Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) that is highly effective in treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL).¹ It has potent activity against BCR::ABL1, including the highly-resistant T315I mutation.¹ Despite this, ponatinib's use has been limited by the risk of cardiovascular (CV) events, including venous thromboembolism (VTE) and arterial occlusive events (AOE).² The rate of CV events in clinical trials ranged 25%–50%, with the highest risk in the first 12 months of therapy and in patients with cardiovascular risk factors.^{3, 4}

Given the risk of CV events with ponatinib, use of cardioprotective medications including aspirin and HMG-CoA reductase inhibitors (statins) has become an important consideration. Additionally, attenuated ponatinib dosing has been used to mitigate toxicity. Data has shown a reduction from 45 mg (FDA-approved starting dose) to 15 mg was associated with an approximately 33% reduction in the risk of a CV event.⁴ Furthermore, the recent phase II OPTIC trial has demonstrated an optimal risk-benefit in CML patients who started ponatinib at 45 mg daily and reduced to 15 mg upon achievement of response.⁵ Available literature on ponatinib-associated CV events has limited generalizability due to heterogeneous patient populations, and reporting in real-life patient cohorts is rare. We, therefore, aimed to determine the incidence of AOE and VTE in a real-life CML and Ph-ALL population receiving ponatinib-based therapy.

We retrospectively collected data on a single-center cohort of patients ≥18 years old with CML or Ph-ALL treated with ponatinib-based therapy between March 2016 and April 2020. VTE was defined as pulmonary embolism (PE) or deep vein thrombosis; peripherally inserted central catheter-associated events were excluded. AOE was defined as myocardial infarction (MI), unstable angina, stroke, or transient ischemic attack. High-risk of a CV event was defined as ≥2 risk factors (Table 1 footnote), and low-risk was defined as ≤1 based on prior literature and guidelines.^{3, 4} Cardioprotective medications included aspirin and statins. The incidence of VTE and AOE was assessed as the primary endpoint. The incidence of major or minor bleeding and time to first CV event were secondary endpoints. Exposure-adjusted CV event rate was calculated as the number of CV events divided by the total treatment exposure time. For patients with events, the exposure time was the time from the first dose to event onset.

A total of 165 patients with a median age of 48 years (range, 20–89 years) and diagnosis of Ph-ALL (61%) or CML (39%) were included for analysis (Table 1). Most CML patients were in the blast phase (58%). Among Ph-ALL patients, 26% initiated ponatinib at 45 mg, 63% at 30 mg, and 11% at 15 mg. For CML patients, 14% started therapy at 45 mg, 63% at 30 mg, and 22% at 15 mg. Overall, the mean ponatinib daily dose was 25 mg (range, 7.5–45 mg) and the median time on therapy was 219 days (range, 4–536 days). Most patients received ponatinib as first-line (30%) or second-line therapy (30%). Most patients used ponatinib in combination with high-intensity therapy (41%) such as the Hyper-CVAD regimen or low-intensity therapy (35%) such as blinatumomab. The median number of CV risk factors was 1 (range 0–9) and most patients (82%) had ≥1. During ponatinib therapy, 32% of patients were taking a statin and 29% were taking aspirin.

The overall incidence of CV events in our study population was 10% (n = 16). The incidence of VTE and AOE was 7% (n = 11) and 3% (n = 5), respectively. The exposure-adjusted VTE rate was 11.4% and the exposure-adjusted AOE rate was 5.2%. VTEs consisted of 10 DVTs and 1 PE. AOEs consisted of 2 MIs and 3 strokes. The incidence of CV events in patients categorized as low-risk was 7% compared to 11% for high-risk. The AOE incidence was 1% for low-risk and 5% for high-risk patients. The incidence of CV events in CML patients was 11% compared to 9% in Ph-ALL patients. In the CML cohort, the CV event incidence was 22% in patients who started ponatinib at 45 mg, 10% at 30 mg, and 7% at 15 mg. For Ph-ALL patients, the CV event incidence was 15% in patients starting at 45 mg and 8% at 30 mg (none for 15 mg). Patients who experienced a CV event had a higher mean daily dose than those who did not (29 vs. 25 mg) and were on therapy for a shorter duration (195 vs. 221 days). The CV event incidence was 8% in patients who were dose-reduced versus 10% in those who were not. There were five minor bleeding events (none in patients receiving aspirin) and no major bleeding events. Median time to CV event was 95 days (range 24–319) for VTE and 312 days (range 112–543) for AOE. Median survival was 1.5 years for patients who experienced a CV event and 2.3 years for those who did not.

Of the 5 patients who experienced an AOE, 2 started ponatinib at 45 mg, 2 at 30 mg, and 1 at 15 mg. At the time of AOE, 4 patients were on 30 mg and 1 on 15 mg. Only one patient (Ph-ALL) was receiving ponatinib as part of a high-intensity regimen, and 3 patients (all CML) were using it as 4th line therapy or beyond. Four of 5 patients who had an AOE were classified as high-risk for a CV event. Their most common risk factors were hypertension, tobacco use, obesity, and hyperlipidemia. No event-related death occurred.

The AOE incidence of 3% seen in our cohort of leukemia patients receiving ponatinib is lower than reported in the literature. Results of the PACE trial showed a 14% cumulative incidence of grade 3–4 AOE in CML and Ph-ALL patients on ponatinib with a starting dose of 45 mg.⁴ The OPTIC trial, in which CML patients were evenly assigned to starting doses of 45, 30, and 15 mg, reports a 5% incidence of grade 3–4 AOE.⁵ Like the OPTIC trial, we found an increased incidence of AOE at higher starting doses of ponatinib. Our lower incidence of AOE may be related to a larger portion of patients starting on lower doses, with a median starting dose of 30 mg (Table 1).

We also demonstrated a higher incidence of AOE in high-risk versus low-risk patients. Patients with ≥2 cardiovascular risk factors had a 5% AOE incidence compared to 1% in low-risk patients. The PACE trial similarly found patients with ≥2 risk factors had the highest risk for AOE occurrence.⁴ Lastly, the median time to AOE (10.2 months) in our patient population is similar to the PACE trial which showed a median onset of 13.4 months.⁴

Ponatinib is reserved for patients who fail therapy with at least two TKIs or harbor a T315I mutation; its frontline use has been hampered by cardiotoxicity. However, dose optimization and risk reduction strategies may expand the use of this effective therapy, as was demonstrated in a study combining ponatinib with high-intensity chemotherapy for Ph-ALL.⁶ We present a real-life cohort of patients with a lower incidence of CV events on ponatinib therapy, likely owing to reduced doses and the use of cardioprotective medications. Limitations of this study include its single-centered, retrospective design and inability to account for all confounding factors.

In conclusion, the CV event incidence of 10% and AOE incidence of 3% reported in our real-life cohort of leukemia patients taking ponatinib were lower than prior reports. Given the considerable risk of thrombosis, dose optimization and preventative strategies should be considered as part of the management of patients on ponatinib.

Ponatinib 是第三代 BCR::ABL1 酪氨酸激酶抑制剂 (TKI)，对治疗慢性粒细胞白血病 (CML) 和费城染色体阳性急性淋巴细胞白血病 (Ph-ALL) 非常有效。¹它对 BCR::ABL1 具有强大的活性，包括高度耐药的 T315I 突变。¹尽管如此，普纳替尼的使用受到心血管 (CV) 事件风险的限制，包括静脉血栓栓塞 (VTE) 和动脉闭塞事件 (AOE)。²临床试验中的 CV 事件发生率为 25%–50%，在治疗的前 12 个月和有心血管危险因素的患者中风险最高。^{3, 4}

考虑到普纳替尼的心血管事件风险，使用包括阿司匹林和 HMG-CoA 还原酶抑制剂（他汀类药物）在内的心脏保护药物已成为一个重要的考虑因素。此外，已使用减毒的普纳替尼剂量来减轻毒性。数据显示，从 45 毫克（FDA 批准的起始剂量）减少到 15 毫克与心血管事件风险降低约 33% 相关。⁴此外，最近的 II 期 OPTIC 试验表明，在 CML 患者中，普纳替尼的起始剂量为每天 45 毫克，并在达到反应后减至 15 毫克，可带来最佳的风险收益。^5个由于不同的患者人群，关于普纳替尼相关 CV 事件的现有文献的普遍性有限，并且在现实生活中的患者队列中的报告很少。因此，我们旨在确定接受基于普纳替尼治疗的现实生活中 CML 和 Ph-ALL 人群中 AOE 和 VTE 的发生率。

我们回顾性地收集了 2016 年 3 月至 2020 年 4 月期间接受基于普纳替尼治疗的≥18 岁 CML 或 Ph-ALL 患者单中心队列的数据。VTE 被定义为肺栓塞 (PE) 或深静脉血栓形成；外周插入中心导管相关事件被排除在外。AOE 被定义为心肌梗塞 (MI)、不稳定型心绞痛、中风或短暂性脑缺血发作。根据先前的文献和指南，CV 事件的高风险定义为 ≥ 2 个风险因素（表 1 脚注），低风险定义为 ≤ 1。^{3, 4}心脏保护药物包括阿司匹林和他汀类药物。VTE 和 AOE 的发生率被评估为主要终点。大出血或小出血的发生率以及首次 CV 事件的发生时间是次要终点。暴露调整后的 CV 事件率计算为 CV 事件数除以总治疗暴露时间。对于发生事件的患者，暴露时间是从第一次给药到事件发生的时间。

共有 165 名中位年龄为 48 岁（范围 20-89 岁）且诊断为 Ph-ALL (61%) 或 CML (39%) 的患者被纳入分析（表 1）。大多数 CML 患者处于母细胞期 (58%)。在 Ph-ALL 患者中，26% 的患者以 45 mg、63% 的 30 mg 和 11% 的 15 mg 开始普纳替尼。对于 CML 患者，14% 的患者以 45 mg 开始治疗，63% 的患者以 30 mg 开始治疗，22% 的患者以 15 mg 开始治疗。总体而言，普纳替尼的平均日剂量为 25 毫克（范围，7.5-45 毫克），中位治疗时间为 219 天（范围，4-536 天）。大多数患者接受普纳替尼作为一线 (30%) 或二线治疗 (30%)。大多数患者使用普纳替尼联合高强度治疗 (41%)，例如 Hyper-CVAD 方案或低强度治疗 (35%)，例如博纳吐单抗。CV 危险因素的中位数为 1（范围 0–9），大多数患者 (82%) ≥ 1。

在我们的研究人群中，CV 事件的总体发生率为 10% ( n  = 16)。VTE 和 AOE 的发生率分别为 7% ( n  = 11) 和 3% ( n = 5), 分别。暴露调整后的 VTE 率为 11.4%，暴露调整后的 AOE 率为 5.2%。VTE 包括 10 个 DVT 和 1 个 PE。AOE 包括 2 次 MI 和 3 次中风。归类为低风险的患者的心血管事件发生率为 7%，而归类为高风险的患者为 11%。低风险患者的 AOE 发生率为 1%，高风险患者为 5%。CML 患者的 CV 事件发生率为 11%，而 Ph-ALL 患者为 9%。在 CML 队列中，开始使用普纳替尼 45 mg 的患者的 CV 事件发生率为 22%，30 mg 为 10%，15 mg 为 7%。对于 Ph-ALL 患者，CV 事件发生率在 45 mg 开始的患者中为 15%，在 30 mg 时为 8%（15 mg 时无）。经历过 CV 事件的患者的平均每日剂量高于未经历过 CV 事件的患者（29 对 25 mg），并且接受治疗的持续时间较短（195 对 221 天​​）。CV 事件发生率在剂量减少的患者中为 8%，而在没有剂量减少的患者中为 10%。有 5 起轻微出血事件（接受阿司匹林的患者无一例发生），没有发生大出血事件。VTE 至 CV 事件的中位时间为 95 天（范围 24-319），AOE 为 312 天（范围 112-543）。经历过 CV 事件的患者的中位生存期为 1.5 年，而没有经历过 CV 事件的患者的中位生存期为 2.3 年。

在发生 AOE 的 5 名患者中，2 名开始服用 45 mg 普纳替尼，2 名开始服用 30 mg，1 名开始服用 15 mg。在 AOE 时，4 名患者服用 30 mg，1 名患者服用 15 mg。只有一名患者（Ph-ALL）接受普纳替尼作为高强度治疗方案的一部分，而 3 名患者（均为 CML）将其用作四线治疗或以上。发生 AOE 的 5 名患者中有 4 名被归类为发生 CV 事件的高风险。他们最常见的危险因素是高血压、吸烟、肥胖和高脂血症。没有发生与事件相关的死亡。

在接受普纳替尼治疗的白血病患者队列中，AOE 发生率为 3%，低于文献报道的水平。PACE 试验的结果显示，在接受起始剂量为 45 mg 的普纳替尼治疗的 CML 和 Ph-ALL 患者中，3-4 级 AOE 的累积发生率为 14%。⁴ OPTIC 试验报告了 5% 的 3-4 级 AOE 发生率，其中 CML 患者被平均分配到 45、30 和 15 mg 的起始剂量。⁵与 OPTIC 试验一样，我们发现普纳替尼起始剂量较高时 AOE 的发生率增加。我们较低的 AOE 发生率可能与大部分患者开始使用较低剂量有关，中位起始剂量为 30 mg（表 1）。

我们还证明了高危患者与低危患者的 AOE 发生率更高。具有 ≥ 2 个心血管危险因素的患者的 AOE 发生率为 5%，而低风险患者为 1%。PACE 试验同样发现具有 ≥ 2 个危险因素的患者发生 AOE 的风险最高。⁴最后，我们的患者群体中出现 AOE 的中位时间（10.2 个月）与 PACE 试验相似，后者显示中位发作时间为 13.4 个月。^4个

普纳替尼适用于至少使用两种 TKI 治疗失败或携带 T315I 突变的患者；它的前线使用受到心脏毒性的阻碍。然而，剂量优化和风险降低策略可能会扩大这种有效疗法的使用范围，正如一项将普纳替尼与高强度化疗相结合治疗 Ph-ALL 的研究所证明的那样。⁶我们展示了一个现实生活中的患者队列，这些患者接受普纳替尼治疗后 CV 事件的发生率较低，这可能是由于剂量减少和心脏保护药物的使用。本研究的局限性包括其单中心、回顾性设计以及无法考虑所有混杂因素。

总之，在我们服用普纳替尼的白血病患者的真实队列中报告的 10% 的 CV 事件发生率和 3% 的 AOE 发生率低于之前的报告。鉴于血栓形成的风险相当大，剂量优化和预防策略应被视为普纳替尼患者管理的一部分。