Olverembatinib 30 Mg
Versus
40 Mg Every Other Day (QOD) in Patients with Tyrosine Kinase Inhibitor (TKI) Resistant or Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP): A Multi-Center Propensity Score-Matched Analysis
Authors: Zhang Xiaoshuai , Yu Lu , Zhou Li , Zhang Yanli , Zhu Huanling , Liu Bingcheng , Du Xin , Wang Xiaodong , Yang Linhua , Ma Yanping , Meng Li , Zhang Yanqing , Li Guohui , Yang Lijie , Wang Baohong , Ran Xuehong , Huang Jian , Wen Qin , Wen Yan , Zhao Yuxia , Zhu Yu , Han Yanqiu , Liu Zhenfang , Du Xin , Weng Jianyu , Jiang Qian 
Published: December 2024

Background There is limited data comparing the efficacy and safety of olverembatinib in patients with TKI-resistant and/or intolerant CML-CP between 30 mg and 40 mg QOD.

Aims To compare the efficacy and safety of olverembatinib at initial doses of 30 mg versus 40 mg QOD in CML patients.

Methods Data from patients with TKI-resistant and/or intolerant CML-CP receiving olverembatinib 30 mg or 40 mg QOD from 33 hospital in China were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to compare the efficacy and safety between the 30 mg and 40 mg cohorts. Cox model was utilized to identify co-variates associated with treatment responses and outcomes. Plasma concentrations of patients from Peking University People's Hospital, who had been receiving olverembatinib therapy regularly for at least one month, were measured using the UHPLC-MS/MS method before dosing (C0) and 6 hours after dosing (C6).

Results 282 patients with CML-CP receiving olverembatinib 30 mg (n = 66) or 40 mg (n = 216) QOD were included in the study. Of these, 145 patients (51%) were enrolled from clinical trials, while 137 patients (49%) were from real-world post-marketing settings. Median age at the start of olverembatinib therapy was 39 years (IQR, 25-46 years). 130 (46%) received ≥ 3 prior TKIs. Median duration of prior TKI-therapy was 47 months (IQR, 25-80 months). BCR::ABL kinase domain mutations were detected by Sanger sequencing, revealing that 161 (57%) patients harbored the single T315I mutation. There were no significant differences in baseline co-variates between the two dose cohorts, except for better prior TKI-therapy responses (p = 0.04) in the 30 mg cohort. Median follow-up period were 25 months (IQR: 8-75 months) in the 30 mg cohort and 23 months (IQR: 7-54 months) in the 40 mg cohort. There were no significant differences in the 4-year cumulative incidences of MCyR (p = 0.43), CCyR (p = 0.46), MMR (p = 0.45) and MR4 (p = 0.17), as well as PFS (p = 0.99) and survival (p = 0.56) between the 2 dose cohorts. Multi-variable Cox analyses further confirmed that the dose of olverembatinib was not significantly associated with treatment responses and outcomes.

During treatment, 36 patients (55%) in the 30 mg cohort and 99 patients (46%) in the 40 mg cohort temporarily reduced their dose or discontinued treatment due to treatment-related adverse events (TRAEs) (p = 0.22). However, the proportion of patients still receiving the original dose at the last follow-up was significantly higher in the 30 mg cohort compared to the 40 mg cohort (67% versus 46%, p = 0.003). Additionally, the proportion of patients who reduced dose or permanently discontinued treatment due to TRAEs in the 30 mg cohort was significantly lower than that in the 40 mg cohort (18% versus 39%, p = 0.002). During the treatment, there was no significant differences in the prevalence of hematologic (≥ 3 grade) and non-hematologic (any grade) TRAEs between the 30mg and 40mg cohorts: severe thrombocytopenia, 50% versus 44% (p = 0.36); skin pigmentation, 65% versus 61% (p = 0.57); hypertriglyceridemia, 40% versus 37% (p = 0.71); sexual dysfunction, 23% versus 16% (p = 0.17). For the cardiovascular and cerebrovascular TRAEs of interest, there was still no difference between the 2 cohorts: hypertension,11% versus 18% (p = 0.24); sinus tachycardia,11% versus 7% (p = 0.28); arterial and/or venous obstructive events, 5% versus 7% (p = 0.72); pericardial effusion, 3% versus 2% (p = 0.66); atrial fibrillation, 2% versus 2% (p = 0.66), sinus bradycardia, 2% versus 2% (p = 0.99). However, no cases of pulmonary arterial hypertension were observed in the 30mg cohort, while 2 cases were reported in the 40mg cohort. PSM analyses further validated these results. Sensitivity analyses were performed in the clinical trial and the real-world cohorts, respectively, which did not alter these results.

Plasma concentrations at C0 and C6 were measured in 96 patients regularly receiving olverembatinib (30 mg cohort, n = 64; 40 mg cohort, n = 32). The C0 (p = 0.001) and C6 (p &lt; 0.001) levels in the 40 mg cohort were significantly higher than those in the 30 mg cohort.

Conclusions Olverembatinib 30 mg QOD as an initial dose demonstrated equivalent effectiveness but better safety and tolerability compared to 40 mg QOD in TKI-resistant and/or intolerant patients with chronic-phase CML. This conclusion needs to be further validated in the longer-observation studies or randomized controlled trials.