PhD15*, Kensuke Usuki, MD, PhD16, Kenji Yokoyama, MD, PhD17, Koh Yamamoto, MD, PhD18*, Nobuyuki Aotsuka, MD, PhD19*, Kenichi Ishizawa, MD, PhD20*, Naoki Takezako, MD, PhD21, Takuto Miyagishima, MD, PhD22*, Tadao Ishida, MD, PhD23, Atsushi Shinagawa, MD, PhD24*, Kentaro Wakasa, MD25*, Tsuyoshi Nakamaki, MD, PhD26, Naoto Tomita, MD, PhD27, Katsutoshi Ozaki, MD, PhD28, Takayoshi Itoh, MD29*, Shugo Kowata, MD, PhD.30*, Kenji Tajika, MD31*, Takayuki Fujio, MD32*, Masahiro Onozawa, MD, PhD33, Masahide Yamamoto, MD, PhD34*, Takeshi Kondo, MD, PhD35, Yuho Najima3, Noriyoshi Iriyama, MD, PhD6*, Ikuyo Tsutsumi, MD, MPH, PhD1*, Koji Oba, PhD36*, Hiroshi Kojima, MD, PhD37*, Hisashi Sakamaki, MD, PhD3* and Koiti Inokuchi, MD, PhD, Prof.2*

1Department of Hematology, National Hospital Organization Mito Medical Center, Ibaraki, Japan
2Department of Hematology, Nippon Medical School, Tokyo, Japan
3Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
4Department of Hematology, Iwate Prefectural Central Hospital, Morioka, Japan
5Department of Medical Oncology, Yamanashi Prefectural Central Hospital, Kofu, Japan
6Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
7Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan
8Department of Hematology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
9Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan
10Department of Hematology, EIJU GENERAL HOSPITAL, Taito-Ku, Japan
11Japanese Red Cross Musashino Hospital, Musashino, Japan
12Division of Hematology, Gunma Prefectural Cancer Center, Ohta, Japan
13Department of Hematology, Ohme Municipal General Hosp., Oume-Shi, TKY, Japan
14Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga-city, Japan
15Division of hematology, Tokyo Metropolitan Otsuka Hospital, Tokyo, Japan
16Department of Hematology, NTT Medical Center, Tokyo, Japan
17Tokai University Hachioji Hospital, Tokyo, Japan
18Department of Hematology, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan
19Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Japan
20Yamagata University Hospital, Yamagata, Japan
21Department of Hematology, Disaster Medical Center of Japan, Tachikawa, Japan
22Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan
23Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
24Department of Hematology, Hitachi General Hospital, Ibaraki, Japan
25Obihiro-Kosei General Hospital, Obihiro, Japan
26Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
27St.Marianna University School of Medicine, Kawasaki, Japan
28NIPPON MEDICAL SCHOOL TAMANAGAYAMA HOSPITAL, Tama, Japan
29JA Toride Medical Center, Toride, Japan
30Iwate Medical University School of Medicine, Yahaba, Japan
31Yokohamaminami-Kyousai Hospital, Yokohama, Japan
32Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
33Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
34Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan
35Blood Disorders Center, Aiiku Hospital, Sapporo, Japan
36Department of Biostatistics, The University of Tokyo, Tokyo, Japan
37Ibaraki Clinical Education and Training Center, University of Tsukuba Hospital, Kasama, Japan

Background: Treatment-free remission (TFR) is a new treatment goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) by treatment with tyrosine kinase inhibitors (TKI). Although several guidelines have proposed clinical factors for successful TFR, they are based primarily on evidence with imatinib. Since 2nd-generation TKI (2G-TKI) achieves a molecular response faster than imatinib, it may lead to TFR in a shorter treatment period. The multicenter phase II study D-FREE (Japan Registry of Clinical Trials: jRCTs031180332) was conducted to clarify optimal conditions for TFR in newly diagnosed patients with CML-CP treated with the 2G-TKI dasatinib.

Methods: Newly diagnosed CML-CP patients were enrolled and treated with dasatinib in the induction phase. When patients achieved MR4.5 (BCR-ABL1IS ≤0.0032%) based on assessment every three months during the induction phase for up to two years, they immediately entered the consolidation phase, where dasatinib is administered for 12 months. Patients with sustained MR4.5 throughout the consolidation phase discontinued dasatinib in the stop phase. Dasatinib was re-administered at molecular relapse, defined as loss of a major molecular response (BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (BCR-ABL1IS > 0.01% on two consecutive assessments). The primary endpoint was the proportion of patients in TFR who showed no molecular relapse and did not need to resume dasatinib 12 months after treatment discontinuation.

Results: Between July 2016 and May 2019, 181 patients with newly diagnosed CP-CML were enrolled in 41 centers in Japan. Four patients were excluded after screening, and no further information was available for 4 patients. Overall, 173 patients received study treatment. The median patient age was 54 years (18-83 years). The rates of Sokal low-, intermediate-, and high-risk groups were 28.6, 52.4, and 19.0%, respectively. The rates of EUTOS low- and high-risk groups were 81.0 and 19.0%, respectively. Of the 123 patients who completed the induction phase, 60 (48.8%) achieved MR4.5 for up to two years (median: 7.7 months, range: 3.0-21.1 months) and entered the consolidation phase. Single and multivariate analyses showed that the achievement of MMR at 3 months, but not sex, Sokal risk score, Hasford risk score, EUTOS risk score, or age (<60 vs. ≥60), was predictive of the achievement of MR4.5 within 2 years. During the consolidation phase, 15 patients could not sustain MR4.5 and finished study treatment. Among the first 21 patients who could sustain MR4.5 for 12 months and discontinued dasatinib treatment in the stop phase, 17 experienced molecular relapse within 12 months (median: 3.5 months, range: 2.0-6.4). In those patients, the median duration of dasatinib treatment was 18.9 months (range: 14.9-25.5) before the cessation of dasatinib. The study was terminated prematurely on December 3, 2019, based on the pre-specified interim analysis criterion that it would be stopped if the TFR rate was less than 25% in the first 20 patients of the stop phase. At termination, 46 patients were in the induction phase and 17 were in the consolidation phase. Four patients were in TFR in the stop phase. Of note, one patient remained in TFR for 18 months after receiving dasatinib treatment for only 18.6 months in induction and consolidation phases. All relapsing patients regained MR4 after a median of 2.1 months (range: 0.9-5.1) of dasatinib retreatment, except one patient who stopped study treatment because of an adverse event. No patients progressed to the accelerated/blastic phase or died due to CML.

Conclusions: D-FREE was the first trial to discontinue TKI treatment in patients with newly diagnosed CML-CP who maintained MR4.5 for 1 year by dasatinib treatment regardless of the treatment duration. Hachhaus et al. previously reported in the ENSTfreedom trial (Leukemia 2017) that CML-CP patients who received at least 2 years of front-line nilotinib treatment, achieved MR 4.5, and then underwent consolidation of nilotinib treatment for 1 year had a TFR of 51.6% at 48 weeks after nilotinib discontinuation. The median duration of TKI treatment in the study was 43.5 months, compared with 18.9 months for D-FREE, suggesting that not only the duration of DMR but also that of TKI treatment is important for successful TFR even with 2G-TKI.

Disclosures: Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku: Honoraria; Novartis KK,: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Yamaguchi: Bristol-Myers Squibb: Research Funding. Murai: Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria; Bristol Myers Squibb: Honoraria. Hatta: Otsuka Pharmaceutical.: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb: Honoraria. Yokose: Bristol Myers Squibb Company: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Novartis KK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Mundipharma K.K.: Honoraria. Oshikawa: Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Eisai Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; MSD K.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene Corporation: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; SymBio Pharmaceuticals.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Kimura: Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Sanifi: Speakers Bureau; Astellas: Speakers Bureau; Eisai: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding; SymBio: Research Funding, Speakers Bureau; Mundi: Research Funding; Chugai: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Ono: Research Funding, Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding. Usuki: Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Apellis Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yokoyama: Kowa: Consultancy; SymBio Pharmaceuticals: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical: Honoraria; Bayer: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Pfizer: Research Funding. Yamamoto: Bristol-Myers Squibb Company: Honoraria; Novartis Japan Co.: Honoraria; Kyowa Kirin Co.: Honoraria; Fujimoto Pharmaceutical Corporation: Honoraria; Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria. Ishizawa: Sanofi: Research Funding; IQVIA: Research Funding; Eisai: Honoraria; Chugai: Honoraria; Ono: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bayer: Research Funding; AbbVie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Otsuka: Research Funding; SymBio: Honoraria, Research Funding; Kyowa Kirin: Consultancy; Pfizer: Research Funding; Bristol Myers Squibb: Speakers Bureau. Ishida: Ono: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Bristol Myers Squibb: Honoraria. Yamamoto: NIPPON SINYAKU CO., LTD: Honoraria; Novartis Pharma: Honoraria; ONO PHARMACEUTICAL CO.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Kondo: Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy. Iriyama: Otsuka: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Oba: Eisai: Honoraria; Chugai pharma: Honoraria; Ono pharma: Honoraria; Asahi-Kasei pharma: Honoraria; Takeda pharma: Honoraria; Daiichi-Sankyo pharma: Honoraria; Bristol Myers Squibb: Honoraria. Inokuchi: Bristol-Myers Squibb: Research Funding.

*signifies non-member of ASH