Based on results from the randomized, placebo-controlled phase 3 VIALE-A (NCT02993523) and VIALE-C (NCT03069352) trials,^1-4 venetoclax in combination with hypomethylating agents or low-dose cytarabine (LDAC) has become standard of care in patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Cytopenias are common adverse events with venetoclax and are primarily managed with protocol-mandated dose modifications, including dose interruptions and cycle delays.^{2, 5} Neutropenia and febrile neutropenia may be mitigated with granulocyte-colony stimulating factor (G-CSF)^{4, 6}; however, limited evidence exists on G-CSF use and impact on safety and efficacy in patients receiving low-intensity therapies. The present analysis assessed outcomes by G-CSF use post-remission (i.e., following blast clearance) among patients with newly diagnosed, intensive-chemotherapy–ineligible AML who received venetoclax-azacitidine or venetoclax-LDAC in the VIALE-A and VIALE-C trials, respectively.

VIALE-A and VIALE-C study designs have been previously described.^{1, 3} Both trials enrolled patients aged ≥18 years with newly diagnosed AML who were ineligible for induction chemotherapy (aged ≥75 years or with comorbid conditions precluding intensive chemotherapy treatment). In VIALE-A, patients received venetoclax-azacitidine or placebo-azacitidine; in VIALE-C, patients received venetoclax-LDAC or placebo-LDAC. Both trial protocols allowed G-CSF use with administration for cytopenia management as per institutional practice. In this exploratory post hoc analysis, patients treated with venetoclax combinations who had achieved a best response of complete remission (CR)/CR with incomplete hematologic recovery (CRi) were assessed for outcomes by G-CSF use, including overall survival (OS), duration of CR/CRi (DOR), and safety. G-CSF use was analyzed from the time of remission achievement (post-remission), defined as blast clearance (<5% bone marrow blasts) for this analysis. Clinical data cutoff was December 1, 2021 for VIALE-A and February 15, 2021 for VIALE-C.^{2, 3} The analysis populations included patients who achieved best response of CR/CRi, unless otherwise specified.^{1, 3} Data presentation is descriptive in nature, and formal statistical comparisons were not performed due to the post hoc nature of this analysis. Additional details are in the Data S1.

Approximately half of patients treated with venetoclax combinations in VIALE-A and VIALE-C received G-CSF post-remission. In VIALE-A, 50% (95/191) of CR/CRi responders in the venetoclax-azacitidine arm and 26% (11/42) in the placebo-azacitidine arm received G-CSF post-remission (Tables S1 and S2). In VIALE-C, 46% (32/69) of CR/CRi responders in the venetoclax-LDAC arm and 22% (2/9) in the placebo-LDAC arm received G-CSF post-remission (Tables S3 and S4). In both trials, baseline characteristics, including baseline grade ≥3 neutropenia, were generally similar between patients who received G-CSF and those who did not (Tables S5 and S6). In VIALE-A, the median time to first G-CSF use after remission was 36 days (range, 2–483) in the venetoclax-azacitidine arm, and 45/95 patients (47%) received G-CSF in ≥50% of treatment cycles; similar results were observed in the placebo arm (Table S2). Patients received concomitant G-CSF for a median of five treatment cycles in both arms (Table S2). Time to G-CSF use and treatment cycles for VIALE-C are in Table S3.

In the venetoclax-azacitidine arm of VIALE-A, 89% of CR/CRi responders who received G-CSF and 83% of those who did not had ≥1 occurrence of grade 4 neutropenia (defined as a laboratory value of ANC <500/μL) after remission (Table S7). The median time to neutrophil count recovery (absolute neutrophil count ≥500/μL) from onset of grade 4 neutropenia was similar in the venetoclax arm regardless of G-CSF use (14 days [IQR, 8–22] in patients who received G-CSF; 14 days [IQR, 8.5–30.5] in those who did not). Similarly, most patients in the placebo-azacitidine arm (73% of those who received G-CSF; 55% of those who did not) had ≥1 occurrence of grade 4 neutropenia after remission. The median time to neutrophil count recovery from first post-remission grade 4 neutropenia was shorter with G-CSF use (12 days [IQR, 10.5–21.5] in patients who received G-CSF; 21 days [IQR, 13–39] in those who did not). Nadir and median neutrophil counts per treatment cycle among patients who achieved CR/CRi and received G-CSF in the venetoclax-azacitidine arm of the VIALE-A trial generally increased with each cycle (Figure S1). Similar trends were observed in VIALE-C (Table S8 and Figure S2).

In the venetoclax-azacitidine arm of VIALE-A, grade ≥3 neutropenia occurred in 34% (32/95) of patients receiving G-CSF versus 28% (27/96) not receiving G-CSF (median duration, 16.0 vs. 15.5 days post-remission; Tables S9 and S10). Grade ≥3 febrile neutropenia occurred in 44% (42/95) of patients receiving G-CSF versus 21% (20/96) of patients not receiving G-CSF (median duration, 8.5 vs. 9.5 days). Grade ≥3 infections occurred in 62 patients (65%) who received G-CSF and 47 patients (49%) who did not. Selected grade ≥3 treatment-emergent adverse events and durations among CR/CRi responders are summarized in Tables S9 and S10 for VIALE-A and Tables S11 and S12 for VIALE-C. A clear impact of G-CSF use on incidence or duration of febrile neutropenia was not observed, which may be confounded by more frequent G-CSF use in patients experiencing neutropenia.

Among CR/CRi responders treated with venetoclax-azacitidine in VIALE-A, the median DOR was 25.5 months (95% CI, 18.1–32.4) for those receiving G-CSF and 12.8 months (95% CI, 7.9–18.0) for those not receiving G-CSF (Figure 1A, Table S13). In the placebo-azacitidine arm, the median DOR was 15.1 months (95% CI, 8.5–25.0) for patients receiving G-CSF and 6.7 months (95% CI, 3.5–13.5) for those not receiving G-CSF. The median OS was 30.8 months (95% CI, 24.4–38.8) for CR/CRi responders in the venetoclax-azacitidine arm receiving G-CSF versus 21.1 months (95% CI, 15.8–27.3) for those not receiving G-CSF (Figure 1B, Table S13). In the placebo-azacitidine arm, the median OS was 25.0 months (95% CI, 15.4–39.4) for CR/CRi responders receiving G-CSF versus 15.2 months (95% CI, 10.6–27.5) for those not receiving G-CSF. Similar outcomes were observed in VIALE-C (Figure S3, Table S14).

In both trials, patients who received venetoclax and achieved MRD response (<10⁻³) appeared more likely to receive G-CSF. In VIALE-A, among CR/CRi responders in the venetoclax-azacitidine arm who received G-CSF, 51% (41/80) achieved an MRD response, whereas 49% (39/80) did not. Among patients who did not receive G-CSF, 33% (28/85) achieved an MRD response, whereas 67% (57/85) did not (Table S15). This may partially explain the numerically higher OS and DOR observed in patients who received G-CSF. The median OS among patients with MRD response in the venetoclax-azacitidine arm was 38.8 months (95% CI, 28.8-not estimable) for patients who received G-CSF and 29.3 months (95% CI, 21.1–40.1) for those who did not. Among patients who did not achieve MRD response, the median OS was 22.9 months (95% CI, 12.7–36.3) for patients who received G-CSF and 15.2 months (95% CI, 11.2–21.8) for those who did not. The placebo-azacitidine arm showed similar trends. VIALE-C results are in Table S16.

In the venetoclax-azacitidine arm of VIALE-A, the median venetoclax dosing duration was 21 days (IQR, 21–28) per cycle among all CR/CRi responders, irrespective of G-CSF use (Table S17, Figure S4). Among all CR/CRi responders, the median duration of end-of-cycle dose holds (defined as reduced venetoclax duration per cycle plus delay of next cycle) was 12 days (IQR, 7–18) versus 14 (IQR, 7–21) days in patients with versus without G-CSF use, respectively (Table S17, Figure S4). The median time from day 1 of one cycle to day 1 of the next cycle was 32 days (IQR, 28–38) for those receiving G-CSF and 35 days (IQR, 28–42) for those who did not. The median duration of end-of-cycle dose holds in CR/CRi responders was 10 days (IQR, 7–15) in those who frequently received G-CSF (≥50% of cycles) versus 13 days (IQR, 7–20) in those who received G-CSF in <50% of cycles. The median time from the start of one cycle to the start of the next cycle was 30 days (IQR, 28–36) in responders with frequent G-CSF use versus 33 days (IQR, 28–38) in patients receiving G-CSF in <50% of cycles. Shorter delays between treatment cycles were also observed in long-term CR/CRi responders who received ≥6 cycles of venetoclax-azacitidine (Table S17). VIALE-C results are in Figure S4 and Table S18.

In this exploratory analysis of the VIALE-A and VIALE-C trials, post-remission G-CSF use was not associated with new safety signals and had no negative impact on DOR or OS among venetoclax-treated patients. Delays between treatment cycles were shorter in patients who received post-remission G-CSF. While G-CSF itself is unlikely to provide direct anti-leukemic benefits, the ability to maintain treatment cycles with shorter delays may translate into benefit for patients. Limitations of this analysis include small patient numbers and administration of G-CSF as per institutional practice rather than protocol-mandated, potentially leading to heterogeneous G-CSF use. Although VIALE-A and VIALE-C studies were not designed to evaluate the impact of G-CSF on cytopenia management, this post hoc analysis supports the use of G-CSF in addition to recommended dose modifications for management of cytopenias in patients with intensive-chemotherapy–ineligible AML who receive venetoclax-based therapy.

根据随机、安慰剂对照的 3 期 VIALE-A （NCT02993523） 和 VIALE-C （NCT03069352） 试验的结果，^1-4 维奈托克联合低甲基化药物或低剂量阿糖胞苷 （LDAC） 已成为不适合强化化疗的新诊断急性髓性白血病 （AML） 患者的标准治疗。血细胞减少是维奈托克的常见不良事件，主要通过方案规定的剂量调整进行管理，包括剂量中断和周期延迟。^2、5粒细胞集落刺激因子 （G-CSF） 可缓解中性粒细胞减少症和发热性中性粒细胞减少症^{4， 6};然而，关于 G-CSF 的使用以及对接受低强度治疗的患者的安全性和有效性的影响的证据有限。本分析分别在 VIALE-A 和 VIALE-C 试验中评估了接受维奈托克-阿扎胞苷或维奈托克-LDAC 的新诊断、强化化疗不合格 AML 患者缓解后（即快速清除后）G-CSF 使用的结果。

VIALE-A 和 VIALE-C 研究设计之前已经描述过。^1、3两项试验均招募了年龄≥18岁但不适合诱导化疗的新诊断AML患者（年龄≥75岁或患有无法接受强化化疗的合并症）。在 VIALE-A 中，患者接受维奈托克-阿扎胞苷或安慰剂-阿扎胞苷;在 VIALE-C 中，患者接受维奈托克-LDAC 或安慰剂-LDAC。两种试验方案都允许根据机构实践将 G-CSF 与血细胞减少症管理一起使用。在这项探索性事后分析中，接受维奈托克联合治疗的患者达到完全缓解 （CR）/CR 但不完全血液学恢复 （CRi） 的最佳反应，通过 G-CSF 使用评估结局，包括总生存期 （OS） 、CR/CRi 持续时间 （DOR） 和安全性。从达到缓解的时间（缓解后）开始分析 G-CSF 的使用，定义为原始细胞清除率 （<5% 骨髓原始细胞） 用于此分析。VIALE-A 的临床数据截止日期为 2021 年 12 月 1 日，VIALE-C 的临床数据截止日期为 2021 年 2 月 15 日。^2、3除非另有说明，否则分析人群包括达到 CR/CRi 最佳反应的患者。^1、3数据呈现本质上是描述性的，由于该分析的事后性质，未进行正式的统计比较。其他详细信息位于数据 S1 中。

在 VIALE-A 和 VIALE-C 中接受维奈托克联合治疗的患者中，约有一半接受了缓解后的 G-CSF。在 VIALE-A 中，维奈托克-阿扎胞苷组 50% （95/191） 的 CR/CRi 应答者和安慰剂-阿扎胞苷组 26% （11/42） 的 CR/CRi 应答者在缓解后接受了 G-CSF（表 S1 和 S2）。在 VIALE-C 中，维奈托克-LDAC 组 46% （32/69） 的 CR/CRi 应答者和安慰剂-LDAC 组 22% （2/9） 的 CR/CRi 应答者接受了缓解后的 G-CSF（表 S3 和 S4）。在这两项试验中，接受 G-CSF 的患者和未接受 G-CSF 的患者之间的基线特征，包括基线 ≥3 级中性粒细胞减少症）通常相似（表 S5 和 S6）。在 VIALE-A 中，维奈托克-阿扎胞苷组缓解后首次使用 G-CSF 的中位时间为 36 天 （范围，2-483），45/95 名患者 （47%） 在 ≥50% 的治疗周期中接受了 G-CSF;在安慰剂组中观察到类似的结果（表 S2）。患者同时接受 G-CSF，双组中位治疗周期为 5 个（表 S2）。VIALE-C 的 G-CSF 使用时间和治疗周期见表 S3。

在 VIALE-A 的维奈托克-阿扎胞苷组中，89% 接受 G-CSF 的 CR/CRi 应答者和 83% 的未出现 ≥4 级中性粒细胞减少症（定义为 ANC <500/μL 的实验室值）缓解后出现 4 级中性粒细胞减少症（定义为 ANC <500/μL 的实验室值）（表 S7）。无论 G-CSF 使用如何，维奈托克组从 4 级中性粒细胞减少症发作到中性粒细胞计数恢复（中性粒细胞绝对计数 ≥500/μL）的中位时间相似（接受 G-CSF 的患者为 14 天 [IQR，8-22];未接受 G-CSF 的患者为 14 天 [IQR，8.5-30.5]）。同样，安慰剂-阿扎胞苷组的大多数患者（73% 的接受 G-CSF 的患者;55% 的未接受 G-CSF 的患者）在缓解后出现 ≥1 级 4 级中性粒细胞减少症。使用 G-CSF 后首次缓解后 4 级中性粒细胞计数恢复的中位时间较短（接受 G-CSF 的患者为 12 天 [IQR，10.5-21.5];未接受 G-CSF 的患者为 21 天 [IQR，13-39]）。在 VIALE-A 试验的维奈托克-阿扎胞苷组中，达到 CR/CRi 并接受 G-CSF 的患者每个治疗周期的最低点和中位中性粒细胞计数通常随着每个周期的增加而增加（图 S1）。在 VIALE-C 中观察到类似的趋势（表 S8 和图 S2）。

在 VIALE-A 的维奈托克-阿扎胞苷组中，34% （32/95） 接受 G-CSF 的患者发生 ≥3 级中性粒细胞减少症，而未接受 G-CSF 的患者为 28% （27/96）（中位持续时间，缓解后 16.0 天 vs. 15.5 天;表 S9 和 S10）。44% （42/95） 接受 G-CSF 的患者发生 ≥3 级发热性中性粒细胞减少症，而未接受 G-CSF 的患者为 21% （20/96） （中位持续时间为 8.5 天对 9.5 天）。62 例接受 G-CSF 的患者 （65%） 和 47 例未接受 G-CSF 的患者 （49%） 发生 ≥ 级感染。VIALE-A 的表 S9 和 S10 以及 VIALE-C 的表 S11 和 S12 总结了 CR/CRi 反应者中选定的 ≥3 级治疗中出现的不良事件和持续时间。未观察到 G-CSF 使用对中性粒细胞减少性发热发生率或持续时间的明显影响，这可能与中性粒细胞减少症患者更频繁地使用 G-CSF 相混淆。

在 VIALE-A 中接受维奈托克-阿扎胞苷治疗的 CR/CRi 反应者中，接受 G-CSF 的患者中位 DOR 为 25.5 个月（95% CI，18.1-32.4），未接受 G-CSF 的患者为 12.8 个月（95% CI，7.9-18.0）（图 1A，表 S13）。在安慰剂-阿扎胞苷组中，接受 G-CSF 的患者的中位 DOR 为 15.1 个月（95% CI，8.5-25.0），未接受 G-CSF 的患者为 6.7 个月（95% CI，3.5-13.5）。接受 G-CSF 的维奈托克-阿扎胞苷组 CR/CRi 反应者的中位 OS 为 30.8 个月 （95% CI，24.4-38.8），而未接受 G-CSF 的患者为 21.1 个月 （95% CI，15.8-27.3） （图 1B，表 S13）。在安慰剂-阿扎胞苷组中，接受 G-CSF 的 CR/CRi 反应者的中位 OS 为 25.0 个月 （95% CI，15.4-39.4），而未接受 G-CSF 的 CR/CRi 反应者为 15.2 个月 （95% CI，10.6-27.5）。在 VIALE-C 中观察到类似的结果（图 S3，表 S14）。

在这两项试验中，接受维奈托克并达到 MRD 反应 （%^3C10-3） 的患者似乎更有可能接受 G-CSF。在 VIALE-A 中，在接受 G-CSF 的维奈托克-阿扎胞苷组的 CR/CRi 反应者中，51% （41/80） 达到 MRD 反应，而 49% （39/80） 没有。在未接受 G-CSF 的患者中，33% （28/85） 达到 MRD 反应，而 67% （57/85） 未达到 MRD 反应（表 S15）。这可能部分解释了在接受 G-CSF 的患者中观察到的数值较高的 OS 和 DOR。维奈托克-阿扎胞苷组有 MRD 反应的患者的中位 OS 对于接受 G-CSF 的患者为 38.8 个月 （95% CI，28.8-不可估计），对于未接受 G-CSF 的患者，中位 OS 为 29.3 个月 （95% CI，21.1-40.1）。在未达到 MRD 反应的患者中，接受 G-CSF 的患者的中位 OS 为 22.9 个月 （95% CI，12.7-36.3），未接受 G-CSF 的患者为 15.2 个月 （95% CI，11.2-21.8）。安慰剂-阿扎胞苷组显示出类似的趋势。VIALE-C 结果见表 S16。

在 VIALE-A 的维奈托克-阿扎胞苷组中，所有 CR/CRi 反应者的中位维奈托克给药持续时间为每个周期 21 天 （IQR，21-28），无论 G-CSF 的使用如何（表 S17，图 S4）。在所有 CR/CRi 反应者中，周期结束剂量暂留的中位持续时间（定义为每个周期的维奈托克持续时间减少加上下一个周期的延迟）分别为 12 天 （IQR，7-18） 与使用 G-CSF 的患者 14 天 （IQR，7-21） 天（表 S17，图 S4）。接受 G-CSF 的患者从一个周期的第 1 天到下一个周期的第 1 天的中位时间为 32 天 （IQR， 28-38），未接受 G-CSF 的患者为 35 天 （IQR， 28-42）。CR/CRi 反应者周期末剂量暂停的中位持续时间为经常接受 G-CSF 的患者 （≥50% 的周期） 为 10 天 （IQR， 7-15），而接受 G-CSF 的患者为 13 天 （IQR， 7-20） <50% 的周期。在频繁使用 G-CSF 的反应者中，从一个周期开始到下一个周期开始的中位时间为 30 天 （IQR， 28-36），而接受 G-CSF 的患者为 33 天 （IQR， 28-38），周期为 <50%。在接受 ≥6 个周期的维奈托克-阿扎胞苷治疗的长期 CR/CRi 反应者中也观察到治疗周期之间的延迟较短（表 S17）。VIALE-C 结果如图 S4 和表 S18 所示。

在对 VIALE-A 和 VIALE-C 试验的探索性分析中，缓解后 G-CSF 的使用与新的安全信号无关，并且对维奈托克治疗患者的 DOR 或 OS 没有负面影响。在接受缓解后 G-CSF 的患者中，治疗周期之间的延迟更短。虽然 G-CSF 本身不太可能提供直接的抗白血病益处，但以更短的延迟维持治疗周期的能力可能会转化为对患者的益处。该分析的局限性包括患者数量少和根据机构实践而不是协议强制使用 G-CSF，这可能导致 G-CSF 使用的异质性。尽管 VIALE-A 和 VIALE-C 研究并非旨在评估 G-CSF 对血细胞减少症管理的影响，但这项事后分析支持使用 G-CSF 以及推荐的剂量调整来管理接受维奈克拉治疗的强化化疗不合格的 AML 患者的血细胞减少症。