酪氨酸激酶抑制剂停药后慢性髓性白血病患者结局评估：一项非随机临床试验。

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

机构信息

Department of Medicine, Medical College of Wisconsin, Milwaukee.

Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.

出版信息

JAMA Oncol. 2021 Jan 1;7(1):42-50. doi: 10.1001/jamaoncol.2020.5774.

DOI:10.1001/jamaoncol.2020.5774

PMID:33180106

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7662490/

Abstract

IMPORTANCE

Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.

OBJECTIVE

To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.

DESIGN, SETTING, AND PARTICIPANTS: The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.

INTERVENTION

Discontinuation of TKIs.

MAIN OUTCOMES AND MEASURES

Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).

RESULTS

Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.

CONCLUSIONS AND RELEVANCE

In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT02269267.

摘要

重要性

酪氨酸激酶抑制剂（TKIs）已被证明可改善慢性髓性白血病（CML）患者的生存，但也与不良反应有关，尤其是疲劳和腹泻。TKI 的停药是安全的，并且与一些患者成功实现无治疗缓解（TFR）有关。

目的

评估美国 CML 患者停止 TKI 治疗后的分子复发（MRec）和患者报告的结局（PROs）。

设计、地点和参与者：Life After Stopping TKIs（LAST）研究是一项前瞻性、单组非随机临床试验，于 2014 年 12 月 18 日至 2016 年 12 月 12 日从美国 14 家学术医疗中心招募了 172 名患者，随访时间至少 3 年。参与者为慢性期 CML 的成年人，其疾病在伊马替尼、达沙替尼、尼洛替尼或博舒替尼的控制下得到很好的控制。统计分析于 2019 年 8 月 13 日至 2020 年 3 月 23 日进行。

干预措施

TKI 的停药。

主要结果和测量

分子复发，定义为中心实验室检测到主要分子反应（BCR-ABL1 国际比例>0.1%）的丧失，以及 PROs（患者报告的结果测量信息系统计算机自适应测试）进行监测。通过标准实时定量聚合酶链反应（RQ-PCR）检测到不可检测的 BCR-ABL1 的样本进行液滴数字聚合酶链反应（ddPCR）。

结果

在 172 名患者中，89 名为女性（51.7%），中位年龄为 60 岁（范围，21-86 岁）。在 171 名可进行分子分析的患者中，112 名（65.5%）仍处于主要分子反应中，104 名（60.8%）达到 TFR。TKI 停药时（危险比，3.60；95%置信区间，1.99-6.50；P<0.001）和 3 个月时（危险比，5.86；95%置信区间，3.07-11.1；P<0.001）通过 ddPCR 或 RQ-PCR 检测到的 BCR-ABL1 不可检测与 MRec 独立相关。通过 RQ-PCR 检测到 BCR-ABL1 可检测的患者的分子复发率为 50.0%（28 例中的 14 例），通过 RQ-PCR 检测到 BCR-ABL1 不可检测但通过 ddPCR 检测到的患者的分子复发率为 64.3%（56 例中的 36 例），通过 ddPCR 和 RQ-PCR 均检测到 BCR-ABL1 不可检测的患者的分子复发率为 10.3%（87 例中的 9 例）（P≤0.001）。在 12 个月时处于 TFR 的 112 名患者中，90 名（80.4%）在疲劳方面有显著改善，39 名（34.8%）在抑郁方面有显著改善，98 名（87.5%）在腹泻方面有显著改善，24 名（21.4%）在睡眠障碍方面有显著改善，5 名（4.5%）在疼痛干扰方面有显著改善。重新开始 TKI 治疗会导致 PROs 的恶化。

结论和相关性

在这项研究中，TKI 的停药是安全的，60.8%的患者仍处于 TFR。TKI 的停药与 PROs 的改善有关。这些发现应该有助于患者和医生在是否停止 TKI 治疗方面做出决策。TKI 停药时通过 RQ-PCR 或 ddPCR 检测到的 BCR-ABL1 与更高的 MRec 风险相关；这一发现的临床应用应在其他研究中得到证实。