Sydney Pharmacy School, The University of Sydney, Sydney, New South Wales, Australia.
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline R &D, Sydney, New South Wales, Australia.
Pharmacol Res Perspect. 2022 Oct;10(5):e01005. doi: 10.1002/prp2.1005.
Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. To investigate the real-world use and outcomes of imatinib in patients with CML in Australia, a retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, and survival and molecular response were evaluated. 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32%-53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92%-100%) and 81% (95% CI, 72%-92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50%-73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. In conclusion, imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.
酪氨酸激酶抑制剂 (TKI) 彻底改变了慢性髓性白血病 (CML) 的治疗方法，但患者仍会经历治疗受限的毒性或治疗失败。为了研究澳大利亚 CML 患者使用伊马替尼的真实世界情况和结果，在两个地点进行了一项回顾性队列研究，纳入了 2001 年至 2018 年开始接受伊马替尼治疗的 CML 患者。评估了用药模式、耐受性结果、生存和分子反应。86 例患者接受了 89 次伊马替尼治疗。经常观察到剂量调整（12 个月时为 58%）。最后一次随访时，62 例患者（5 年时为 55%）已永久性停用伊马替尼治疗，其中 44 例转为另一种 TKI（5 年时为 46%）。在开始伊马替尼治疗的 3 个月内，43%（95%CI，32%-53%）的患者发生了与伊马替尼相关的≥3 级不良药物反应（ADR）。多变量分析（MVA）显示，合并症评分较高、体重较低、伊马替尼起始剂量较高以及中东或北非血统与较高的≥3 级 ADR 发生风险相关。3 年时的总生存率和无事件生存率估计分别为 97%（95%CI，92%-100%）和 81%（95%CI，72%-92%）。3 年时主要分子反应（MMR）的累积发生率为 63%（95%CI，50%-73%）。在 MVA 中，伊马替尼起始剂量、ELTS 评分、BCR-ABL1 转录类型、预先存在的肺部疾病和潜在的药物相互作用是 MMR 的预测因素。总之，伊马替尼诱导了深度分子反应，在真实环境中转化为良好的生存结果，但与临床试验相比，ADR 发生率较高、剂量调整和治疗中断的发生率较高。
