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220 Tamibarotene Compared to All-Trans Retinoic Acid (ATRA) As Add-on to Arsenic Trioxide (ATO) in Subjects with Relapsed Acute Promyelocytic Leukemia (APL)

Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation: New Approaches Using Older Drugs
Sunday, December 6, 2015: 10:15 AM
W109, Level 1 (Orange County Convention Center)

Jianxiang Wang, MD, PhD1, Yingchang Mi, MD, PhD2, Bin Jiang3*, Xiequn Chen4*, Chunyan Ji, MD, PhD5*, Yan Li6*, Xielan Zhao7*, Yongrong Lai8*, Yu Hu, M.D., Ph.D.9*, Aiping Tang10*, Ting Liu, MD, PhD11, Jie Jin, MD, PhD12, Junmin Li13*, Linhua Yang14*, Jianyong Li, MD, PhD15 and Fanyi Meng16

1Institute of Hematology, Hospital of Blood Diseases, CAMS, Tianjin, China
2State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
3Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
4Xijing Hospital of the Fourth Military Medical University, Xian, China
5Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
6The First Hospital Affiliated of China Medical University, Shenyang, China
7The Xiangya Hospital of Central-South University, Changsha, China
8The First Affiliated Hospital of Guangxi Medical University, Nanning, China
9Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
10The Second Affiliated Hospital of Nanchang University, Nanchang, China
11Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
12Department of Hematology & Institute of Hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
13Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, China
14The Second Hospital of Shanxi Medical University, Taiyuan, China
15Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
16Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China


Combination therapy with ATRA and ATO is a standard therapy for relapsed APL. Despite the high complete remission (CR) rate with ATRA-ATO combination therapy, patients administered this combination for relapsed disease may acquire tolerance to ATRA, which reduces the CR rate in relapsed APL patients. Tamibarotene is a novel synthetic retinoid created in Japan with a several-fold-higher differentiation-inducing effect than ATRA, as well as low affinity for cellular retinoic acid-binding protein and absence of binding affinity for RARγ, unlike ATRA. It has been used for treating patients relapsed after ATRA therapy since 2005 in Japan. We conducted a phase III, randomized, open-label, parallel-group, active-controlled, multicenter clinical trial to compare tamibarotene-ATO and ATRA-ATO combination therapies in relapsed APL patients.


A Phase III, randomized, open-label, parallel-group, active-controlled, multicenter, study of 56 days treatment duration will evaluate the efficacy and safety of 6mg/m2/day Tamibarotene versus 25mg/m2/day ATRA as add-on to 0.15mg/kg/day ATO in subjects with relapsed APL. 71 subjects were randomly assigned to 1 of 2 treatment groups: ATRA-ATO (control group) or tamibarotene-ATO (study group).


The number of subjects for efficacy analysis constituting a full analysis set (FAS) of all subjects administered study drugs, including drop-outs, was 35 each in the control and study groups. The number of subjects in each per protocol set (PPS), excluding drop-outs, was 27 and 33 in the control and study groups, respectively. CR rate for the FAS was significantly higher in the study group (80.00% vs. 54.29%; P = 0.0220, Table 1). In contrast, CR rate for the PPS was 84.85% and 70.37% for the study and control groups, respectively. The intergroup difference was 14.48% with a 97.1% confidence interval of -9.06 to 38.01%, which fulfilled requirements for non-inferiority of Δ = 0.10. These results verified the non-inferiority of the study to the control group. Of the patients who attained CR, the number who showed complete molecular remission (CRm) was higher in the study group, suggesting that a higher quality of remission was possibly attained in the study group (Table 2).

Serious adverse events occurred in 3 control group patients (intracerebral hemorrhage, 2 and retinoic acid syndrome, 1) and 1 patient in the study group (type I respiratory failure). There was no significant intergroup difference in the incidences of serious adverse events. The most commonly reported adverse reactions included hypertriglyceridemia, hypercholesterolemia, rash, and elevation of ALT and AST levels; there was no significant intergroup difference in the incidences of any of these adverse reactions. Other adverse reaction findings were similar between the groups. Therefore, the tolerability observed in the study group was considered to be similar to that in the control. The only adverse finding that showed an appreciable intergroup difference was leukocytosis, which occurred at a significantly lower frequency in the study group than in the control group. Therefore, the therapeutic regimen of the study group might reduce the risk of retinoic acid syndrome, an important adverse reaction in treatment of APL, when the association of leukocytosis with development of retinoic acid syndrome is considered.


This controlled clinical trial demonstrated the efficacy and safety of combination therapy with tamibarotene and ATO in patients with relapsed APL. Tamibarotene-ATO combination therapy was considered not inferior in efficacy and safety to the standard combination of ATRA and ATO, and may be a useful new combination regimen for treating relapsed APL.


Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH