Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are BCR/ABL1-(Philadelphia chromosome [Ph−]) negative myeloproliferative neoplasms (MPNs).¹ Mutations of Janus Kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are implicated in these MPNs, leading to clonal hematopoietic stem cell proliferation.¹ The most dreaded complication of PV, ET, and PMF is transformation to acute myeloid leukemia (AML).² While ET and PV have significantly longer survival compared to PMF, their life expectancy has been shown to be inferior to the age- and sex-matched US population.^{2, 3}

There is a plurality of factors leading to impaired longevity in MPN patients; however, the relative contributions of these complications to mortality in the MPN phenotypes are not known. Similarly, the propensity for leukemic transformation has not been studied at the population level. This study aims to describe population-based outcomes of these MPNs, with an emphasis on cause-specific mortality and leukemic transformation.

We studied outcomes of PV, ET, and PMF using the Surveillance, Epidemiology, and End Results (SEER) Registry. MPN patients were identified using the International Classification of Diseases for Oncology, third revision (ICD-O-3) codes for PV (9950/3), ET (9962/3), and PMF (9961/3). The database was searched for cases diagnosed between 2001 and 2015 and SEER*Stat was utilized to calculate standardized mortality ratios (SMRs) in order to evaluate the comparative risk of cause-specific mortality. We compared the survival and leukemic transformation trends to a contemporaneous cohort of validated Ph− MPN patients at Mayo Clinic, Rochester. Please see the Supplement for additional information regarding our study methods.

10 725 patients with PV, 8768 patients with ET, and 3689 with PMF are the subject of this report. Additional information regarding patient demographics, incidence, and cohort definition is available in the corresponding Supplement (Tables S1 and S2, Figure S1). The median follow-up was 5.8 years for PV, 5.7 years for ET, and 3.1 years for PMF. Five-year relative survival (RS) for PV, ET, and PMF was 88.3%, 88.7%, and 44.9% respectively. The median overall survival (OS) in PV, ET, and PMF was 11.9 years, 12.1 years, and 4.0 years respectively. Incidence and OS noted in our study are predictably similar to a recent SEER analysis.⁴ Graphical representations of RS and OS are available in the Supplement (Figures S2 and S3). During the study period, 105 (1.0%) PV, 134 (1.5%) ET, and 122 (3.3%) PMF patients progressed to AML. The median time to AML transformation was 4.4 years, 5.8 years, and 2.3 years for PV, ET, and PMF respectively.

At Mayo Clinic, 1952 patients were diagnosed with the MPNs of interest between 2000 and 2017 (444 with PV, 551 with ET, and 957 with PMF). The median follow-up in this cohort was 5.3 years. Rates of leukemic transformation were as follows: 2.7% in PV, 1.6% in ET, and 9.2% in PMF. The median OS in this case series was 12.7 years for PV, 14.9 years for ET, and 4.4 years for PMF (Figure S4).

OS between SEER and our case series was in general agreement for PV and PMF; however, shorter survival for ET was noted in the population database. In a previously published Mayo Clinic series, the risk of leukemic transformation at 20 years was 3.9%, 2.6%, and 9.3% in PV, ET, and PMF respectively.³ The proportion of patients in SEER with leukemic transformation was lower at 1%, 1.5%, and 3.3%. Two potential explanations for the perceived discrepancy are (i) inaccurate record of leukemic transformation in SEER and (ii) short duration follow-up. Given that our median follow-up was 3.1–5.8 years, we suspected that the lower proportion of leukemic transformation was primarily due to the latter. The contemporaneous Mayo Clinic cohort demonstrated almost identical leukemia-free survival compared to SEER. However, an exception was noted in PMF, where our institutional series demonstrated a rate of transformation of 9.2%. Though this discrepancy may be partially rooted in referral center bias, when considering that a similar rate of transformation was also published in an Italian cohort of 755 MPN patients, a potential limitation in the population database is apparent.²

We utilized SEER to evaluate cause-specific mortality. 3840 (35.8%) PV patients, 3095 (35.3%) ET patients, and 2430 (65.9%) PMF patients died during the study period. Causes of death were divided into eight categories: myeloid cancer, nonmyeloid hematologic malignancy, solid tumor, other malignancies (referring to “in situ, benign or unknown behavior neoplasm” and “miscellaneous malignant cancer”), cerebrovascular disease, cardiovascular disease, infection, and “other.” A summary of these categories is available in the Supplement.

Common causes of death in PV included cardiovascular disease (26.1%) and solid tumors (12.7%). A total of 193 (5%) PV patient deaths were related to myeloid cancer. In ET, cardiovascular disease and solid tumors contributed 25.0% and 12.6% of deaths, respectively. Around 282 (9.1%) ET patient deaths were related to myeloid cancer. In PMF, “other malignancies” and myeloid cancer contributed to 41.8% and 15.9% of patient deaths.

SMRs are presented in Table 1. Patients with PV, ET, and PMF had more observed deaths than expected when compared with the general population. Patients with PV were at the greatest risk of dying from myeloid cancer (SMR = 14.30, p < .05) and “other malignancies” (SMR 10.03). Similar findings were noted in ET (myeloid cancer SMR = 26.31 p < .05, other malignancies SMR = 8.87 p < .05). For PMF, patients had increased observed mortality from myeloid cancer (SMR = 129.97, p < .05), “other malignancies” (SMR = 97.14, p < .05), nonmyeloid hematologic malignancies (SMR = 8.44, p < .05), and infections (SMR = 4.84, p < .05).

When stratified by age, we noted an increased relative burden of observed mortality in younger patients. For PV, this was prominently noted in deaths related to myeloid cancer, “other malignancies,” cerebrovascular disease, and cardiovascular disease. In ET, we noted this phenomenon in myeloid cancer, other malignancies, and cerebrovascular disease. In PMF, the greatest observed-to-expected mortality ratios in younger patients were in myeloid cancer, other malignancies, nonmyeloid hematologic malignancies, infection, and cardiovascular disease.

The cause-specific mortality data with corresponding SMR provide important insights into these MPNs. First, while considered to be a lower risk for leukemic transformation, both PV and ET patients were at 14.3- and 26.3-fold higher observed risk of death from myeloid malignancies compared to the general population. Additionally, cardiovascular disease was a prominent cause of death in both PV and ET, accounting for 26.1% and 25.0% of all deaths, respectively. The SMR data clearly demonstrate an increased relative risk of mortality from cardiovascular disease and cerebrovascular disease, especially in younger patients with PV and ET. This finding, not previously described at a population level, supports the dictum that in Ph− MPNs, the management of cardiovascular and cerebrovascular complications is of utmost interest, especially in younger patients.

Most patients with PMF died from myeloid cancers and “other malignancies” (15.9% and 41.8% of all deaths, respectively), while a high rate of cardiovascular-related and infection-related death was also noted. Similar findings were demonstrated in a previous report of cause-specific mortality in PMF.⁵ Though the SMR, as expected, demonstrated a markedly elevated observed/expected ratio for mortality from myeloid cancers in PMF, an increased risk of mortality related to infections and cardiovascular disease was also noted. This finding is perhaps related to the overall increased morbidity associated with PMF³ and should prompt clinicians to address and optimize comorbidities accordingly. Interestingly, patients with PMF had an increased observance of nonmyeloid hematologic cancers (SMR = 8.44), corroborating findings of prior reports.⁶

Given the low incidence of myeloid malignancies, the SMR for myeloid cancer is extremely high for all three Ph− MPN phenotypes across all age demographics. In the absence of disease-modifying therapies, it is not unsurprising to see that Ph− MPN is associated with significantly shorter survival, attesting to the increased morbidity and mortality they cause.

Study limitations include the use of the population database which contains limitations including uncertainty about the diagnosis, lack of molecular data which are known to be prognostic, and lack of treatment data. As no cause of death output code exists in SEER for PV, ET, and PMF, respectively, our analysis was limited in capacity to describe specific MPN-related mortality. Additionally, the high proportion of patient deaths attributed to “other malignancies,” has likely resulted in underreported disease-related mortality, namely progression and transformation to secondary AML. Finally, the study observation time is relatively short to assess survival in ET and PV. We have attempted to overcome some of these limitations by using a Mayo Clinic cohort for comparison.

In summary, the incidence and OS of BCR-ABL-1 negative MPNs were similar to prior reports. MPN patients succumbed to a plurality of conditions, with the greatest increased risk of mortality stemming from subsequent malignancies, namely myeloid cancers. PMF portended the worst prognosis among MPN phenotypes, with increased observed mortality not only to malignancies but also to infections and cardiovascular disease, demonstrating the morbidity associated with this MPN. An increased relative burden of cardiovascular and cerebrovascular disease was noted in younger patients with PV and ET, which should prompt clinicians to address and optimize cardiovascular risk factors in the longitudinal care of MPN patients.

真性红细胞增多症 (PV)、原发性血小板增多症 (ET) 和原发性骨髓纤维化 (PMF) 是BCR/ABL1-（费城染色体 [Ph-]）阴性骨髓增殖性肿瘤 (MPN)。¹ Janus 激酶 2 ( JAK2 )、钙网蛋白 ( CALR ) 和骨髓增殖性白血病病毒癌基因 ( MPL ) 的突变与这些 MPN 相关，导致克隆造血干细胞增殖。¹ PV、ET 和 PMF 最可怕的并发症是转化为急性髓系白血病 (AML)。²虽然与 PMF 相比，ET 和 PV 的生存期明显更长，但它们的预期寿命已被证明不如年龄和性别匹配的美国人口。^2、3

导致MPN患者寿命受损的因素有很多；然而，这些并发症对 MPN 表型死亡率的相对贡献尚不清楚。同样，尚未在人群水平研究白血病转化的倾向。本研究旨在描述这些 MPN 的基于人群的结果，重点是特定原因的死亡率和白血病转化。

我们使用监测、流行病学和最终结果 (SEER) 注册表研究了 PV、ET 和 PMF 的结果。MPN 患者使用国际肿瘤疾病分类第三版 (ICD-O-3) 代码 PV (9950/3)、ET (9962/3) 和 PMF (9961/3) 进行识别。在数据库中搜索了 2001 年至 2015 年间诊断出的病例，并使用 SEER*Stat 计算标准化死亡率 (SMR)，以评估特定原因死亡率的比较风险。我们将生存率和白血病转化趋势与罗切斯特梅奥诊所的同期验证 Ph- MPN 患者队列进行了比较。有关我们的研究方法的更多信息，请参阅补充资料。

10725 名 PV 患者、8768 名 ET 患者和 3689 名 PMF 患者是本报告的主题。有关患者人口统计学、发病率和队列定义的其他信息可在相应的补充资料中获得（表 S1 和 S2，图 S1）。PV 的中位随访时间为 5.8 年，ET 为 5.7 年，PMF 为 3.1 年。PV、ET 和 PMF 的五年相对生存率 (RS) 分别为 88.3%、88.7% 和 44.9%。PV、ET 和 PMF 的中位总生存期 (OS) 分别为 11.9 年、12.1 年和 4.0 年。我们研究中注意到的发生率和 OS 与最近的 SEER 分析可以预见地相似。⁴RS 和 OS 的图形表示可在补充中获得（图 S2 和 S3）。在研究期间，105 (1.0%) 名 PV、134 (1.5%) 名 ET 和 122 (3.3%) 名 PMF 患者进展为 AML。PV、ET 和 PMF 发生 AML 转化的中位时间分别为 4.4 年、5.8 年和 2.3 年。

在梅奥诊所，2000 年至 2017 年间，1952 名患者被诊断出患有感兴趣的 MPN（444 名患有 PV，551 名患有 ET，957 名患有 PMF）。该队列的中位随访时间为 5.3 年。白血病转化率如下：PV 为 2.7%，ET 为 1.6%，PMF 为 9.2%。在这个病例系列中，PV 的中位 OS 为 12.7 年，ET 为 14.9 年，PMF 为 4.4 年（图 S4）。

SEER 和我们的病例系列之间的 OS 在 PV 和 PMF 方面基本一致；然而，在人群数据库中注意到 ET 的生存期较短。在先前发表的 Mayo Clinic 系列中，PV、ET 和 PMF 的 20 年白血病转化风险分别为 3.9%、2.6% 和 9.3%。³SEER 中发生白血病转化的患者比例较低，分别为 1%、1.5% 和 3.3%。对感知差异的两个潜在解释是 (i) SEER 中白血病转化的不准确记录和 (ii) 短期随访。鉴于我们的中位随访时间为 3.1-5.8 年，我们怀疑较低比例的白血病转化主要是由于后者。与 SEER 相比，同期的 Mayo Clinic 队列显示出几乎相同的无白血病生存期。然而，在 PMF 中注意到了一个例外，我们的机构序列显示了 9.2% 的转换率。虽然这种差异可能部分源于转诊中心的偏见，但考虑到类似的转化率也在意大利 755 名 MPN 患者队列中发表，²

我们利用 SEER 来评估特定原因死亡率。在研究期间，3840 (35.8%) 名 PV 患者、3095 (35.3%) 名 ET 患者和 2430 (65.9%) 名 PMF 患者死亡。死因分为8类：髓系肿瘤、非髓系血液系统恶性肿瘤、实体瘤、其他恶性肿瘤（指“原位、良性或行为不明的肿瘤”和“杂癌”）、脑血管疾病、心血管疾病、感染、和别的。” 这些类别的摘要可在补充资料中找到。

PV 中常见的死亡原因包括心血管疾病 (26.1%) 和实体瘤 (12.7%)。共有 193 (5%) 名 PV 患者死亡与骨髓癌有关。在 ET 中，心血管疾病和实体瘤分别占死亡人数的 25.0% 和 12.6%。大约 282 (9.1%) 名 ET 患者死亡与骨髓癌有关。在 PMF 中，“其他恶性肿瘤”和骨髓癌导致 41.8% 和 15.9% 的患者死亡。

SMR 见表 1。与一般人群相比，PV、ET 和 PMF 患者的观察到的死亡人数超过预期。PV 患者死于骨髓癌 (SMR = 14.30, p  < .05) 和“其他恶性肿瘤”(SMR 10.03) 的风险最大。在 ET 中也发现了类似的发现（骨髓癌 SMR = 26.31 p  < .05，其他恶性肿瘤 SMR = 8.87 p  < .05）。对于 PMF，患者因骨髓癌（SMR = 129.97，p  < .05）、“其他恶性肿瘤”（SMR = 97.14，p  < .05）、非骨髓性血液系统恶性肿瘤（SMR = 8.44，p  < .05）而观察到的死亡率增加, 和感染 (SMR = 4.84, p  < .05)。

当按年龄分层时，我们注意到年轻患者观察到的死亡率的相对负担增加。对于 PV，这在与骨髓癌、“其他恶性肿瘤”、脑血管疾病和心血管疾病相关的死亡中尤为突出。在 ET 中，我们在骨髓癌、其他恶性肿瘤和脑血管疾病中发现了这种现象。在 PMF 中，年轻患者的最大观察到预期死亡率是髓系癌、其他恶性肿瘤、非髓系血液系统恶性肿瘤、感染和心血管疾病。

具有相应 SMR 的特定原因死亡率数据提供了对这些 MPN 的重要见解。首先，虽然被认为是较低的白血病转化风险，但与一般人群相比，PV 和 ET 患者观察到的髓系恶性肿瘤死亡风险高 14.3 倍和 26.3 倍。此外，心血管疾病是 PV 和 ET 的主要死亡原因，分别占所有死亡人数的 26.1% 和 25.0%。SMR 数据清楚地表明心血管疾病和脑血管疾病死亡的相对风险增加，尤其是在年轻的 PV 和 ET 患者中。这一发现，以前没有在人群水平上描述过，支持这样的格言，即在 Ph- MPNs 中，心脑血管并发症的管理是最令人感兴趣的，

大多数 PMF 患者死于骨髓癌和“其他恶性肿瘤”（分别占所有死亡人数的 15.9% 和 41.8%），而心血管相关和感染相关的死亡率也很高。之前一份关于 PMF 特定原因死亡率的报告也证实了类似的发现。⁵尽管 SMR 正如预期的那样，表明 PMF 中髓样癌死亡率的观察/预期比率显着升高，但也注意到与感染和心血管疾病相关的死亡风险增加。这一发现可能与 PMF ³相关的总体发病率增加有关并应提示临床医生相应地解决和优化合并症。有趣的是，PMF 患者对非髓样血液系统癌症的观察增加 (SMR = 8.44)，证实了先前报告的发现。⁶

鉴于髓系恶性肿瘤的低发病率，对于所有年龄人口统计学的所有三种 Ph-MPN 表型，髓系癌的 SMR 都非常高。在缺乏疾病改善疗法的情况下，Ph- MPN 与显着缩短的生存期相关，这证明它们导致的发病率和死亡率增加并不令人惊讶。

研究限制包括使用人口数据库，该数据库包含的限制包括诊断的不确定性、已知可预测预后的分子数据的缺乏以及治疗数据的缺乏。由于 SEER 中分别不存在 PV、ET 和 PMF 的死因输出代码，我们的分析在描述特定 MPN 相关死亡率方面的能力有限。此外，归因于“其他恶性肿瘤”的患者死亡比例很高，可能导致漏报的疾病相关死亡率，即进展和转化为继发性 AML。最后，研究观察时间相对较短，以评估 ET 和 PV 的存活率。我们试图通过使用 Mayo Clinic 队列进行比较来克服其中的一些限制。

总之，BCR-ABL-1阴性 MPN的发生率和 OS与之前的报告相似。MPN 患者死于多种疾病，其中最大的增加的死亡风险源于随后的恶性肿瘤，即骨髓癌。PMF 预示着 MPN 表型中最差的预后，观察到的死亡率不仅增加，而且增加了对感染和心血管疾病的死亡率，证明了与这种 MPN 相关的发病率。在年轻的 PV 和 ET 患者中注意到心脑血管疾病的相对负担增加，这应该促使临床医生在 MPN 患者的纵向护理中解决和优化心血管危险因素。