伊布替尼治疗中断的病因及慢性淋巴细胞白血病患者的结局。
Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia.
机构信息
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
Department of Pathology, The Ohio State University, Columbus.
出版信息
JAMA Oncol. 2015 Apr;1(1):80-7. doi: 10.1001/jamaoncol.2014.218.
IMPORTANCE
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.
OBJECTIVE
To determine features associated with discontinuation of ibrutinib therapy and outcomes.
DESIGN, SETTING, AND PARTICIPANTS: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014.
MAIN OUTCOMES AND MEASURES
Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse.
RESULTS
With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient.
CONCLUSIONS AND RELEVANCE
This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not.
TRIAL REGISTRATIONS
clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.
重要性
布鲁顿酪氨酸激酶（BTK）抑制剂依鲁替尼在慢性淋巴细胞白血病（CLL）患者中有效。在临床试验之外，由于这种药物的治疗中断以及停药后的结果尚未得到评估，而临床试验的随访时间相对较短。
目的
确定与依鲁替尼治疗中断相关的特征和停药后的结果。
设计、地点和参与者：俄亥俄州立大学综合癌症中心的 4 项依鲁替尼临床试验共纳入 308 例患者。这些临床试验从 2010 年 5 月到 2014 年 4 月期间纳入了本分析中的患者，数据于 2014 年 6 月锁定。
主要结果和测量
对患者的治疗中断时间、中断原因以及停药后的生存情况进行评估。对于因疾病进展而停止治疗的患者，在基线和复发时对样本进行靶向深度测序。
结果
中位随访 20 个月时，232 例患者仍在接受治疗，31 例因疾病进展而停止治疗，45 例因其他原因停止治疗。疾病进展包括里希特转化（RT）或进行性 CLL。RT 似乎很早就发生，而 CLL 进展较晚（12 个月时累积发生率分别为 4.5%[95%CI，2.0%-7.0%]和 0.3%[95%CI，0%-1.0%]）。RT 后的中位生存时间为 3.5 个月（95%CI，0.3-6.0 个月），CLL 进展后的中位生存时间为 17.6 个月（95%CI，4.7 个月-“未达到”）。对 8 例 RT 患者的外周血进行测序显示，有 2 例患者的 BTK 发生突变，淋巴结样本显示 BTK 或 PLCG2 无突变。对 11 例 CLL 进展患者进行深度测序显示，所有患者均存在 BTK 或 PLCG2 突变。在任何患者的治疗前均未发现这些突变。
结论和相关性
该单机构依鲁替尼治疗经验证实其为一种有效疗法，并首次确定了与依鲁替尼治疗中断相关的基线因素。结果数据显示停药后预后不良，特别是 RT 患者。最后，测序数据证实了最初的报告，即 BTK 和 PLCG2 突变与进展相关，并明确显示 CLL 进展与这些突变相关，而 RT 可能并非如此。
试验注册
clinicaltrials.gov 标识符：NCT01105247、NCT01217749、NCT01589302 和 NCT01578707。
Zotero 插件