American Journal of Hematology ( IF 10.1 ) Pub Date : 2024-12-19 , DOI: 10.1002/ajh.27563 Nilanjan Ghosh, Toby A. Eyre, Jennifer R. Brown, Nicole Lamanna, Beenish S. Manzoor, Catherine C. Coombs, Hande H. Tuncer, Chaitra Ujjani, Lori A. Leslie, Lindsey E. Roeker, Matthew S. Davids, Joanna M. Rhodes, Alan P. Skarbnik, Wendy Sinai, Isabelle Fleury, Brian T. Hill, Nicolas Martinez‐Calle, Paul M. Barr, Dureshahwar Jawaid, Nnadozie Emechebe, Laurie Pearson, Frederick Lansigan, Yun Choi, Christopher E. Jensen, Bita Fakhri, Deborah M. Stephens, Steven E. Marx, Stephen J. Schuster, Michael Coyle, Irina Pivneva, Talissa Watson, Annie Guerin, Mazyar Shadman
The treatment landscape of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has evolved drastically with the introduction of targeted agents, including covalent Bruton tyrosine kinase inhibitors (cBTKis) and B-cell lymphoma 2 inhibitors (BCL2is) [1]. However, the development of cBTKi resistance (leading to disease progression) and intolerance due to adverse events limits durable cBTKi efficacy [1].
Venetoclax-based therapy, including fixed-treatment-duration combinations, has demonstrated improved and sustained efficacy and manageable toxicity versus chemotherapy/chemoimmunotherapy (CT/CIT) for patients with previously untreated or relapsed/refractory CLL in phase 3 clinical trials [1]. Because cBTKis were not yet or were just recently approved during patient recruitment for the initial venetoclax landmark clinical trials, there were few patients with previous exposure to cBTKis and, thus, limited evidence supporting venetoclax efficacy in these settings [2].
Although clinical trials like M14-032 have established the clinical benefit of venetoclax after cBTKis, real-world studies report on small subgroups of patients with CLL or patients who received venetoclax primarily in later lines of therapy, following CT/CIT [2-5]. Additionally, there is limited literature evaluating real-world venetoclax outcomes among patients stratified by reasons for cBTKi discontinuation [3], venetoclax-based regimen (particularly, VR combination) [4, 5], or prior CT/CIT exposure. This study assessed real-world clinical outcomes of patients with CLL/SLL, who received venetoclax-based therapy after cBTKi therapy, overall and stratified by line of therapy, prior CT/CIT exposure, discontinuation of cBTKi therapy due to intolerance or disease progression, and for treatment with venetoclax + rituximab (VR).
Data for the current analysis (06/01/2018–12/27/2023) were collected as part of the CLL Collaborative Study of Real-World Evidence (CORE; Supporting Information). Adult patients diagnosed with CLL/SLL were included if they initiated a first-line (1 L) or new line of therapy in a relapsed/refractory setting after 02/12/2014 (US approval date of ibrutinib for CLL/SLL) and if they received a venetoclax-based therapy (i.e., monotherapy or combination therapy with rituximab or obinutuzumab) following discontinuation of a cBTKi-based regimen.
Clinical outcomes assessed following initiation of venetoclax-based therapy included overall response rate (ORR), time to next treatment or death (TTNT-D), and progression-free survival (PFS). Outcomes were assessed for the overall population and stratified by line of therapy (1 L cBTKi➔second-line [2 L] venetoclax; 2 L cBTKi➔third-line [3 L] venetoclax), CT/CIT exposure before cBTKi treatment for 2 L cBTKi➔3 L venetoclax, primary reason for cBTKi discontinuation (either intolerance [DI group] or progression [DP group]), and VR treatment. Additional details are provided in Supporting Information.
Among the 2293 patients in CORE, 205 received venetoclax after cBTKi and were included in the analyses (Figure S1). The median (IQR) age at venetoclax initiation was 68.7 (62.2, 76.4) years and 68.8% were male (Table S1). Of patients with documented genetic characterization, 69.6% (48/69) had unmutated IGHV (DI: 63.0% [17/27], DP: 73.1% [19/26], VR: 69.6% [16/23]) and 24.2% (30/124) had 17p deletion or TP53 mutation (DI: 14.3% [7/49], DP: 34.6% [18/52], VR: 17.4% [8/46]) at venetoclax-based therapy initiation. The most common comorbidities were cardiovascular (46.8%) and endocrine/metabolic (23.4%) conditions. Additional patient characteristics are provided in Supporting Information.
Overall, 123 patients initiated venetoclax monotherapy (60.0%), 64 initiated VR (31.2%), and 18 initiated venetoclax + obinutuzumab (VO; 8.8%; Table S2). Seventy-one patients (34.6%) initiated venetoclax-based therapy in the 2 L (i.e., 1 L cBTKi➔2 L venetoclax group; VR: 31/71 [43.7%]), while 73 (35.6%) did so in the 3 L (i.e., 2 L cBTKi➔3 L venetoclax group; VR: 23/73 [31.5%]); the remaining 61 initiated venetoclax in the fourth line or later. A median (IQR) of 2 (1, 3) prior lines of therapy was received among all patients. The median (IQR) treatment duration with venetoclax was 14.4 (3.9, 28.0) months (monotherapy: 14.1 [3.7, 30.1]; VR: 16.4 [7.17, 28.2], VO: 6.3 [2.6, 16.5]), and 80.0% maintained the same dose through the treatment; only 18.0% of patients required a dose reduction. The median (IQR) follow-up after venetoclax-based therapy initiation was 16.5 (6.0, 30.5) months. Additional treatment characteristics are provided in Supporting Information.
For all patients who initiated venetoclax-based therapy, the median (IQR) treatment duration for the prior cBTKi was 20.2 (8.4, 39.2) months, and the most common reasons for discontinuation included intolerance (42.9%) and disease progression (37.1%, Table S2). The prior cBTKi treatment regimens received included ibrutinib (85.4%), acalabrutinib (6.8%), and ibrutinib + rituximab (2.9%). Among the 73 patients who initiated venetoclax-based therapy as 2 L cBTKi➔3 L venetoclax, 1 L treatment regimens prior to cBTKi included CT/CIT (86.3%), targeted agents (11.0%; i.e., ibrutinib: 6.9%; other: 4.1%), and rituximab (2.7%).
Clinical outcomes are presented in Table 1, Figure S2 (ORR), Figure S3, (PFS), and Figure S4 (TTNT-D).
| Response | PFSa | TTNT-Db | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N | ORRc | N | Median (CI), months | Rate, % | N | Median (CI), months | Rate, % | ||||
| 12 months | 18 months | 12 months | 18 months | ||||||||
| Overall (N = 205) | Overall | 141 | 79.4% | 201 | 44.1 (36.3, NR) | 84.0% | 76.2% | 205 | 44.2 (31.9, NR) | 83.5% | 73.7% |
| 1 L → 2 L | 47 | 85.1% | 70 | 43.2 (39.5, NR) | 87.5% | 80.8% | 71 | NR (31.9, NR) | 86.1% | 73.6% | |
| 2 L → 3 L | 51 | 80.4% | 70 | 44.3 (36.3, NR) | 86.5% | 82.1% | 73 | 44.2 (37.0, NR) | 84.5% | 78.4% | |
| DId (N = 88) | Overall | 60 | 85.0% | 86 | NR | 87.8% | 84.1% | 88 | NR | 84.4% | 79.3% |
| 1 L → 2 L | 22 | 86.4% | 35 | 39.5 (39.5, NR) | 92.7% | 84.1% | 36 | 39.5 (39.5, NR) | 89.7% | 77.5% | |
| 2 L → 3 L | 26 | 88.5% | 32 | NR | 89.0% | 89.0% | 33 | NR | 87.2% | 87.2% | |
| Dpd (N = 76) | Overall | 51 | 76.5% | 74 | 30.1 (22.1, NR) | 82.2% | 71.0% | 76 | 30.4 (26.3, NR) | 86.2% | 75.3% |
| 1 L → 2 L | 10 | 90.0% | 15 | 31.9 (13.2, NR) | 77.8% | 62.2% | 15 | 31.9 (12.5, NR) | 77.8% | 53.3% | |
| 2 L → 3 L | 19 | 68.4% | 28 | 31.8 (22.1, NR) | 82.6% | 73.1% | 30 | 37.4 (26.3, NR) | 84.0% | 75.2% | |
| VR (N = 64) | Overall | 42 | 71.4% | 60 | 39.5 (31.8, NR)e | 86.2% | 77.0% | 64 | 37.4 (31.6, NR)e | 82.3% | 75.7% |
| 1 L → 2 L | 19 | 78.9% | 30 | 43.2 (39.5, NR) | 88.4% | 88.4% | 31 | NR (39.5, NR) | 85.0% | 85.0% | |
| 2 L → 3 L | 15 | 73.3% | 20 | 36.3 (23.7, NR) | 93.8% | 85.9% | 23 | 37.4 (31.6, NR) | 85.9% | 79.8% | |
- Abbreviations: 1 L, first-line; 2 L, second-line; 3 L, third-line; cBTKi, covalent Bruton tyrosine kinase inhibitor; CI, confidence intervals; CR, complete response; CT, computed tomography; DI, discontinuation of prior cBTKi due to intolerance; DP, discontinuation of prior cBTKi due to disease progression; NR, not reached; ORR, overall response rate; PFS, progression-free survival; PR, partial response; TTNT-D, time to next treatment or death; VR, venetoclax + rituximab.
- a PFS was defined as the time from the start of venetoclax-based therapy to disease progression or death (i.e., event). Patients without events were censored at the last date of follow-up; medians and corresponding 95% CIs were estimated using the Kaplan–Meier method. Kaplan–Meier estimates at 12 and 18 months were also reported.
- b TTNT-D was defined as the time from the start of venetoclax-based therapy to alternative treatment or death (i.e., event). Patients without events were censored at the last date of follow-up; medians and corresponding 95% CIs were estimated using the Kaplan–Meier method. Kaplan–Meier estimates at 12 and 18 months were also reported.
- c ORR was measured as the proportion of patients with CR or PR among those with available information on responses in their medical charts based on physician assessment. CR and PR were based on physician-reported information as recorded in the patient charts. Although CT scans and bone marrow biopsies were not mandated to assess response, abstractors were provided with the 2018 International Workshop on Chronic Lymphocytic Leukemia response criteria for reference when completing data collection.
- d Seven patients for whom both intolerance and progression were selected were excluded from the cBTKi discontinuation stratified analyses.
- e The longer median PFS than TTNT-D observed in the VR subgroup may be due to progression events not being systematically reported in the charts for all patients or because progression may not have occurred (in the case of intolerance) prior to initiation of the subsequent treatment in the real-world data.
中文翻译：
Bruton 酪氨酸激酶抑制剂治疗慢性淋巴细胞白血病后基于 Venetoclax 的治疗效果：一项国际真实世界研究
随着靶向药物的引入，包括共价布鲁顿酪氨酸激酶抑制剂 （cBTKis） 和 B 细胞淋巴瘤 2 抑制剂 （BCL2is），慢性淋巴细胞白血病 （CLL）/小淋巴细胞淋巴瘤 （SLL） 的治疗前景发生了巨大变化 [1]。然而，cBTKi 耐药性的发展（导致疾病进展）和不良事件引起的不耐受限制了持久的 cBTKi 疗效 [1]。
3 期临床试验显示，与化疗/化学免疫疗法 （CT/CIT） 相比，基于维奈克拉的疗法（包括固定治疗持续时间的组合）对既往未治疗或复发/难治性 CLL 患者的疗效改善且持续，毒性可控[1]。由于 cBTKis 尚未或最近才在维奈托克初始标志性临床试验的患者招募期间获得批准，因此很少有患者既往暴露于 cBTKis，因此支持维奈托克在这些情况下疗效的证据有限 [2]。
虽然 M14-032 等临床试验已经确定了 cBTKis 后维奈托克的临床获益，但真实世界研究报道了 CT/CIT 后小部分 CLL 患者或主要在后期治疗中接受维奈托克的患者亚组[2-5]。此外，根据 cBTKi 停药原因 [3]、基于维奈克拉的方案（尤其是 VR 联合方案）[4， 5] 或既往 CT/CIT 暴露分层评估患者真实世界维奈托克结局的文献有限。本研究评估了 cBTKi 治疗后接受基于维奈托克的治疗的 CLL/SLL 患者的真实世界临床结果，总体和按治疗线、既往 CT/CIT 暴露、因不耐受或疾病进展而停止 cBTKi 治疗以及维奈托克 + 利妥昔单抗 （VR） 治疗。
当前分析的数据 （06/01/2018–12/27/2023） 是作为 CLL 真实世界证据合作研究 （CORE;支持信息）。诊断为 CLL/SLL 的成年患者如果在 2014 年 2 月 12 日（美国批准伊布替尼用于 CLL/SLL 的日期）之后在复发/难治性环境中开始一线 （1 L） 或新线治疗，并且如果他们在停止基于 cBTKi 的方案后接受基于维奈克拉的治疗（即与利妥昔单抗或 obinutuzumab 的单药治疗或联合治疗）。
开始基于维奈托克的治疗后评估的临床结局包括总缓解率 （ORR） 、下次治疗或死亡时间 （TTNT-D） 和无进展生存期 （PFS）。对总体人群进行评估，并按治疗线 （1 L cBTKi➔二线 [2 L] 维奈托克;2 L cBTKi➔三线 [3 L] 维奈托克）、2 L cBTKi➔3 L 维奈托克 cBTKi 治疗前 CT/CIT 暴露、cBTKi 停药的主要原因 （不耐受 [D 组] 或进展 [D P 组]）和 VR 治疗。支持信息中提供了其他详细信息。
在 CORE 的 2293 名患者中，205 名在 cBTKi 后接受了维奈托克治疗，并被纳入分析（图 S1）。维奈托克开始时的中位 （IQR） 年龄为 68.7 （62.2， 76.4） 岁，其中 68.8% 为男性 （表 S1）。在有遗传学特征记录的患者中，69.6% （48/69） 在基于维奈托克的治疗开始时有未突变的 IGHV （D： 63.0% [17/27]， D P ： 73.1% [19/26]， VR： 69.6% [16/23]）和 24.2% （30/124） 有 17p 缺失或 TP53 突变 （D： 14.3% [7/49]， D P ： 34.6% [18/52]， VR： 17.4% [8/46]）。最常见的合并症是心血管 （46.8%） 和内分泌/代谢 （23.4%） 疾病。支持信息中提供了其他患者特征。
总体而言，123 例患者开始维奈托克单药治疗 （60.0%），64 例开始 VR （31.2%），18 例开始维奈托克 + 奥妥珠单抗治疗 （VO;8.8%;表 S2）。71 例患者 （34.6%） 在 2 L （即 1 L cBTKi➔2 L venetoclax 组;VR：31/71 [43.7%]），而 3 L 组（即 2 L cBTKi➔3 L venetoclax 组）中有 73 例 （35.6%） 这样做;VR：23/73 [31.5%]）;其余 61 例在四线或更晚的治疗中开始使用维奈托克。所有患者接受 2 （1， 3） 线治疗的中位 （IQR）。维奈托克的中位 （IQR） 治疗持续时间为 14.4 （3.9， 28.0） 个月 （单药治疗： 14.1 [3.7， 30.1];VR：16.4 [7.17， 28.2]，VO：6.3 [2.6， 16.5]），80.0% 的患者在治疗期间保持相同的剂量;只有 18.0% 的患者需要减少剂量。基于维奈托克的治疗开始后的中位 （IQR） 随访时间为 16.5 （6.0， 30.5） 个月。支持信息中提供了其他治疗特征。
对于所有开始基于维奈托克的治疗的患者，既往 cBTKi 的中位 （IQR） 治疗持续时间为 20.2 （8.4， 39.2） 个月，最常见的停药原因包括不耐受 （42.9%） 和疾病进展 （37.1%，表 S2）。既往接受的 cBTKi 治疗方案包括依鲁替尼 （85.4%） 、阿卡替尼 （6.8%） 和依鲁替尼 + 利妥昔单抗 （2.9%）。在 73 例开始以 2 L cBTKi➔3 L 维奈托克为基础的维奈托克治疗的患者中，cBTKi 之前的 1 L 治疗方案包括 CT/CIT （86.3%）、靶向药物 （11.0%;即伊布替尼：6.9%;其他：4.1%） 和利妥昔单抗 （2.7%）。
临床结果见表 1、图 S2 （ORR）、图 S3 （PFS） 和图 S4 （TTNT-D）。
| 响应 | PFS （英文） a | TTNT-D b 系列 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 奥尔 c | N | 中位数 （CI），月 | 比率，% | N | 中位数 （CI），月 | 比率，% | ||||
| 12 个月 | 18 个月 | 12 个月 | 18 个月 | ||||||||
| 总 （n = 205） | 整体 | 141 | 79.4% | 201 | 44.1 （36.3， NR） | 84.0% | 76.2% | 205 | 44.2 （31.9， NR） | 83.5% | 73.7% |
| 1 升 → 2 升 | 47 | 85.1% | 70 | 43.2 （39.5， NR） | 87.5% | 80.8% | 71 | NR （31.9， NR） | 86.1% | 73.6% | |
| 2 升 → 3 升 | 51 | 80.4% | 70 | 44.3 （36.3， NR） | 86.5% | 82.1% | 73 | 44.2 （37.0， NR） | 84.5% | 78.4% | |
| D d （N = 88） | 整体 | 60 | 85.0% | 86 | NR | 87.8% | 84.1% | 88 | NR | 84.4% | 79.3% |
| 1 升 → 2 升 | 22 | 86.4% | 35 | 39.5 （39.5， 降噪） | 92.7% | 84.1% | 36 | 39.5 （39.5， 降噪） | 89.7% | 77.5% | |
| 2 升 → 3 升 | 26 | 88.5% | 32 | NR | 89.0% | 89.0% | 33 | NR | 87.2% | 87.2% | |
D p d （N = 76） |
整体 | 51 | 76.5% | 74 | 30.1 （22.1， NR） | 82.2% | 71.0% | 76 | 30.4 （26.3， NR） | 86.2% | 75.3% |
| 1 升 → 2 升 | 10 | 90.0% | 15 | 31.9 （13.2， NR） | 77.8% | 62.2% | 15 | 31.9 （12.5， NR） | 77.8% | 53.3% | |
| 2 升 → 3 升 | 19 | 68.4% | 28 | 31.8 （22.1， NR） | 82.6% | 73.1% | 30 | 37.4 （26.3， NR） | 84.0% | 75.2% | |
| 虚拟现实 （N = 64） | 整体 | 42 | 71.4% | 60 | 39.5 （31.8， NR） e |
86.2% | 77.0% | 64 | 37.4 （31.6， NR） e |
82.3% | 75.7% |
| 1 升 → 2 升 | 19 | 78.9% | 30 | 43.2 （39.5， NR） | 88.4% | 88.4% | 31 | NR （39.5， NR） | 85.0% | 85.0% | |
| 2 升 → 3 升 | 15 | 73.3% | 20 | 36.3 （23.7， NR） | 93.8% | 85.9% | 23 | 37.4 （31.6， NR） | 85.9% | 79.8% | |
缩写：1 L，一线;2 L，二线治疗;3 L，三线;cBTKi，共价布鲁顿酪氨酸激酶抑制剂;CI，置信区间;CR，完全缓解;CT，计算机断层扫描;D，由于不耐受而停用先前的 cBTKi;D P ，由于疾病进展而停用先前的 cBTKi;NR，未到达;ORR，总体缓解率;PFS，无进展生存期;PR，部分反应;TTNT-D，下次治疗或死亡的时间;VR、维奈托克 + 利妥昔单抗。
PFS 定义为从基于维奈托克的治疗开始到疾病进展或死亡（即事件）的时间。无事件的患者在最后一次随访时被删失;使用 Kaplan-Meier 方法估计中位数和相应的 95% CI。还报告了 12 个月和 18 个月的 Kaplan-Meier 估计值。
b TTNT-D 定义为从基于维奈托克的治疗开始到替代治疗或死亡 （即事件） 的时间。无事件的患者在最后一次随访时被删失;使用 Kaplan-Meier 方法估计中位数和相应的 95% CI。还报告了 12 个月和 18 个月的 Kaplan-Meier 估计值。
c ORR 测量为根据医生评估，在病历中拥有可用反应信息的患者中，CR 或 PR 患者的比例。CR 和 PR 基于患者图表中记录的医生报告信息。虽然 CT 扫描和骨髓活检没有被强制要求来评估反应，但在完成数据收集时，为摘要作者提供了 2018 年慢性淋巴细胞白血病国际研讨会反应标准以供参考。
d 从 cBTKi 停药分层分析中排除了 7 例不耐受和进展的患者。
e 在 VR 亚组中观察到的中位 PFS 长于 TTNT-D，这可能是由于图表中没有系统地报告所有患者的疾病进展事件，或者因为在真实世界数据中，在后续治疗开始之前可能没有发生进展（在不耐受的情况下）。
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