Patient-Reported Quality of Life before and after Stopping Treatment in the ENESTop Trial of Treatment-Free Remission for Patients with Chronic Myeloid Leukemia in Chronic Phase
Patient-Reported Quality of Life before and after Stopping Treatment in the ENESTop Trial of Treatment-Free Remission for Patients with Chronic Myeloid Leukemia in Chronic Phase
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在 ENEStop 慢性粒细胞白血病慢性期无治疗缓解试验中，患者报告停止治疗前后的生活质量
DOI：
10.1182/blood.v128.22.1891.1891
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发表时间：
2016
期刊：
影响因子：
20.3
通讯作者：
T. Hughes
中科院分区：
文献类型：
--
作者：
F. Mahon;C. Boquimpani;N. Takahashi;N. Benyamini;N. Clementino;V. Shuvaev;S. Ailawadhi;J. Lipton;A. Turkina;E. Moiraghi;F. Nicolini;J. Dengler;T. Sacha;Dong;R. Fellague;Sandip Acharya;P. Brandt;A. Gnanasakthy;Yu Jin;T. Hughes
背景：许多慢性髓系白血病慢性期（CML-CP）患者（pts）在一线尼罗替尼（NIL）治疗下实现了持续的深度分子反应（DMR）。ENESTfreedom （NCT01784068）是一项正在进行的2期研究，评估此类患者停止治疗并保持无治疗缓解（TFR）的潜力。ENESTfreedom的初步结果显示，在48周时，51.6%尝试TFR的患者没有失去主要分子反应（MMR [BCR-ABL1≤0.1%的国际标准，BCR-ABL1IS]）。尽管入组的患者已确定对NIL有耐受性，但与停止治疗前一年相比，TFR前48周不良事件（ae）的频率有所下降（分别为65.8%和83.2%），而与肌肉骨骼疼痛相关的ae在TFR期间更为常见（分别为24.7%和16.3%）。近年来，酪氨酸激酶抑制剂治疗患者的生活质量（QOL）越来越受到关注。为了评估TFR对生活质量的影响，我们分析了患者在TFR之前和期间报告的结果。方法：纳入CML-CP患者和≥2年一线NIL治疗（前≥1年400 - 600mg /天）且NIL MR4.5 （BCR-ABL1IS≤0.0032%）的患者，并进入1年巩固期，在此期间，他们每12周进行RQ-PCR评估。在巩固期持续DMR的患者（没有评估低于MR4 [BCR-ABL1IS≤0.01%]，MR4和MR4.5之间≤2次评估，最后一次评估为MR4.5）进入TFR期并停止治疗。在TFR期失去MMR的患者重新开始了NIL治疗（重新开始期）。在指定的时间点，患者完成MD安德森CML症状量表（MDASI-CML），其中患者对一组定义的症状的严重程度和对日常生活的干扰程度进行评分，评分范围从0到10,0表示最低的严重程度/干扰)。在每个时间点，患者还完成了EQ- 5d - 5l问卷，在问卷中，他们报告了与行动能力、自我保健、日常活动、焦虑/抑郁和疼痛/不适相关的问题的存在/不存在和严重程度（轻微、中度、严重或极端），并使用EQ VAS量表将他们的整体健康水平从0到100进行排名，0表示最差的健康水平。结果：在215名入组患者中，190名患者在巩固期持续DMR并进入TFR期。在巩固期第48周，完成问卷的患者MDASI-CML严重程度、干扰评分和EQ VAS评分的平均值分别为1.4、1.7和80.5；在TFR期第12周时为1.1、1.3和81.1；TFR期第48周时分别为1.2、1.4和81.4（表）。在持续TFR的患者中，在巩固期第48周和TFR期第12周或第48周均有评分的患者中，未检测到停止治疗对MDASI-CML或EQ VAS评分的影响。在TFR阶段失去MMR并重新启动NIL的可评估患者中，重新开始治疗后24周的平均评分为1.3 （MDASI-CML严重程度），1.5 （MDASI-CML干扰）和77.8 （EQ VAS）。在巩固期第48周和重新启动期第24周可评估的得分中，两个时间点的平均得分相似。在完成EQ-5D-5L问卷的患者中，在巩固期的第48周，TFR期的第12周和第48周以及重新启动期的第24周报告问题（任何严重程度）的比例倾向于相似。患者报告焦虑/抑郁问题的比例在重新开始阶段最低（表）。结论：停止治疗后，患者报告的结果变化很小。这可能与患者在停止治疗前的相对较高的生活质量有关，因为他们在入组前耐受了≥2年的NIL。这些数据表明，TFR期较高频率的肌肉骨骼疼痛相关ae并没有显著影响患者的生活质量；然而，随着时间的推移，只有一小部分PTS可以评估报告结果的变化。尽管许多患者对TFR有恐惧，但报告的焦虑/抑郁水平在停止治疗前后相似，但在重新开始治疗的患者中有所下降。Hochhaus:BMS：酬金，研究经费；诺华：研究经费；辉瑞：研究经费；酬金，研究经费。Casares：诺华：咨询，演讲局；BMS：咨询、演讲局；Ariad：演讲局顾问。Stentoft：辉瑞：研究经费；Ariad：研究经费；Bristol-Myers-Squibb：研究经费；诺华：研究经费。Conneally:Novartis：名誉、实体董事会或咨询委员会成员；BMS：酬金、实体董事会或咨询委员会成员；辉瑞公司：名誉、董事会或咨询委员会成员；吉利德：名誉、实体董事会或咨询委员会成员。Garcia-Gutierrez:Ariad：咨询，研究资金；BMS：咨询、研究资助；诺华：咨询、研究经费；辉瑞：咨询，研究资金。Gattermann:Celgene：咨询，荣誉，研究经费；诺华：咨询、酬金、其他：差旅费、住宿费、研究经费。Wiktor-Jedrzejczak: Sandoz:咨询公司;BMS：研究经费；诺华：咨询、研究经费；Janssen-Cilag:咨询公司;Angelini:咨询公司;诺华：咨询、研究经费；Celgene公司:咨询公司;安进公司：研究经费。Le Coutre:Ariad：咨询公司；辉瑞：咨询，酬金；BMS：咨询、酬金、其他：差旅、住宿、费用；诺华：咨询、酬金、其他：差旅、住宿、费用、研究经费。Saussele:阿瑞雅德:谢礼;诺华：酬金，其他：差旅补助，研究经费；辉瑞：酬金，其他：差旅补助；BMS：酬金，其他：旅行补助，研究经费。Giles：诺华：咨询，研究资金。Radich:阿瑞雅德:咨询公司;百时美施贵宝:咨询公司;诺华：咨询，研究资金。罗斯:百时美施贵宝:谢礼;诺华制药：酬金，研究经费。门森：诺华制药：就业。邓：诺华制药公司：就业。布兰德:诺华:就业。Gnanasakthy：诺华：咨询，股权，研究资金。Bedoucha:诺华:就业。Saglio：诺华：咨询公司；BMS：咨询公司；Ariad：咨询公司；辉瑞：咨询，酬金；罗奇：咨询公司。
Background: Many patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) achieve a sustained deep molecular response (DMR) with frontline nilotinib (NIL) therapy. ENESTfreedom (NCT01784068) is an ongoing phase 2 study evaluating the potential for such pts to stop treatment and remain in treatment-free remission (TFR). Initial results from ENESTfreedom showed that 51.6% of pts who attempted TFR remained off treatment without loss of major molecular response (MMR [BCR-ABL1 ≤ 0.1% on the International Scale, BCR-ABL1IS]) at 48 weeks. Despite the enrollment of pts with established tolerance of NIL, the frequency of adverse events (AEs) decreased during the first 48 weeks of TFR compared with the year prior to stopping treatment (65.8% vs 83.2%, respectively), while AEs related to musculoskeletal pain were more common during TFR (24.7% vs 16.3%, respectively). The quality of life (QOL) of tyrosine kinase inhibitor-treated pts has gained increasing interest in recent years. To evaluate the impact of TFR on QOL, we analyzed patient-reported outcomes prior to and during TFR. Methods: Pts with CML-CP and ≥ 2 years of frontline NIL therapy (400 to 600 mg/day for the previous ≥ 1 year) who achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%) on NIL were enrolled and entered a 1-year consolidation phase, during which they continued NIL with RQ-PCR assessments every 12 weeks. Pts with sustained DMR during the consolidation phase (no assessment worse than MR4 [BCR-ABL1IS ≤ 0.01%], ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment) entered the TFR phase and stopped treatment. Pts with loss of MMR during the TFR phase reinitiated NIL treatment (reinitiation phase). At specified time points, pts completed the MD Anderson Symptom Inventory for CML (MDASI-CML, in which pts rate the levels of severity and interference with daily life for a defined set of symptoms on a scale from 0 to 10, with 0 indicating the lowest severity/interference). At each time point, pts also completed the EQ-5D-5L questionnaire, in which they report the presence/absence and severity (slight, moderate, severe, or extreme) of problems related to mobility, self-care, usual activities, anxiety/depression, and pain/discomfort and rank their overall level of health from 0 to 100 using the EQ VAS scale, with 0 indicating the poorest level of health. Results: Among 215 pts enrolled, 190 remained in sustained DMR during the consolidation phase and entered the TFR phase. Mean MDASI-CML severity and interference scores and EQ VAS scores, respectively, among pts who completed each questionnaire were 1.4, 1.7, and 80.5 at week 48 of the consolidation phase; 1.1, 1.3, and 81.1 at week 12 of the TFR phase; and 1.2, 1.4, and 81.4 at week 48 of the TFR phase (Table). Among pts who sustained TFR and who had scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, no impact of stopping treatment on MDASI-CML or EQ VAS scores was detected. Among evaluable pts who lost MMR during the TFR phase and reinitiated NIL, mean scores at 24 weeks after treatment reinitiation were 1.3 (MDASI-CML severity), 1.5 (MDASI-CML interference), and 77.8 (EQ VAS). Among pts evaluable at both week 48 of the consolidation phase and week 24 of the reinitiation phase, mean scores were similar at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions reporting problems (of any severity) at week 48 of the consolidation phase, weeks 12 and 48 of the TFR phase, and week 24 of the reinitiation phase tended to be similar. The proportion of pts reporting problems with anxiety/depression was lowest during the reinitiation phase (Table). Conclusion: Minimal changes in patient-reported outcomes were observed after stopping treatment. This may be related to pts having a relatively high QOL prior to stopping treatment, given that they had tolerated ≥ 2 years of NIL prior to enrollment. These data suggest that the higher frequency of musculoskeletal pain-related AEs in the TFR phase did not substantially impact pts9 QOL; however, only a subset of pts were evaluable for changes in reported outcomes over time. Although many pts have fears about TFR, reported levels of anxiety/depression were similar before and after stopping treatment but decreased among pts who reinitiated treatment. Disclosures Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Casares:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Stentoft:Pfizer: Research Funding; Ariad: Research Funding; Bristol-Myers-Squibb: Research Funding; Novartis: Research Funding. Conneally:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Garcia-Gutierrez:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gattermann:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding. Wiktor-Jedrzejczak:Sandoz: Consultancy; BMS: Research Funding; Novartis: Consultancy, Research Funding; Janssen-Cilag: Consultancy; Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Amgen Inc.: Research Funding. Le Coutre:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Giles:Novartis: Consultancy, Research Funding. Radich:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy, Research Funding. Ross:BMS: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding. Menssen:Novartis Pharma AG: Employment. Deng:Novartis Phamaceuticals Corp.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Bedoucha:Novartis: Employment. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria.