The efficacy of venetoclax in chronic lymphocytic leukemia (CLL) is well established.^1-3 Venetoclax is approved with a 5-week dose ramp-up schedule to mitigate risk of tumor lysis syndrome (TLS); dosing is increased weekly according to a schedule of 20 mg, 50 mg, 100 mg, 200 mg, reaching a target dose of 400 mg daily in Week 5 per United States prescribing information.

Although this standard 5-week ramp-up is appropriate for most patients with CLL, rapid disease control is needed for some patients with very aggressive disease. While many such patients respond to venetoclax treatment it remains critical, especially for those who progress on B-cell receptor pathway inhibitor (BCRi) therapies such as ibrutinib, to rapidly achieve a therapeutically-relevant dose of venetoclax.⁴ Thus, certain patients with CLL might benefit from expedited venetoclax ramp-up, per National Comprehensive Cancer Network Clinical Practice Guidelines.

Limited data are available on strategies for more rapid escalation of venetoclax in CLL.⁵ We report the first multicenter study to characterize the safety and feasibility of an accelerated venetoclax ramp-up schedule in patients with rapid progression of relapsed/refractory (R/R) CLL.

This retrospective chart review was conducted across four large academic medical centers in the United States from 2019 to 2020. Patients with R/R CLL who had received prior treatment and had a documented accelerated venetoclax ramp-up period (<5 weeks) were retrospectively identified from medical charts. The study period began 1 month before ramp-up initiation and continued until 1 month after ramp-up completion. The primary endpoint was the proportion of patients with Grade ≥3 adverse events (AEs) during ramp-up, chosen to capture a comprehensive safety profile of venetoclax in this setting. Further details are provided in Appendix S1.

Twenty-eight patients were identified and included in the analysis (Table S1). Seven patients (25.0%) had an absolute lymphocyte count (ALC) of ≥ 100 × 10⁹ cells/L (median 27.5; range 0.03–2160), and 7 patients (25.0%) had lymph node involvement > 5 cm. Median creatinine clearance was 84.0 mL/min (range 51.0–136.3).

Patients had a median of 3 prior lines of CLL therapy (range 1–7; Table S1). Last line of therapy was discontinued before venetoclax ramp-up in 25 patients (89.3%). One patient discontinued last line of therapy during ramp-up. Two other patients (7.1%) discontinued their last line of therapy once the stable dose of venetoclax was reached. Among these three patients who did not discontinue prior therapy before venetoclax initiation, two patients (7.1%) were receiving ibrutinib and one patient (3.6%) was receiving idelalisib.

Nine patients (32.1%) experienced Grade ≥ 3 AEs (primary endpoint; Table S2), including anemia (n = 5; 17.9%), neutropenia (n = 2; 7.1%), thrombocytopenia (n = 1; 3.6%), and febrile neutropenia (n = 1; 3.6%). Additional Grade ≥ 3 AEs included hyperkalemia (n = 2; 7.1%), hypocalcemia (n = 2; 7.1%), hypovolemic shock (n = 2; 7.1%), lymphopenia (n = 2; 7.1%), cardiovascular insufficiency (n = 1; 3.6%), and hypophosphatemia (n = 1; 3.6%). Three patients (10.7%) discontinued venetoclax due to AEs; two did not reach a stable dose and one patient discontinued after 12 days of ramp-up and a maximum dose of 200 mg (Table S3).

The venetoclax ramp-up schedules initiated are described in Table S4. All patients received antihyperuricemic drugs during ramp-up, and all but one patient (96.4%) received intravenous hydration. The majority of the patients (n = 15, 53.6%) had a ramp-up period of between 3 and < 5 weeks (Table S5). Twenty-six patients (92.9%) reached a stable dose of venetoclax; of these, 20 patients (71.4%) reached the target dose of 400 mg. The median time to reach any stable dose of venetoclax was 21 days (range 11–25) and was also 21 days (range 18–25) for the 20 patients who reached a stable dose of 400 mg. All patients underwent accelerated ramp-up as inpatients, with median hospital stay of 11 days (range 4–28) overall (Table S4). Timing of hospital admission varied, with 18 patients (64.3%) admitted 1–5 days before ramp-up initiation; 9 (32.1%) admitted on the day of initiation, and 1 (3.6%) admitted 1 day after initiation.

At least one AE of TLS was experienced by seven patients (25.0%; Table 1), including five cases of laboratory TLS (17.9%) and two cases of clinical TLS (7.1%). Two additional patients (7.1%) experienced metabolic abnormalities (hyperuricemia, hypocalcemia, and acute kidney disease) that did not meet the Howard Criteria for laboratory TLS per investigator assessment. Of the seven patients who developed TLS (at doses ranging between 20 and 200 mg), six had event onset within the first week of ramp-up; one had onset in the second week of ramp-up. Three of five patients (10.7% of all patients) who experienced a single AE of laboratory TLS did not receive any interventions because the TLS was self-limited with ongoing hydration and TLS prophylaxis.

Of the two patients (7.1%; Table 1) who developed clinical TLS, one was assessed as being at high risk of TLS at baseline, and experienced increased creatinine levels following venetoclax initiation (20 mg dose); the patient received aggressive hydration and close laboratory monitoring, with creatinine returning to baseline within 24 h. Venetoclax was escalated to 50 mg, and the patient then experienced grade 4 acute kidney injury, hyperphosphatemia, and hyperkalemia. The other patient, assessed as being at medium risk of TLS at baseline, experienced hyperphosphatemia, hypocalcemia, and hyperkalemia, 1 day after initiation of venetoclax monotherapy; hyperuricemia 2 days after initiation; and acute kidney injury 3 days after the single initial dose of 20 mg. Both patients required interventions (Table 1) administered in an intensive care unit but did not require hemodialysis. All AEs of TLS (including clinical events) resolved without long-term clinical sequelae.

Between-group comparisons of patients who developed TLS (n = 7, 25.0%) versus patients who did not (n = 21, 75.0%) reveal that none of the baseline patient characteristics analyzed (including ALC and lymph node size) were significantly associated with subsequent risk of TLS. None of the genetic features analyzed, number of prior lines of therapy (≤3 or >3), type of prior line of therapy (BCRis, chemoimmunotherapy, or other), or timing of discontinuation of prior therapy (during/after ramp-up or prior to venetoclax initiation) were found to be associated with the development of TLS.

In this multicenter, retrospective chart review study, 32.1% of patients with R/R CLL treated with accelerated venetoclax ramp-up experienced an AE of Grade ≥3 (primary endpoint), and 10.7% of patients discontinued venetoclax during the treatment period due to AEs. Rates of discontinuation due to AEs were similar to those observed in an integrated safety analysis of three phase 1/2 studies of venetoclax monotherapy (10.0%), although the study period here was shorter.⁶ The median time to reach the approved dose of venetoclax 400 mg was substantially shorter at 21 days than the 35 days per the standard ramp-up schedule. While TLS was observed in one-quarter of patients, all TLS events were manageable and recovered without clinical sequelae. This high rate of observed TLS could be explained in part by the patient selection, which was enriched for high risk of TLS. These confirmatory findings will help to inform future changes in dose ramp-up for patients that require more urgent treatment.

Our data indicate that patients with R/R CLL requiring rapid disease control could receive a more rapid dose acceleration if they receive appropriate inpatient monitoring and administration of adequate prophylactic hydration and antihyperuricemics to reduce risk of TLS. Clinical decision-making should balance the possible increased risk of TLS with the risk of rapid progression of CLL. The rates of laboratory and clinical TLS noted in our cohort were higher than those associated with the approved 5-week ramp-up schedule (range 0%–2.6% laboratory TLS and 0%–0.5% clinical TLS) but lower than rates reported from other studies of accelerated ramp-up schedules (range up to 52% laboratory TLS and up to 15% clinical TLS).^{1-3, 5}

Our report describes a select group of patients who were assessed to be at higher risk of rapid disease progression following discontinuation of BCRi therapy; therefore, patient selection may have affected the results. Additional limitations include the heterogeneity of the venetoclax ramp-up schedule used in our patients due to the real-world nature of the study, the challenge of comparing to other studies that did not use Howard Criteria for TLS, and our relatively small sample size.

Overall, with close inpatient monitoring, accelerated venetoclax ramp-up was feasible in a population of patients with aggressive R/R CLL. Although TLS was observed in a higher proportion of patients than is commonly reported with standard ramp-up, all cases were manageable and did not result in long-term clinical sequelae. Thus, accelerated venetoclax ramp-up may benefit patients with aggressive CLL, particularly those progressing on/after BCRi therapy, or patients who would find a shorter ramp-up schedule performed in the inpatient setting more convenient than the standard 5-week ramp-up in the outpatient setting. As all of the patients in our study were treated at experienced academic centers with close inpatient monitoring, we do not believe that our data can be extrapolated outside of this setting. A prospective clinical trial of accelerated venetoclax ramp-up in CLL is now underway (NCT04843904) to validate the findings of our retrospective study.

venetoclax 在慢性淋巴细胞白血病 (CLL) 中的疗效已得到充分证实。^1-3 Venetoclax 获批 5 周剂量递增计划，以降低肿瘤溶解综合征 (TLS) 的风险；根据美国处方信息，每周增加 20 毫克、50 毫克、100 毫克、200 毫克的剂量，在第 5 周达到每天 400 毫克的目标剂量。

虽然这个标准的 5 周加速治疗适用于大多数 CLL 患者，但对于一些非常侵袭性疾病的患者，需要快速控制疾病。尽管许多此类患者对 venetoclax 治疗有反应，但它仍然至关重要，特别是对于那些在 ibrutinib 等 B 细胞受体途径抑制剂 (BCRi) 疗法上取得进展的患者，以快速达到治疗相关剂量的 venetoclax。⁴因此，根据国家综合癌症网络临床实践指南，某些 CLL 患者可能会受益于加快 venetoclax 的增加。

有限的数据可用于在 CLL 中更快速升级 venetoclax 的策略。⁵我们报告了第一项多中心研究，以描述在快速进展的复发/难治性 (R/R) CLL 患者中加速 venetoclax 加速计划的安全性和可行性。

这项回顾性图表审查是在 2019 年至 2020 年期间在美国的四个大型学术医疗中心进行的。回顾性确定了接受过先前治疗并有记录的加速 venetoclax 加速期（<5 周）的 R/R CLL 患者从医学图表。研究期从加速开始前 1 个月开始，一直持续到加速完成后 1 个月。主要终点是在加速阶段发生 ≥ 3 级不良事件 (AE) 的患者比例，选择用于在这种情况下获取 venetoclax 的全面安全性概况。附录 S1 提供了更多详细信息。

确定了 28 名患者并将其纳入分析（表 S1）。7 名患者 (25.0%) 的绝对淋巴细胞计数 (ALC) ≥ 100 × 10 ^{9 个}细胞/L（中位数 27.5；范围 0.03-2160），7 名患者（25.0%）的淋巴结受累> 5 cm。中位肌酐清除率为 84.0 mL/min（范围 51.0–136.3）。

患者之前接受过 3 线 CLL 治疗的中位数（范围 1-7；表 S1）。在 25 名患者 (89.3%) 中，在 venetoclax 升级前停止了最后一线治疗。一名患者在加速期间停止了最后一线治疗。一旦达到venetoclax的稳定剂量，另外两名患者（7.1%）就停止了最后一线治疗。在 venetoclax 开始前未停止先前治疗的这三名患者中，两名患者 (7.1%) 正在接受依鲁替尼，一名患者 (3.6%) 正在接受 idelalisib。

9 名患者 (32.1%) 出现 ≥ 3 级 AE（主要终点；表 S2），包括贫血（n  = 5；17.9%）、中性粒细胞减少症（n  = 2；7.1%）、血小板减少症（n  = 1；3.6%）、和发热性中性粒细胞减少症（n  = 1；3.6%）。其他 ≥ 3 级 AE 包括高钾血症（n  = 2；7.1%）、低钙血症（n  = 2；7.1%）、低血容量性休克（n  = 2；7.1%）、淋巴细胞减少症（n  = 2；7.1%）、心血管功能不全（n  = 1；3.6%）和低磷血症（n = 1; 3.6%）。3 名患者 (10.7%) 因 AE 停用维奈托克；两名患者未达到稳定剂量，一名患者在增加 12 天后停药，最大剂量为 200 毫克（表 S3）。

表 S4 中描述了启动的 venetoclax 加速计划。所有患者在加速期间都接受了抗高尿酸血症药物，除一名患者（96.4%）外，所有患者都接受了静脉补液。大多数患者（n = 15, 53.6%）的加速期为 3 至 < 5 周（表 S5）。26 名患者 (92.9%) 达到了稳定剂量的维奈托克；其中，20 名患者（71.4%）达到了 400 mg 的目标剂量。达到任何稳定剂量 venetoclax 的中位时间为 21 天（范围 11-25），对于达到 400 mg 稳定剂量的 20 名患者也是 21 天（范围 18-25）。所有患者在住院期间都经历了加速提升，总体中位住院时间为 11 天（范围 4-28 天）（表 S4）。入院时间各不相同，18 名患者 (64.3%) 入院时间为加速开始前 1-5 天；9 人 (32.1%) 入院当天入院，1 人 (3.6%) 入院后 1 天入院。

7 名患者（25.0%；表 1）至少经历了 1 次 TLS AE，其中包括 5 例实验室 TLS（17.9%）和 2 例临床 TLS（7.1%）。另外两名患者 (7.1%) 出现代谢异常（高尿酸血症、低钙血症和急性肾病），这些异常不符合研究者评估的实验室 TLS 霍华德标准。在发生 TLS 的 7 名患者中（剂量范围在 20 和 200 mg 之间），有 6 名患者在增加的第一周内发生了事件；一个在加速的第二周开始发作。经历过实验室 TLS 单次 AE 的 5 名患者中有 3 名（占所有患者的 10.7%）未接受任何干预，因为 TLS 是自限性的，持续补水和 TLS 预防。

在发生临床 TLS 的两名患者（7.1%；表 1）中，一名在基线时被评估为 TLS 高风险，并且在开始使用 venetoclax（20 mg 剂量）后肌酐水平升高；患者接受了积极的水合作用和密切的实验室监测，肌酐在 24 小时内恢复到基线水平。Venetoclax 增加至 50 mg，患者随后出现 4 级急性肾损伤、高磷血症和高钾血症。另一名患者在基线时被评估为 TLS 中等风险，在开始 venetoclax 单药治疗后 1 天出现高磷血症、低钙血症和高钾血症；开始后 2 天出现高尿酸血症；单次初始剂量 20 mg 后 3 天出现急性肾损伤。两名患者都需要在重症监护病房进行干预（表 1），但不需要进行血液透析。TLS 的所有 AE（包括临床事件）均已解决，没有长期临床后遗症。

发生 TLS 的患者（n  = 7, 25.0%）与未发生 TLS 的患者（n  = 21, 75.0%）的组间比较显示，所分析的基线患者特征（包括 ALC 和淋巴结大小）均无显着相关性随后有 TLS 的风险。未分析任何遗传特征、先前治疗线的数量（≤3 或 >3）、先前治疗线的类型（BCris、化学免疫疗法或其他）或停止先前治疗的时间（在加速期间/之后或在开始使用 venetoclax 之前）被发现与 TLS 的发展有关。

在这项多中心、回顾性图表审查研究中，32.1% 的 R/R CLL 患者接受加速 venetoclax 加速治疗后出现 ≥ 3 级的 AE（主要终点），10.7% 的患者在治疗期间因以下原因停止使用 venetoclax不良事件。因 AE 导致的停药率与对 venetoclax 单药治疗的三项 1/2 期研究的综合安全性分析中观察到的相似（10.0%），尽管此处的研究时间较短。⁶达到批准剂量的 venetoclax 400 mg 的中位时间在 21 天时明显短于标准加速计划的 35 天。虽然在四分之一的患者中观察到 TLS，但所有 TLS 事件都是可控的并且可以恢复，没有临床后遗症。观察到的这种高 TLS 发生率可以部分由患者选择来解释，这丰富了 TLS 的高风险。这些确认性发现将有助于为需要更紧急治疗的患者提供未来剂量增加的变化。

我们的数据表明，需要快速疾病控制的 R/R CLL 患者如果接受适当的住院监测并给予足够的预防性补液和抗高尿酸药物以降低 TLS 的风险，则可以更快地接受剂量加速。临床决策应平衡可能增加的 TLS 风险与 CLL 快速进展的风险。在我们的队列中注意到的实验室和临床 TLS 的发生率高于与批准的 5 周加速计划相关的那些（范围 0%–2.6% 实验室 TLS 和 0%–0.5% 临床 TLS），但低于报告的比率其他关于加速加速计划的研究（范围高达 52% 的实验室 TLS 和高达 15% 的临床 TLS）。^{1-3, 5}

我们的报告描述了一组被评估为在停止 BCRi 治疗后疾病快速进展风险较高的患者；因此，患者的选择可能会影响结果。其他限制包括由于研究的真实世界性质，我们的患者使用的 venetoclax 加速计划的异质性，与未使用霍华德标准 TLS 的其他研究进行比较的挑战，以及我们相对较小的样本量。

总体而言，通过密切的住院监测，在患有侵袭性 R/R CLL 的患者群体中加速 venetoclax 增加是可行的。尽管 TLS 在患者中观察到的比例高于标准增加时通常报告的比例，但所有病例都是可控的，并且不会导致长期临床后遗症。因此，加速 venetoclax 加速升级可能会使侵袭性 CLL 患者受益，尤其是那些在 BCRi 治疗期间/之后进展的患者，或者会发现在住院环境中进行更短的加速升级计划比标准 5 周加速升级更方便的患者在门诊环境中。由于我们研究中的所有患者都在经验丰富的学术中心接受了密切的住院监护，因此我们认为我们的数据不能在此设置之外进行推断。