J Hematol Oncol. 2022 Aug 18. 15(1):
113
Qian Jiang,
Zongru Li,
Yazhen Qin,
Weiming Li,
Na Xu,
Bingcheng Liu,
Yanli Zhang,
Li Meng,
Huanling Zhu,
Xin Du,
Suning Chen,
Yang Liang,
Yu Hu,
Xiaoli Liu,
Yongping Song,
Lichuang Men,
Zi Chen,
Qian Niu,
Hengbang Wang,
Ming Lu,
Dajun Yang,
Yifan Zhai,
Xiaojun Huang.
BACKGROUND: BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP).METHODS: In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses.
RESULTS: A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia.
CONCLUSIONS: Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation.
TRIAL REGISTRATION: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).
Keywords: Accelerated phase; Chronic myeloid leukemia; Chronic phase; T315I mutation; Tyrosine kinase inhibitor