Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors.
Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).
Dong-A University Medical Center, Busan, South Korea.
Sung-Hyun
SH
Kim
Tata Memorial Hospital, Parel, Mumbai, India.
Hari
H
Menon
Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Saengsuree
S
Jootar
Prince Aly Khan Hospital, Mazagaon, Mumbai, India.
Tapan
T
Saikia
Chonbuk National University Medical School & Hospital, Jeonju, South Korea.
Jae-Yong
JY
Kwak
Kyungpook National University Hospital, Daegu, South Korea.
Sang-Kyun
SK
Sohn
Ajou University Hospital, Suwon, South Korea.
Joon Seong
JS
Park
Ajou University Hospital, Suwon, South Korea.
Seong Hyun
SH
Jeong
Chonnam National University, Hwasun Hospital, Hwasun, South Korea.
Hyeoung Joon
HJ
Kim
Chonnam National University, Hwasun Hospital, Hwasun, South Korea.
Yeo-Kyeoung
YK
Kim
Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Suk Joong
SJ
Oh
Ulsan University Hospital, Ulsan, South Korea.
Hawk
H
Kim
Hallym University Sacred Heart Hospital, Anyang, South Korea.
Dae Young
DY
Zang
Pusan National University Hospital, Pusan, South Korea.
Joo Seop
JS
Chung
Pusan National University Hospital, Pusan, South Korea.
Ho Jin
HJ
Shin
Dongsan Medical Center, Keimyung University, Daegu, South Korea.
Young Rok
YR
Do
St. Vincent Hospital, The Catholic University of Korea, Suwon, South Korea.
Jeong-A
JA
Kim
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Dae-Young
DY
Kim
Korea University, Guro Hospital, Seoul, South Korea.
Chul Won
CW
Choi
Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea.
Sahee
S
Park
Central Research Institute, IL-YANG Pharm. Co. Ltd., Yongin, South Korea.
Hye Lin
HL
Park
Central Research Institute, IL-YANG Pharm. Co. Ltd., Yongin, South Korea.
Gong Yeal
GY
Lee
Central Research Institute, IL-YANG Pharm. Co. Ltd., Yongin, South Korea.
Dae Jin
DJ
Cho
Central Research Institute, IL-YANG Pharm. Co. Ltd., Yongin, South Korea.
Jae Soo
JS
Shin
Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea dwkim@catholic.ac.kr.
Dong-Wook
DW
Kim
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
C000606751:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl