Chronic myelomonocytic leukemia (CMML) is a clonal myeloid disorder characterized by peripheral blood (PB) monocytosis (absolute monocyte count (AMC) ≥ 1 × 10⁹/L and ≥ 10% of the total white blood cell count (WBC) and features overlapping with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms.¹ Blast transformation (BT) is associated with high mortality in CMML (median survival < 6 months).^{2, 3} Hypomethylating agents (HMA) are thus far the only U.S. Food and Drug Administration (FDA) approved therapies for CMML, largely based on the inclusion of a limited number of predominantly dysplastic CMML patients in MDS centered trials.⁴ The prospective DACOTA trial was the first to randomize higher risk proliferative CMML patients to decitabine versus hydroxyurea and showed no differences in overall survival (OS) and event-free survival (EFS).⁵ Based on the results of phase II and III studies of HMA/low-dose cytarabine (LDAC) and venetoclax, a novel bcl-2 inhibitor, these combination therapies have been approved by the U.S. FDA for the management of elderly or medically unfit patients with acute myeloid leukemia (AML).^{6, 7} While these combinations were associated with a median OS of 15 months in AML, based on preclinical data, these were not anticipated to be effective in CMML given the disease dependence on MCL-1 and the presence of factors shown to lead to resistance in AML, including monocytosis and oncogenic RAS-pathway mutations.⁸

A recent retrospective study using venetoclax based regimens documented an overall response rate (ORR) of 67% in CMML and 81% in CMML-BT patients.⁹ The median duration of response was reported to be 4.0 months for both the CMML and CMML-BT groups.⁹ In an attempt to add to the clinical literature, we conducted this study to describe the characteristics and outcomes of patients with CMML and CMML-BT who received venetoclax-based regimens at our institution.

After institutional review board approval, we retrospectively reviewed our enterprise-wide institutional database (Arizona, Florida and Minnesota) for patients with CMML and CMML-BT who had received at least one cycle of venetoclax-based combination therapy, with a HMA (azacitidine or decitabine) or LDAC between April 2017 to April 2021. Both CMML and CMML-BT were defined per the World Health Organization (WHO) 2016 criteria.¹ Our study excluded patients with de novo acute myelomonocytic leukemia or AML with myelodysplasia-related changes (AML-MRC) without an antecedent history of CMML. All patients underwent bone marrow (BM) aspiration and biopsy with morphology, reticulin staining, cytogenetics, and molecular genetics at diagnosis.¹⁰ Categorical variables were compared by Fisher exact test. Continuous variables were compared by Wilcoxon test. The OS was defined as the time from venetoclax-based therapy to death from any cause. For CMML-BT, complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial remission (PR), and morphologic leukemia-free state (MLFS) were defined according to the 2017 European LeukemiaNet criteria.¹¹ For CMML, response was defined according to the MDS/MPN International Working Group 2015 criteria.¹² Overall response rate (ORR) included (i) CR, CRi, PR, and MLFS for CMML-BT and (ii) CR, marrow CR (mCR), and PR for CMML. And, OS was estimated by the Kaplan–Meier method.

We identified 20 patients, median age 74 years (range, 39–83 years), 25% female, who met inclusion criteria for (i) diagnosis of CMML or CMML-BT and (ii) treatment with at least one cycle of venetoclax-based combination therapy. Six (30%) patients had CMML (all CMML-2) and 14 (70%) had CMML-BT at initiation of venetoclax-based therapy. Baseline characteristics are described in Figure 1A. Median age at first diagnosis of CMML was 71 years (39–81 years). Median time from diagnosis of CMML to initiation of venetoclax-based treatment was 19 months (range: 0–80) and median time from CMML diagnosis to CMML-BT was 13 months (range: 1–71). Fifty percent and 57.1% of patients had proliferative disease at CMML diagnosis in the CMML and CMML-BT cohorts, respectively. Fifty percent of CMML and 57.1% of CMML-BT patients had a normal karyotype, with trisomy 8 being the most common abnormality identified in 50.0% of CMML and 21.4% of CMML-BT patients. The frequency of somatic mutations prior to venetoclax-based therapy is shown in Figure 1A, with the most common somatic mutations being TET2 (nine patients, 47.4%), SRSF2 (nine patients, 47.4%), and ASXL1 (eight patients, 42.1%). Three (50.0%) of six CMML and 10 (71.4%) of 14 CMML-BT patients had received at least one prior line of therapy, with seven (50.0%) CMML-BT patients and three (50.0%) CMML patients having received prior HMA. Two (33.3%) CMML and four (28.6%) CMML-BT patients had received ≥ 2 lines of leukemia-directed therapies (Table S1).

Patients received a median of 2.5 cycles of venetoclax-based therapy (range: 1–37), with the venetoclax being administered on days 1–28 for each cycle. The ORR was 42.9% for the CMML-BT group [two (14.3%) CR, three (21.4%) CRi, one (7.1%) MLFS] after a median of 1.5 cycles (range: 1–2) of therapy and 50.0% for the CMML group (three mCR) after a median of two cycles (range: 1–5) of therapy. One (16.7%) patient with CMML and two (14.3%) patients with CMML-BT were successfully bridged to allogeneic hematopoietic stem cell transplantation (SCT). The patient with CMML experienced prolonged remission for 13 months (ongoing at the time of data analysis) while those with CMML-BT died of graft-versus-host disease related complications and unknown causes, respectively. Cumulative RAS pathway mutations (NRAS, KRAS, CBL, and PTPN11) did not appear to be associated with response or lack of response in CMML (33.3% in responders vs. 50.0% in non-responders) or CMML-BT (50.0% in responders vs. 37.5% in non-responders). Specifically, KRAS mutations were detected in one (33.3%; p.D33E) responding patient with CMML (vs. none in non-responders) and in three (50.0%; including p.G13D and p.V14I) responding patients with CMML-BT (vs. 12.5% in non-responders; p.G12R). Thirteen (65.0%; four with CMML and nine with CMML-BT) patients died from disease relapse. At last follow-up (median 7.2 months), median OS was estimated at 8.1 months for the combined cohort, 5.8 months for the CMML-BT group, and 13.8 months for the CMML group (Figure 1B). In this series, the adverse event profile was similar to previously reported AML-clinical trial data with venetoclax-based combination regimens. The treatment-emergent adverse events (graded per the Common Terminology Criteria for Adverse Events, version 5.0) included cytopenias (with 100.0% experiencing at least one grade 3–4 cytopenia including neutropenia, anemia, and/or thrombocytopenia), grade 3 neutropenic fever (15.0%), grade 3–4 heart failure (10.0%), grade 3–4 sepsis (10.0%), grade 2–3 COVID-19 respiratory infection (10.0%), grade 3 tumor lysis syndrome (10.0%; venetoclax was adequately ramped up in both patients, while one patient did have hyperleukocytosis with a white blood cell count of 97 × 10³/μL at the time of bone marrow assessment and 240 × 10³/μL at the time of presentation, he did receive pretreatment with one session of leukapheresis and hydroxyurea, and HMA with venetoclax therapy was initiated when the white blood cell count was 19 × 10³/μL), grade 2 neutropenic enterocolitis (5.0%), grade 3 pneumonia (5.0%), grade 2 intracranial hemorrhage (5.0%), and bilateral retinal hemorrhage (5.0%), with seven (35.0%) patients requiring at least one hospital admission while on venetoclax-based therapy (median:1, range: 1–3).

Our manuscript focuses on the benefit derived from venetoclax-based therapies in CMML and AML arising from antecedent CMML. In our series of 20 patients with CMML and CMML-BT, ORR with venetoclax-based therapies (50.0% for CMML and 42.9% for CMML-BT) was lower than what has been recently reported in the literature (67.0% in CMML and 81.0% in CMML-BT), with CR rates of 10.0%.⁹ While this combination has certainly improved outcomes in AML patients ineligible for induction chemotherapy, its role in CMML and CMML-BT needs to be better defined.⁷ The ORR of 50.0% in CMML (33.3% in patients previously treated with HMA) is fairly similar to response rates seen with HMA alone (40%–50%), raising questions regarding the efficacy of venetoclax in monocytic neoplasms. The ORR in CMML-BT (42.9% in the BT subgroup and 42.9% in patients previously treated wih HMA) was also similar to those seen in blast phase MPN (42.0%), where OS was similar with HMA monotherapy versus the combination of HMA and venetoclax.^{13, 14} The limitations of our study include its retrospective design, small sample size, lack of longitudinal genomic data, and lack of measurable residual disease data. The smaller patient numbers could potentially explain why RAS mutations were not predictive of response/resistance. While off-label use of venetoclax-based therapies in CMML and CMML-BT can be considered in the absence of other approved therapies, especially as a bridge to allogenic SCT in eligible patients, randomized prospective clinical trials are clearly needed to assess for efficacy and durability of responses.

慢性粒单核细胞白血病（CMML）是一种克隆性髓系疾病，其特征是外周血（PB）单核细胞增多症（绝对单核细胞计数（AMC）≥1×10 ⁹ /L，占总白细胞计数（WBC）≥10%），并具有重叠与骨髓增生异常综合征 (MDS) 和骨髓增殖性肿瘤^。1爆炸转化 (BT) 与 CMML 的高死亡率有关（中位生存期 < 6 个月）^{。2, 3}低甲基化剂 (HMA) 是迄今为止唯一的美国食品和药物管理局（ FDA) 批准了 CMML 疗法，主要是基于在以 MDS 为中心的试验中纳入了数量有限的主要发育不良的 CMML 患者^4。前瞻性 DACOTA 试验是第一个将高风险增殖性 CMML 患者随机分配到地西他滨与羟基脲组的试验，并且显示总生存期 (OS) 和无事件生存期 (EFS) 没有差异。⁵基于 HMA/低剂量阿糖胞苷 (LDAC) 和 venetoclax（一种新型 bcl-2 抑制剂）的 II 期和 III 期研究结果，这些联合疗法已被美国 FDA 批准用于管理老年或医学上不适合的患者与急性髓细胞白血病 (AML)。^6、7虽然这些组合与 AML 的中位 OS 为 15 个月相关，但根据临床前数据，鉴于疾病对 MCL-1 的依赖性以及存在导致 AML 耐药的因素，预计这些组合在 CMML 中无效，包括单核细胞增多症和致癌 RAS 通路突变。⁸

最近使用基于 venetoclax 的方案进行的一项回顾性研究记录了 CMML 和 CMML-BT 患者的总缓解率 (ORR) 为 67% 和 81%。⁹据报道，CMML 和 CMML-BT 组的中位反应持续时间均为 4.0 个月。⁹为了补充临床文献，我们进行了这项研究，以描述在我们机构接受基于 venetoclax 方案的 CMML 和 CMML-BT 患者的特征和结果。

在机构审查委员会批准后，我们​​回顾性地审查了我们的企业范围机构数据库（亚利桑那州、佛罗里达州和明尼苏达州），这些数据库中的 CMML 和 CMML-BT 患者已接受至少一个周期的基于 venetoclax 的联合疗法和 HMA（阿扎胞苷或地西他滨）或 LDAC 于 2017 年 4 月至 2021 年 4 月之间。 CMML 和 CMML-BT 均根据世界卫生组织 (WHO) 2016 年标准进行定义。¹我们的研究排除了新发急性粒单核细胞白血病或伴有骨髓增生异常相关变化 (AML-MRC) 的 AML 患者，而这些患者之前没有 CMML 病史。所有患者在诊断时都接受了骨髓 (BM) 抽吸和活检，包括形态学、网状蛋白染色、细胞遗传学和分子遗传学。¹⁰通过Fisher精确检验比较分类变量。通过 Wilcoxon 检验比较连续变量。OS 定义为从基于 venetoclax 的治疗到任何原因死亡的时间。对于 CMML-BT，完全缓解（CR）、完全缓解伴有不完全血液学恢复（CRi）、部分缓解（PR）和形态学无白血病状态（MLFS）是根据 2017 年欧洲白血病网标准定义的。¹¹对于 CMML，响应是根据 MDS/MPN 国际工作组 2015 标准定义的。¹²总体缓解率 (ORR) 包括 (i) CMML-BT 的 CR、CRi、PR 和 MLFS 和 (ii) CMML 的 CR、骨髓 CR (mCR) 和 PR。并且，OS 是通过 Kaplan-Meier 方法估计的。

我们确定了 20 名患者，中位年龄为 74 岁（范围，39-83 岁），25% 为女性，符合以下纳入标准：(i) CMML 或 CMML-BT 的诊断和 (ii) 至少一个周期的维奈托克-为基础的联合治疗。在基于 venetoclax 的治疗开始时，6 名 (30%) 患者患有 CMML（均为 CMML-2），14 名（70%）患者患有 CMML-BT。图 1A 描述了基线特征。CMML 首次诊断时的中位年龄为 71 岁（39-81 岁）。从 CMML 诊断到开始基于 venetoclax 的治疗的中位时间为 19 个月（范围：0-80），从 CMML 诊断到 CMML-BT 的中位时间为 13 个月（范围：1-71）。在 CMML 和 CMML-BT 队列中，分别有 50% 和 57.1% 的患者在 CMML 诊断时患有增殖性疾病。50% 的 CMML 和 57.1% 的 CMML-BT 患者核型正常，在 50.0% 的 CMML 和 21.4% 的 CMML-BT 患者中，8 三体是最常见的异常。在基于 venetoclax 的治疗之前的体细胞突变频率如图 1A 所示，最常见的体细胞突变是TET2（9 名患者，47.4%）、SRSF2（9 名患者，47.4%）和ASXL1（8 名患者，42.1%）。6 名 CMML 患者中的 3 名 (50.0%) 和 14 名 CMML-BT 患者中的 10 名 (71.4%) 接受过至少一种既往治疗，其中 7 名 (50.0%) CMML-BT 患者和 3 名 (50.0%) CMML 患者接受过之前的 HMA。两名 (33.3%) CMML 和四名 (28.6%) CMML-BT 患者接受了 ≥ 2 线白血病靶向治疗（表 S1）。

患者接受了中位数为 2.5 个基于维奈托克的治疗周期（范围：1-37），维奈托克在每个周期的第 1-28 天给药。CMML-BT 组的 ORR 为 42.9% [两个 (14.3%) CR，三个 (21.4%) CRi，一个 (7.1%) MLFS] 在中位 1.5 个治疗周期（范围：1-2）和 50.0中位两个周期（范围：1-5）治疗后 CMML 组（三个 mCR）的百分比。一名 (16.7%) CMML 患者和两名 (14.3%) CMML-BT 患者成功桥接异基因造血干细胞移植 (SCT)。CMML 患者经历了长达 13 个月的长期缓解（数据分析时仍在进行），而 CMML-BT 患者分别死于移植物抗宿主病相关并发症和不明原因。累积RAS通路突变 ( NRAS、KRAS、CBL和PTPN11 ) 似乎与 CMML（应答者 33.3% vs. 无应答者 50.0%）或 CMML-BT（应答者 50.0% vs. 37.5%）的应答或无应答相关无反应者）。具体来说，KRAS在一名（33.3%；p.D33E）有反应的 CMML 患者（与无反应者中没有）和三名（50.0%；包括 p.G13D 和 p.V14I）有反应的 CMML-BT 患者（相对于无反应者）检测到突变. 12.5% 在无反应者中；p.G12R)。13 名（65.0%；4 名患有 CMML，9 名患有 CMML-BT）患者死于疾病复发。在最后一次随访时（中位 7.2 个月），联合队列的中位 OS 估计为 8.1 个月，CMML-BT 组为 5.8 个月，CMML 组为 13.8 个月（图 1B）。在该系列中，不良事件概况与先前报告的基于维奈托克联合方案的 AML 临床试验数据相似。治疗中出现的不良事件（按照不良事件通用术语标准，5.0 版分级）包括血细胞减少症（100.³ /μL在骨髓评估的时间和240×10 ³，在演示的时候/μL，他确实收到了预处理与白细胞分离和羟基的一个会议，并HMA与venetoclax开始治疗时白细胞计数为19 × 10 ³ /μL)、2 级中性粒细胞减少性小肠结肠炎 (5.0%)、3 级肺炎 (5.0%)、2 级颅内出血 (5.0%) 和双侧视网膜出血 (5.0%)，其中 7 名 (35.0%) 患者需要在接受基于 venetoclax 的治疗期间至少入院一次（中位数：1，范围：1-3）。

我们的手稿侧重于基于 venetoclax 的疗法在 CMML 和 AML 中由先行 CMML 引起的益处。在我们的 20 名 CMML 和 CMML-BT 患者系列中，基于维奈托克的治疗的 ORR（CMML 为 50.0%，CMML-BT 为 42.9%）低于最近文献报道的结果（CMML 为 67.0% 和 81.0 % 在 CMML-BT)，CR 率为 10.0%。⁹虽然这种组合确实改善了不适合诱导化疗的 AML 患者的结果，但需要更好地定义其在 CMML 和 CMML-BT 中的作用。⁷CMML 的 ORR 为 50.0%（先前接受过 HMA 治疗的患者为 33.3%）与单独使用 HMA 的反应率（40%–50%）非常相似，这引发了关于 venetoclax 在单核细胞肿瘤中的疗效的问题。CMML-BT 的 ORR（BT 亚组为 42.9%，之前接受过 HMA 治疗的患者为 42.9%）也与急变期 MPN 中的 ORR（42.0%）相似，其中 HMA 单药治疗与 HMA 联合治疗的 OS 相似和维奈托克。^{13, 14}我们研究的局限性包括其回顾性设计、样本量小、缺乏纵向基因组数据以及缺乏可测量的残留疾病数据。较小的患者数量可能解释了为什么RAS突变不能预测反应/抗性。虽然在没有其他批准的疗法的情况下可以考虑在 CMML 和 CMML-BT 中使用基于维奈托克的疗法的标签外使用，特别是作为合格患者同种异体 SCT 的桥梁，但显然需要随机前瞻性临床试验来评估疗效和响应的持久性。