Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

Sung Hyun Kim, Hari Menon, Saengsuree Jootar, Tapan Saikia, Jae Yong Kwak, Sang Kyun Sohn, Joon Seong Park, Seong Hyun Jeong, Hyeoung Joon Kim, Yeo Kyeoung Kim, Suk Joong Oh, Hawk Kim, Dae Young Zang, Joo Seop Chung, Ho Jin Shin, Young Rok Do, Jeong A. Kim, Dae Young Kim, Chul Won Choi, Sahee ParkHye Lin Park, Gong Yeal Lee, Dae Jin Cho, Jae Soo Shin, Dong Wook Kim

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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 nonhematologic 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).

Original languageEnglish
Pages (from-to)1191-1196
Number of pages6
JournalHaematologica
Volume99
Issue number7
DOIs
Publication statusPublished - 2014 Jul 1

Fingerprint

Leukemia, Myeloid, Chronic Phase
Protein-Tyrosine Kinases
Cytogenetics
Safety
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide
Asthenia
Philadelphia Chromosome
Hyperbilirubinemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Thrombocytopenia
Biochemistry
Nausea
Disease-Free Survival
Fatigue
Anemia
Survival Rate
Mutation

ASJC Scopus subject areas

  • Hematology

Cite this

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. / Kim, Sung Hyun; Menon, Hari; Jootar, Saengsuree; Saikia, Tapan; Kwak, Jae Yong; Sohn, Sang Kyun; Park, Joon Seong; Jeong, Seong Hyun; Kim, Hyeoung Joon; Kim, Yeo Kyeoung; Oh, Suk Joong; Kim, Hawk; Zang, Dae Young; Chung, Joo Seop; Shin, Ho Jin; Do, Young Rok; Kim, Jeong A.; Kim, Dae Young; Choi, Chul Won; Park, Sahee; Park, Hye Lin; Lee, Gong Yeal; Cho, Dae Jin; Shin, Jae Soo; Kim, Dong Wook.

In: Haematologica, Vol. 99, No. 7, 01.07.2014, p. 1191-1196.

Research output: Contribution to journalArticle

Kim, SH, Menon, H, Jootar, S, Saikia, T, Kwak, JY, Sohn, SK, Park, JS, Jeong, SH, Kim, HJ, Kim, YK, Oh, SJ, Kim, H, Zang, DY, Chung, JS, Shin, HJ, Do, YR, Kim, JA, Kim, DY, Choi, CW, Park, S, Park, HL, Lee, GY, Cho, DJ, Shin, JS & Kim, DW 2014, 'Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors', Haematologica, vol. 99, no. 7, pp. 1191-1196. https://doi.org/10.3324/haematol.2013.096776
Kim, Sung Hyun ; Menon, Hari ; Jootar, Saengsuree ; Saikia, Tapan ; Kwak, Jae Yong ; Sohn, Sang Kyun ; Park, Joon Seong ; Jeong, Seong Hyun ; Kim, Hyeoung Joon ; Kim, Yeo Kyeoung ; Oh, Suk Joong ; Kim, Hawk ; Zang, Dae Young ; Chung, Joo Seop ; Shin, Ho Jin ; Do, Young Rok ; Kim, Jeong A. ; Kim, Dae Young ; Choi, Chul Won ; Park, Sahee ; Park, Hye Lin ; Lee, Gong Yeal ; Cho, Dae Jin ; Shin, Jae Soo ; Kim, Dong Wook. / Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. In: Haematologica. 2014 ; Vol. 99, No. 7. pp. 1191-1196.
@article{a2e9fce77f1749d8ae0cc1a10fd90176,
title = "Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors",
abstract = "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 nonhematologic 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).",
author = "Kim, {Sung Hyun} and Hari Menon and Saengsuree Jootar and Tapan Saikia and Kwak, {Jae Yong} and Sohn, {Sang Kyun} and Park, {Joon Seong} and Jeong, {Seong Hyun} and Kim, {Hyeoung Joon} and Kim, {Yeo Kyeoung} and Oh, {Suk Joong} and Hawk Kim and Zang, {Dae Young} and Chung, {Joo Seop} and Shin, {Ho Jin} and Do, {Young Rok} and Kim, {Jeong A.} and Kim, {Dae Young} and Choi, {Chul Won} and Sahee Park and Park, {Hye Lin} and Lee, {Gong Yeal} and Cho, {Dae Jin} and Shin, {Jae Soo} and Kim, {Dong Wook}",
year = "2014",
month = "7",
day = "1",
doi = "10.3324/haematol.2013.096776",
language = "English",
volume = "99",
pages = "1191--1196",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "7",

}

TY - JOUR

T1 - Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

AU - Kim, Sung Hyun

AU - Menon, Hari

AU - Jootar, Saengsuree

AU - Saikia, Tapan

AU - Kwak, Jae Yong

AU - Sohn, Sang Kyun

AU - Park, Joon Seong

AU - Jeong, Seong Hyun

AU - Kim, Hyeoung Joon

AU - Kim, Yeo Kyeoung

AU - Oh, Suk Joong

AU - Kim, Hawk

AU - Zang, Dae Young

AU - Chung, Joo Seop

AU - Shin, Ho Jin

AU - Do, Young Rok

AU - Kim, Jeong A.

AU - Kim, Dae Young

AU - Choi, Chul Won

AU - Park, Sahee

AU - Park, Hye Lin

AU - Lee, Gong Yeal

AU - Cho, Dae Jin

AU - Shin, Jae Soo

AU - Kim, Dong Wook

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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 nonhematologic 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).

AB - 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 nonhematologic 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).

UR - http://www.scopus.com/inward/record.url?scp=84903650301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903650301&partnerID=8YFLogxK

U2 - 10.3324/haematol.2013.096776

DO - 10.3324/haematol.2013.096776

M3 - Article

C2 - 24705186

AN - SCOPUS:84903650301

VL - 99

SP - 1191

EP - 1196

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 7

ER -