Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy.
Laboratory of B-cell Neoplasia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy.
Blood. 2022 Dec 1;140(22):2348-2357. doi: 10.1182/blood.2022016901.
Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035.
无法检测到的可测量残留疾病（uMRD）可在接受 BCL2 抑制剂 venetoclax 单药或联合 Bruton 酪氨酸激酶抑制剂 ibrutinib 治疗的慢性淋巴细胞白血病（CLL）患者中实现。这项 2 期、多中心、基于 MRD 的研究旨在在接受 venetoclax 单药或在添加 ibrutinib 后达到 uMRD4（<10-4）的复发/难治性 CLL 患者中停止治疗。该研究的主要终点是 venetoclax ± ibrutinib 的 uMRD4 比例。次要终点是总体缓解率、部分缓解、完全缓解、无进展生存期、缓解持续时间、总生存期和 venetoclax ± ibrutinib 的安全性。在第 12 周期第 1 天达到 uMRD4 的患者停止使用 venetoclax。MRD+患者加用 ibrutinib，并持续使用两种药物直至第 24 周期第 28 天/uMRD4/进展/毒性。第 24 周期第 28 天后，MRD+患者继续使用 ibrutinib。38 例患者（29%有 TP53 异常；79%IGHV 未突变）开始使用 venetoclax。venetoclax 的总体缓解率为 38 例患者中的 36 例（20 例完全缓解；16 例部分缓解）。17 例（45%）患者在第 12 周期第 1 天达到 uMRD4，停止使用 venetoclax。19 例（55%）MRD+患者加用 ibrutinib。在联合治疗中位时间为 7 个月（范围，3-10 个月）后，19 例（84%）患者达到 uMRD4，从而停止使用两种药物。第 24 周期第 28 天的 2 例 MRD+患者因进展/毒性继续使用 ibrutinib。中位随访 36.5 个月后，无进展生存期未达到；10 例患者进展（4 例重新开始使用 venetoclax，3 例无需治疗，2 例发生 Richter 转化，1 例退出）。32 例患者中有 7 例（22%）在 3 年随访后仍保持 uMRD4。中性粒细胞减少症是最常见的 3 级和 4 级不良事件；研究中无 5 级事件发生。这种基于 MRD 的序贯方法使 38 例患者中的 33 例（87%）达到 uMRD4，包括 venetoclax 单药或联合 ibrutinib，仅在一小部分患者中使用治疗联合，并最终确定了少数从持续治疗中获益的患者。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT04754035。
